Introducing BREAST-Q Computerized Adaptive Testing: Short and Individualized Patient-Reported Outcome Assessment following Reconstructive Breast Surgery.
The BREAST-Q is a widely used patient-reported outcome instrument measuring health-related quality-of-life and patient satisfaction in breast surgery. Shorter assessment potentially increases patients' willingness to complete scales, but simply offering a shortened version leads to unacceptable loss in measurement precision. The authors aimed to develop a computerized adaptive test (CAT) to shorten the BREAST-Q's Satisfaction with Breasts scale while maintaining reliability of measurement. The authors created a CAT, which repetitively administered questions from the pool of 16 questions, until prespecified levels of reliability were reached [i.e., standard errors (SE) of 0.32 to 0.55]. In a simulation study, the authors tested the CAT's feasibility for all potential satisfaction scores. In a second study using actual patient data, 5000 breast reconstruction patients who had previously completed the full scale were randomly selected from a large database. Their full-scale satisfaction scores were compared with their CAT-derived scores. In both studies, by applying CAT, the Satisfaction with Breasts scale could be reduced to an average of 10 questions when using the minimum level of measurement precision for individual-patient measurement (SE, 0.32), compared with four questions when using the minimum precision level for group-based research (SE, 0.55). Score estimates were highly correlated between the CAT assessment and the full scale (0.91 to 0.98 in the simulation study, and 0.89 to 0.98 in the patient data study). Applying computerized adaptive testing to the BREAST-Q's Satisfaction with Breasts scale facilitates reliable assessment, with 38 to 75 percent fewer questions than the full version. The novel BREAST-Q CAT version may decrease response burden and help overcome barriers to implementation in routine care.


[Infants who cry a lot: incidence and management of this problem in family practice].
To determine how frequently general practitioners (GPs) are consulted because of excessively crying infants and how such infants are managed. A stratified sample of 103 GP practices throughout The Netherlands. Descriptive. 161 GPs from 103 practices for one year (in four groups, each for three months) recorded all their contacts with patients as a part of the National Study of Diseases and Items of Service in General Practice, conducted by the Netherlands Institute for Primary Health Care Research. An inventory was made of the infants who fulfilled the criteria of the 'colic syndrome' as to age, symptomatology and diagnosis. Of the infants seen by the GPs, 10% displayed symptoms of excessive crying, colic or restlessness. In over one-third of this group a colic-like diagnosis was made; of the children from zero to four months this proportion was two-thirds. The probability of a child in the age group of 0 to 4 months being seen by the GP with colic-like symptoms and diagnosis amounted to 7.1% (cumulative incidence). The majority of the GPs were certain of their (mostly somatic) diagnoses. The GPs were consulted more often about these children, apart from the colic problem, than about their contemporaries, the difference being statistically significant. In only 30% of the cases did the GPs prescribe medication or a diet, or made a referral.


Mechanisms of neuronal membrane sealing following mechanical trauma.
Membrane integrity is crucial for maintaining the intricate signaling and chemically-isolated intracellular environment of neurons; disruption risks deleterious effects, such as unregulated ionic flux, neuronal apoptosis, and oxidative radical damage as observed in spinal cord injury and traumatic brain injury. This paper, in addition to a discussion of the current understanding of cellular tactics to seal membranes, describes two major factors involved in membrane repair. These are line tension, the hydrophobic attractive force between two lipid free-edges, and membrane tension, the rigidity of the lipid bilayer with respect to the tethered cortical cytoskeleton. Ca(2+), a major mechanistic trigger for repair processes, increases following flux through a membrane injury site, and activates phospholipase enzymes, calpain-mediated cortical cytoskeletal proteolysis, protein kinase cascades, and lipid bilayer microdomain modification. The membrane tension appears to be largely modulated through vesicle dynamics, cytoskeletal organization, membrane curvature, and phospholipase manipulation. Dehydration of the phospholipid gap edge and modification of membrane packaging, as in temperature variation, experimentally impact line tension. Due to the time-sensitive nature of axonal sealing, increasing the efficacy of axolemmal sealing through therapeutic modification would be of great clinical value, to deter secondary neurodegenerative effects. Better therapeutic enhancement of membrane sealing requires a complete understanding of its intricate underlying neuronal mechanism.


Complex genetic patterns in closely related colonizing invasive species.
Anthropogenic activities frequently result in both rapidly changing environments and translocation of species from their native ranges (i.e., biological invasions). Empirical studies suggest that many factors associated with these changes can lead to complex genetic patterns, particularly among invasive populations. However, genetic complexities and factors responsible for them remain uncharacterized in many cases. Here, we explore these issues in the vase tunicate Ciona intestinalis (Ascidiacea: Enterogona: Cionidae), a model species complex, of which spA and spB are rapidly spreading worldwide. We intensively sampled 26 sites (N = 873) from both coasts of North America, and performed phylogenetic and population genetics analyses based on one mitochondrial fragment (cytochrome c oxidase subunit 3-NADH dehydrogenase subunit I, COX3-ND1) and eight nuclear microsatellites. Our analyses revealed extremely complex genetic patterns in both species on both coasts. We detected a contrasting pattern based on the mitochondrial marker: two major genetic groups in C. intestinalis spA on the west coast versus no significant geographic structure in C. intestinalis spB on the east coast. For both species, geo-graphically distant populations often showed high microsatellite-based genetic affinities whereas neighboring ones often did not. In addition, mitochondrial and nuclear markers provided largely inconsistent genetic patterns. Multiple factors, including random genetic drift associated with demographic changes, rapid selection due to strong local adaptation, and varying propensity for human-mediated propagule dispersal could be responsible for the observed genetic complexities.


The Relationship Between Work-Disability Duration and Claimant's Expected Time to Return to Work as Recorded by Workers' Compensation Claims Managers.
Purpose This research sought to determine whether there is a relationship between claimants' expected time to return to work (RTW) as recorded by claims managers and compensated days of work disability. Methods We utilized workers' compensation data from a large, United States-based insurance company. RTW expectations were collected within 30 days of the claim being reported and these were compared with the termination of total temporary indemnity payments. Bivariate and hierarchical regression analyses were conducted. Results A significant relationship between expected time to RTW and compensated disability duration was observed. The unadjusted correlation between work-disability duration and expected time to RTW was .25 (p < .001). Our multivariate model explained 29.8 % of the variance, with expected time to RTW explaining an additional 9.5 % of the variance in work-disability duration beyond what was explained by the covariates. Conclusion The current study's findings support the hypothesis that claimant RTW estimates as recorded by claims managers are significantly related to compensated-disability duration, and the relationship is maintained after controlling for variance that can be explained by other variables available within workers' compensation databases.


Comparative efficacy of behavior therapy, cognitive therapy, and cognitive behavior therapy for chronic insomnia: a randomized controlled trial.
To examine the unique contribution of behavior therapy (BT) and cognitive therapy (CT) relative to the full cognitive behavior therapy (CBT) for persistent insomnia. Participants were 188 adults (117 women; M age = 47.4 years, SD = 12.6) with persistent insomnia (average of 14.5 years duration). They were randomized to 8 weekly, individual sessions consisting of BT (n = 63), CT (n = 65), or CBT (n = 60). Full CBT was associated with greatest improvements, the improvements associated with BT were faster but not as sustained and the improvements associated with CT were slower and sustained. The proportion of treatment responders was significantly higher in the CBT (67.3%) and BT (67.4%) relative to CT (42.4%) groups at post treatment, while 6 months later CT made significant further gains (62.3%), BT had significant loss (44.4%), and CBT retained its initial response (67.6%). Remission rates followed a similar trajectory, with higher remission rates at post treatment in CBT (57.3%) relative to CT (30.8%), with BT falling in between (39.4%); CT made further gains from post treatment to follow up (30.9% to 51.6%). All 3 therapies produced improvements of daytime functioning at both post treatment and follow up, with few differential changes across groups. Full CBT is the treatment of choice. Both BT and CT are effective, with a more rapid effect for BT and a delayed action for CT. These different trajectories of changes provide unique insights into the process of behavior change via behavioral versus cognitive routes.


Targeting TGFβ Signalling in Cancer: Toward Context-Specific Strategies.
The transforming growth factor beta (TGFβ) signalling pathway regulates a range of important cellular processes in a context-dependent manner. Recent discoveries have provided important insights into the regulation of the TGFβ pathway and its change from an antitumorigenic to a protumorigenic pathway. These findings may have important implications for cancer stem cell (CSC) functions and therapeutic strategies.


Bronchopulmonary Dysplasia and Pulmonary Outcomes of Prematurity.
Bronchopulmonary dysplasia (BPD) is a chronic lung disease most commonly seen in premature infants who require mechanical ventilation and oxygen therapy. Despite advances in neonatal care resulting in improved survival and decreased morbidity, limited progress has been made in reducing rates of BPD. Therapeutic options to protect the vulnerable developing lung are limited as are strategies to treat lung injury, resulting in ongoing concerns for long-term pulmonary morbidity after preterm birth. Lung protective strategies and optimal nutrition are recognized to improve pulmonary outcomes. However, characterization of late outcomes is challenged by rapid advances in neonatal care. As a result, current adult survivors reflect outdated medical practices. Although neonatal pulmonary disease tends to improve with growth, compromised respiratory health has been documented in young adult survivors of BPD. With improved survival of premature infants but limited progress in reducing rates of disease, BPD represents a growing burden on health care systems. [Pediatr Ann. 2019;48(4):e148-e153.].


Neurological sequelae in newborn babies after perinatal asphyxia.
A total of 53 babies, 37 to 44 weeks' gestational age with a history of fetal distress in labour, and severe neurological abnormalities in the early newborn period, were followed up for between 2 and 5 years. Their progress was compared with an equal number of normal babies matched for gestational age, birthweight, sex, and social class, but without a history of fetal distress or delay in establishing spontaneous respiration at birth. In the set of babies with a history of fetal distress no perinatal condition was identified that could predict with certainty the type of neurological status in the newborn period, or the occurrence of neurological abnormality in later childhood. Follow-up disclosed a considerable improvement in function in most of the apparently brain-injured babies. It is suggested that such babies exhibiting apathy initially but subsequently hyperexcitability and extensor hypertonia carry the worst prognosis.


The activation of metabolites of nitric oxide synthase by metals is both redox and oxygen dependent: a new feature of nitrogen oxide signaling.
Nitrite (NO(2)-), N (G)-hydroxy-L-arginine (NOHA), and hydroxylamine (NH(2)OH) are products of nitric oxide synthase (NOS) activity and can also be formed by secondary reactions of nitric oxide (NO). These compounds are commonly considered to be rather stable and as such to be dosimeters of NO biosynthesis. However, each can be converted via metal-catalyzed reactions into either NO or other reactive nitrogen oxide species (RNOS), such as nitrogen dioxide (NO(2)) and nitroxyl (HNO), which have biologic activities distinct from those of the parent molecules. Consequently, certain aspects of tissue regulation controlled by RNOS may be dictated to a significant extent by metal-dependent reactions, thereby offering unique advantages for cellular and tissue regulation. For instance, because many metal-catalyzed reactions depend on the redox and oxygen status of the cellular environment, such reactions could serve as redox indicators. Formation of RNOS by metal-mediated pathways would confine the chemistry of these species to specific cellular sites. Additionally, such mechanisms would be independent both of NO and NOS, thus increasing the lifetime of RNOS that react with NO. Thus metal-mediated conversion of nitrite, NOHA, and NH(2)OH into biologically active agents may provide a unique signaling mechanism. In this review, we discuss the biochemistry of such reactions in the context of their pharmacologic and biologic implications.


Effects of resisted sprint training on acceleration in professional rugby union players.
The use of weighted sled towing as a training tool to improve athlete acceleration has received considerable attention; however, its effectiveness for developing acceleration is equivocal. This study compared the effects of combined weighted sled towing and sprint training against traditional sprint training on 10 and 30 m speed in professional rugby union players (n = 20). After baseline testing of 10 and 30 m speed, participants were assigned to either the combined sled towing and sprint training (SLED) or traditional sprint training (TRAD) groups, matched for 10-m sprint times. Each group completed 2 training sessions per week for 6 weeks, with performance reassessed post-training. Both training programmes improved participants' 10 and 30 m speed (p < 0.001), but the performance changes (from pre to post) in 10 m (SLED -0.04 ± 0.01 vs. TRAD -0.02 ± 0.01 seconds; p < 0.001) and 30 m (SLED -0.10 ± 0.03 vs. TRAD -0.05 ± 0.03 seconds; p = 0.003) sprint times were significantly greater in the SLED training group. Similarly, the percent change within the SLED group for the 10 m (SLED -2.43 ± 0.67 vs. TRAD -1.06 ± 0.80 seconds; p = 0.003) and 30 m (SLED -2.46 ± 0.63 vs. TRAD -1.15 ± 0.72 seconds; p = 0.003) tests were greater than the TRAD group. In conclusion, sprint training alone or combined with weighted sled towing can improve 10 and 30 m sprint times; however, the latter training method promoted greater improvements in a group of professional rugby players.


Down-regulation of Filamin A interacting protein 1-like Is associated with promoter methylation and an invasive phenotype in breast, colon, lung and pancreatic cancers [corrected].
Identifying key mediators of cancer cell invasion and metastasis is critical to the development of more effective cancer therapies. We previously identified Filamin A interacting protein 1-like (FILIP1L) as an important inhibitor of cell migration and invasion in ovarian cancer. FILIP1L expression was inversely correlated with the invasive potential of ovarian cancer cell lines and ovarian cancer specimens. We also demonstrated that DNA methylation in the FILIP1L promoter was a mechanism by which FILIP1L was down-regulated in ovarian cancer. In our present study, we tested this observation in other cancer histologies: breast, colon, lung and pancreatic cancers. Both mRNA and protein expression of FILIP1L were down-regulated in these cancer cells compared with their normal epithelial cells. As in ovarian cancer, DNA methylation is a mechanism by which FILIP1L is down-regulated in these cancer histologies. Methylation status of the FILIP1L promoter was inversely correlated with FILIP1L expression. Reduced methylation in the FILIP1L promoter following treatment with a DNA demethylating agent was associated with restoration of FILIP1L expression in these cancer cells. Further, FILIP1L expression was inversely correlated with the invasive potential of these cancer cells. Re-expression of FILIP1L in FILIP1L-low expressing, highly-invasive cancer cell lines resulted in inhibition of cell invasion. Correspondingly, knockdown of FILIP1L in FILIP1L-high expressing, low-invasive cancer cell lines resulted in increase of cell invasion. Overall, these findings suggest that down-regulation of FILIP1L associated with DNA methylation is related with the invasive phenotype in various cancers. Thus, modulation of FILIP1L expression has the potential to be a target for cancer therapy.


A challenge to all. A primer on inter-country differences of high-need, high-cost patients.
Across countries, a small group of patients accounts for the majority of health care spending. These patients are more likely than other patients to experience problems with quality and safety in their care, suggesting that efforts targeting efficiency and quality among this population might have significant payoffs for health systems. Better understanding of similarities and differences in patient characteristics and health care use in different countries may ultimately inform further efforts to improve care for HNHC patients in these health systems. We conducted a cross-sectional descriptive study using one year of patient-level data on high-cost patients in seven high-income OECD member countries. Countries were selected based on availability of detailed information (large enough samples of claims, administrative, and survey data of high-cost patients). We studied concentration of spending among high-cost patients, characteristics of high-cost patients, and per capita spending on high-cost patients. Cost-concentration of the top 5% of patients varied across countries, from 41% in Japan to 60% in Canada, driven primarily by variation in the top 1% of spenders. In general, high-cost patients were more likely to be female (57.7% on average), had a significant number of multi-morbidities (up to on average 10 major diagnostic categories (ICD chapters), and had a lower socioeconomic status. Characteristics of high-cost patients varied as well: median age ranged from 62 in the Netherlands to 75 in Germany and the difference in socioeconomic status is particularly stark in the US. Lastly, utilization, particularly for inpatient care, varied with an average number of inpatient days ranging from 6.6 nights (US) to 97.7 nights in Japan. In this descriptive study, there is substantial variation in the cost concentration, characteristics, and per capita spending on high-cost patient populations across high-income countries. Differences in the way that health systems are structured likely explains some of this variation, which suggests the potential of cross-system learning opportunities. Our findings highlight the need for further studies including comparable performance metrics and institutional analysis.


Humboldt penguins outmanoeuvring El Niño.
We satellite-tracked five Humboldt penguins during the strong 1997/98 El Niño Southern Oscillation (ENSO) from their breeding island Pan de Azúcar (26 degrees 09'S, 70 degrees 40'W) in Northern Chile and related their activities at sea to satellite-derived information on sea surface temperature (SST), sea surface temperature anomaly (SSTA), wind direction and speed, chlorophyll a concentrations and statistical data on fishery landings. We found that Humboldt penguins migrated by up to 895 km as marine productivity decreased. The total daily dive duration was highly correlated with SSTA, ranging from 3.1 to 12.5 h when the water was at its warmest (+4 degrees C). Birds travelled between 2 and 116 km every day, travelling further when SSTA was highest. Diving depths (maximum 54 m), however, were not increased with respect to previous years. Two penguins migrated south and, independently of each other, located an area of high chlorophyll a concentration 150 km off the coast. Humboldt penguins seem to use day length, temperature gradients, wind direction and olfaction to adapt to changing environmental conditions and to find suitable feeding grounds. This makes Humboldt penguins biological in situ detectors of highly productive marine areas, with a potential use in the verification of trends detected by remote sensors on board satellites.


Methicillin-resistant Staphylococcus aureus outbreak in a veterinary teaching hospital: potential human-to-animal transmission.
During a 13-month period, 11 equine patients visiting a veterinary teaching hospital for various diagnostic and surgical procedures developed postprocedural infections from which methicillin (oxacillin)-resistant Staphylococcus aureus (MRSA) strains were isolated. The S. aureus isolates were identified by conventional methods that included Gram staining, tests for colonial morphology, tests for clumping factor, and tests for coagulase and urease activities and were also tested with the API STAPH IDENT system. Antimicrobial susceptibility tests were performed by the disk diffusion method. The biochemical profile and antibiogram of each isolate suggested that the isolates may have come from a common source. Because MRSA strains are very uncommon animal isolates but are rather common human isolates, a nasal swab specimen for culture was collected voluntarily from five persons associated with equine surgery and recovery in an attempt to identify a possible source of the organisms. MRSA strains were isolated from three of the five people, with one person found to be colonized with two biotypes of MRSA. The MRSA isolates from the people appeared to be identical to the isolates from horses. Further study of the isolates included SmaI and EagI macrorestriction analysis by pulsed-field gel electrophoresis conducted in two different laboratories. The results indicated that both the equine and human isolates were members of a very closely related group which appear to have originated from a common source. On the basis of the pattern associated with the infection, it is speculated that the members of the Veterinary Teaching Hospital staff were the primary source of the infection, although the specific mode of transmission is unclear.


Multidisciplinary rehabilitation for older people with hip fractures.
Hip fracture is a major cause of morbidity and mortality in older people and its impact on society is substantial. To examine the effects of multidisciplinary rehabilitation, in either inpatient or ambulatory care settings, for older patients with hip fracture. We searched the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register (April 2009), The Cochrane Library (2009, Issue 2), MEDLINE and EMBASE (both to April 2009). Randomised and quasi-randomised trials of post-surgical care using multidisciplinary rehabilitation of older patients (aged 65 years or over) with hip fracture. The primary outcome, 'poor outcome' was a composite of mortality and decline in residential status at long-term (generally one year) follow-up. Trial selection was by consensus. Two review authors independently assessed trial quality and extracted data. Data were pooled where appropriate. The 13 included trials involved 2498 older, usually female, patients who had undergone hip fracture surgery. Though generally well conducted, some trials were at risk of bias such as from imbalances in key baseline characteristics.There was substantial clinical heterogeneity in the trial interventions and populations. Multidisciplinary rehabilitation was provided primarily in an inpatient setting in 11 trials. Pooled results showed no statistically significant difference between intervention and control groups for poor outcome (risk ratio 0.89; 95% confidence interval 0.78 to 1.01), mortality (risk ratio 0.90, 95% confidence interval 0.76 to 1.07) or hospital readmission. Individual trials found better results, often short-term only, in the intervention group for activities of daily living and mobility. There was considerable heterogeneity in length of stay and cost data. Three trials reporting carer burden showed no evidence of detrimental effect from the intervention. Overall, the evidence indicates that multidisciplinary rehabilitation is not harmful.The trial comparing primarily home-based multidisciplinary rehabilitation with usual inpatient care found marginally improved function and a clinically significantly lower burden for carers in the intervention group. Participants of this group had shorter hospital stays, but longer periods of rehabilitation. One trial found no significant effect from doubling the number of weekly contacts at the patient's home from a multidisciplinary rehabilitation team. While there was a tendency to a better overall result in patients receiving multidisciplinary inpatient rehabilitation, these results were not statistically significant.Future trials of multidisciplinary rehabilitation should aim to establish both effectiveness and cost effectiveness of multidisciplinary rehabilitation overall, rather than evaluate its components.


On the relationship between conformation and stability in solid pharmaceutical protein formulations.
Long-term stability is critical in the successful development of pharmaceuticals, including macromolecular ones, such as proteins. Due to the relative instability of aqueous solutions of proteins, they are typically stores in a freeze-dried (lyophilized) state. However, proteins reversibly (and sometimes even irreversibly) denature upon lyophilization and consequently adopt conformations markedly distinct from the native ones. This phenomenon may profoundly affect deleterious processes in lyophilized proteins, e.g. moisture-induced aggregation, as illustrated in this review with bovine serum and recombinant human albumins.


Report on EU-USA workshop: how systems biology can advance cancer research (27 October 2008).
The main conclusion is that systems biology approaches can indeed advance cancer research, having already proved successful in a very wide variety of cancer-related areas, and are likely to prove superior to many current research strategies. Major points include: Systems biology and computational approaches can make important contributions to research and development in key clinical aspects of cancer and of cancer treatment, and should be developed for understanding and application to diagnosis, biomarkers, cancer progression, drug development and treatment strategies. Development of new measurement technologies is central to successful systems approaches, and should be strongly encouraged. The systems view of disease combined with these new technologies and novel computational tools will over the next 5-20 years lead to medicine that is predictive, personalized, preventive and participatory (P4 medicine).Major initiatives are in progress to gather extremely wide ranges of data for both somatic and germ-line genetic variations, as well as gene, transcript, protein and metabolite expression profiles that are cancer-relevant. Electronic databases and repositories play a central role to store and analyze these data. These resources need to be developed and sustained. Understanding cellular pathways is crucial in cancer research, and these pathways need to be considered in the context of the progression of cancer at various stages. At all stages of cancer progression, major areas require modelling via systems and developmental biology methods including immune system reactions, angiogenesis and tumour progression.A number of mathematical models of an analytical or computational nature have been developed that can give detailed insights into the dynamics of cancer-relevant systems. These models should be further integrated across multiple levels of biological organization in conjunction with analysis of laboratory and clinical data.Biomarkers represent major tools in determining the presence of cancer, its progression and the responses to treatments. There is a need for sets of high-quality annotated clinical samples, enabling comparisons across different diseases and the quantitative simulation of major pathways leading to biomarker development and analysis of drug effects.Education is recognized as a key component in the success of any systems biology programme, especially for applications to cancer research. It is recognized that a balance needs to be found between the need to be interdisciplinary and the necessity of having extensive specialist knowledge in particular areas.A proposal from this workshop is to explore one or more types of cancer over the full scale of their progression, for example glioblastoma or colon cancer. Such an exemplar project would require all the experimental and computational tools available for the generation and analysis of quantitative data over the entire hierarchy of biological information. These tools and approaches could be mobilized to understand, detect and treat cancerous processes and establish methods applicable across a wide range of cancers.


Nurses promote openness regarding the genetic origins after gamete donation.
To study attitudes and knowledge concerning different aspects of sperm and oocyte donation among paediatric nurses at child health care centres (CHCs) in Sweden. A study-specific questionnaire, to be completed anonymously, was sent to 188 nurses, 141 of whom (75%) responded. The majority of the respondents (62%) stated that they had no professional experience of families created with the help of a donor. A majority (53%) stated that they had good knowledge of the procedure followed in sperm donation, whereas 43% stated that they had good knowledge of the procedure of oocyte donation. More than 80% agreed that the parents should be honest with their child with regard to the child's genetic origin. Among the respondents who were in favour of disclosure, the preferred age for informing the child varied between 0 to 19 years (mean 7.2, SD 5.7). We conclude that the nurses working in CHCs need guidance and information about gamete donation in order to be able to support parents in the disclosure of information to their children and also how to inform or withhold information to significant others in their surrounding milieu.


Femoral head material loss at the head-neck junction in total hip arthroplasty: the effect of head size, stem material and stem offset.
Material loss at the head-neck junction in total hip arthroplasty may cause adverse clinical symptoms and implant failure. The purpose of this study was to quantitatively examine the effects of head size, stem material and stem offset on material loss of the head-neck taper interface of a single trunnion design in retrieval implants of metal on polyethylene bearing surfaces. A retrieval study was performed to identify all 28-mm and 32-mm femoral heads from a single implant/taper design implanted for >2 years. This included n = 56 of the 28-mm heads and n = 23 of the 32-mm heads. The 28-mm femoral heads were matched to 32-mm femoral heads based on time in vivo and head length. A coordinate measuring machine was used to determine maximum linear corrosion depth (MLD). Differences in MLD for head diameter, stem material, and stem offset were determined. There were no differences between groups for age, gender, BMI, or implantation time. There was no difference in MLD between 28 mm and 32 mm matched paired head diameters (p = 0.59). There was also no difference in MLD between titanium or cobalt-chromium stems (p = 0.79), and regular or high-offset stems (p = 0.95). There is no statistical difference in femoral head MLD at the head-neck junction in THA between 28-mm and 32-mm matched paired femoral heads, similar or mixed alloy coupled femoral head stem constructs, and regular or high offset stems.


Serologic evidence of human influenza virus infections in swine populations, Cambodia.
This study was conducted from 2006 to 2010 and investigated the seroprevalence of influenza A viruses in Cambodian pigs, including human H1N1, H3N2, 2009 pandemic H1N1 (A(H1N1)pdm09), and highly pathogenic avian H5N1 influenza A viruses. A total of 1147 sera obtained from pigs in Cambodia were tested by haemagglutination inhibition (HI) assays for antibody to human influenza A viruses along with both HI and microneutralization (MN) tests to assess immunological responses to H5N1 virus. The results were compared by year, age, and province. Antibodies against a human influenza A virus were detected in 14·9% of samples. A(H1N1)pdm09 virus were dominant over the study period (23·1%), followed by those to human H1N1 (17·3%) and H3N2 subtypes (9·9%). No pigs were serologically positive for avian H5 influenza viruses. The seroprevalence of human H1N1 and H3N2 influenza viruses peaked in 2008, while that of A(H1N1)pdm09 reached a peak in 2010. No significant differences in seroprevalence to human influenza subtypes were observed in different age groups. Cambodian pigs were exposed to human strains of influenza A viruses either prior to or during this study. The implications of these high prevalence rates imply human-to-swine influenza virus transmission in Cambodia. Although pigs are mostly raised in small non-commercial farms, our preliminary results provide evidence of sustained human influenza virus circulation in pig populations in Cambodia.


Chromosome cohesion, condensation, and separation.
The faithful segregation of genetic information requires highly orchestrated changes of chromosome structure during the mitotic cell cycle. The linkage between duplicated sister DNAs is established during S phase and maintained throughout G2 phase (cohesion). In early mitosis, dramatic structural changes occur to produce metaphase chromosomes, each consisting of a pair of compacted sister chromatids (condensation). At anaphase onset, a signal is produced to disrupt the linkage between sister chromatids (separation), allowing them to be pulled apart to opposite poles of the cell. This review discusses our current understanding of the three stages of large-scale structural changes of chromosomes in eukaryotic cells. Recent genetic and biochemical studies have identified key components involved in these processes and started to uncover hitherto unexpected functional links between mitotic chromosome dynamics and other important chromosome functions.


A New Feedback-Based Method for Parameter Adaptation in Image Processing Routines.
The parametrization of automatic image processing routines is time-consuming if a lot of image processing parameters are involved. An expert can tune parameters sequentially to get desired results. This may not be productive for applications with difficult image analysis tasks, e.g. when high noise and shading levels in an image are present or images vary in their characteristics due to different acquisition conditions. Parameters are required to be tuned simultaneously. We propose a framework to improve standard image segmentation methods by using feedback-based automatic parameter adaptation. Moreover, we compare algorithms by implementing them in a feedforward fashion and then adapting their parameters. This comparison is proposed to be evaluated by a benchmark data set that contains challenging image distortions in an increasing fashion. This promptly enables us to compare different standard image segmentation algorithms in a feedback vs. feedforward implementation by evaluating their segmentation quality and robustness. We also propose an efficient way of performing automatic image analysis when only abstract ground truth is present. Such a framework evaluates robustness of different image processing pipelines using a graded data set. This is useful for both end-users and experts.


The contractile properties of the M. supracoracoideus In the pigeon and starling: a case for long-axis rotation of the humerus
Wing upstroke in birds capable of powered flight is kinematically the most complicated phase of the wingbeat cycle. The M. supracoracoideus (SC), generally considered to be the primary elevator of the wing, is a muscle with a highly derived but stereotyped morphology in modern flying birds. The contractile portion of the SC arises from a ventral sternum, but its tendon of insertion courses above the glenohumeral joint to insert on the dorsal surface of the humerus. To clarify the role of the SC during wing upstroke, we studied its contractile and mechanical properties in European starlings (Sturnus vulgaris) and pigeons (Columba livia), two birds with contrasting flight styles. We made in situ measurements of isometric forces of humeral elevation and humeral rotation and, in addition, measured the extent of unrestrained humeral excursion during stimulation of the muscle nerve. We also generated passive and active length-force curves for the SC of each species. Stimulation of the SC at humeral joint angles of elevation/depression and protraction/retraction coincident with the downstroke-upstroke transition and mid-upstroke produced substantially higher forces of long-axis rotation than elevation. When the humerus was allowed to move (rotate/elevate) during stimulation, we observed rotation about its longitudinal axis of up to 70-80 degrees , but humeral elevations of only 40-60 degrees above the horizontal (as measured in lateral view). In the active length-force experiments, we measured mean (+/-s.d.) maximal tetanic forces of 6.5+/-1.2 N for starlings (N=4) and 39.4+/-6.2 N for pigeons (N=6), unexpectedly high forces approximately 10 times body weight. The working range of the SC in both species corresponds to the ascending limb (but not the plateau) of the active length-force curve. The potential for greatest active force is high on the ascending limb at joint angles coincident with the downstroke-upstroke transition, a time when the humerus is depressed below the horizontal and rotated forward maximally. As the SC shortens to counterrotate and elevate the humerus during early upstroke, the potential for active force at shorter lengths declines at a relatively rapid rate. These findings reveal that the primary role of the SC is to impart a high-velocity rotation of the humerus about its longitudinal axis, which rapidly elevates the distal wing. This rapid twisting of the humerus is responsible for positioning the forearm and hand so that their subsequent extension orients the outstretched wing in the parasagittal plane appropriate for the subsequent downstroke. We propose that, at the downstroke-upstroke transition, variable levels of co-contraction of the M. pectoralis and SC interact to provide a level of kinematic control at the shoulder that would not be possible were the two antagonists to work independently. The lack of a morphologically derived SC in Late Jurassic and Early Cretaceous birds precluded a high-velocity recovery stroke which undoubtedly limited powered flight in these forms. Subsequent evolution of the derived SC capable of imparting a large rotational force to the humerus about its longitudinal axis was an important step in the evolution of the wing upstroke and in the ability to supinate (circumflex) the manus in early upstroke, a movement fundamental to reducing air resistance during the recovery stroke.


SOX9 is a potent activator of the chondrocyte-specific enhancer of the pro alpha1(II) collagen gene.
The identification of mutations in the SRY-related SOX9 gene in patients with campomelic dysplasia, a severe skeletal malformation syndrome, and the abundant expression of Sox9 in mouse chondroprogenitor cells and fully differentiated chondrocytes during embryonic development have suggested the hypothesis that SOX9 might play a role in chondrogenesis. Our previous experiments with the gene (Col2a1) for collagen II, an early and abundant marker of chondrocyte differentiation, identified a minimal DNA element in intron 1 which directs chondrocyte-specific expression in transgenic mice. This element is also a strong chondrocyte-specific enhancer in transient transfection experiments. We show here that Col2a1 expression is closely correlated with high levels of SOX9 RNA and protein in chondrocytes. Our experiments indicate that the minimal Col2a1 enhancer is a direct target for Sox9. Indeed, SOX9 binds to a sequence of the minimal Col2a1 enhancer that is essential for activity in chondrocytes, and SOX9 acts as a potent activator of this enhancer in cotransfection experiments in nonchondrocytic cells. Mutations in the enhancer that prevent binding of SOX9 abolish enhancer activity in chondrocytes and suppress enhancer activation by SOX9 in nonchondrocytic cells. Other SOX family members are ineffective. Expression of a truncated SOX9 protein lacking the transactivation domain but retaining DNA-binding activity interferes with enhancer activation by full-length SOX9 in fibroblasts and inhibits enhancer activity in chondrocytes. Our results strongly suggest a model whereby SOX9 is involved in the control of the cell-specific activation of COL2A1 in chondrocytes, an essential component of the differentiation program of these cells. We speculate that in campomelic dysplasia a decrease in SOX9 activity would inhibit production of collagen II, and eventually other cartilage matrix proteins, leading to major skeletal anomalies.


Alternative techniques for management of distal anastomoses of aortofemoral and iliofemoral endovascular grafts.
Techniques for managing the distal anastomoses of aortofemoral and iliofemoral endovascular grafts are described. Over a 2(1/2)-year period 46 endovascular grafts were successfully placed to treat severe iliac artery occlusive disease. Endovascular grafts were anchored proximally in the distal aorta or iliac arteries with Palmaz balloon-expandable stents. The distal anastomoses were performed with the use of open, sutured anastomotic techniques. In contrast to stented distal anastomoses, these techniques allowed us to (1) treat occlusive lesions extending from the distal aorta to below the inguinal ligament, (2) terminate endovascular grafts in the groin where stents are contraindicated, (3) vary the distal anastomotic site depending on the local pattern of disease, and (4) standardize the preinsertion length of the endovascular graft. Two distal perianastomotic stenoses and one graft occlusion were detected postoperatively in 11 bypass grafts that had distal anastomoses sewn endoluminally without an overlying patch angioplasty. Only one perianastomotic stenosis was found among 35 anastomoses performed with other techniques. There were no significant differences in primary and secondary patency between grafts originating in the distal aorta or iliac arteries. Hand-sewn distal anastomoses can simplify the insertion of endovascular grafts used for the treatment of aortoiliac occlusive disease. These anastomoses permit tailoring of the graft according to the patients' pattern of disease and eliminate the need to precisely measure the length of the graft preoperatively. In addition, because a distal stent is not required, endovascular grafts can be safely terminated in the groin instead of the external iliac artery where disease progression can lead to graft failure. Finally, endovascular distal anastomoses should be closed with a patch or the hood of a more distal bypass graft to prevent perianastomotic stenoses or occlusions in the postoperative period.


Trichinellosis surveillance--United States, 2008-2012.
Trichinellosis is a parasitic disease caused by nematodes in the genus Trichinella, which are among the most widespread zoonotic pathogens globally. Infection occurs following consumption of raw or undercooked meat infected with Trichinella larvae. Clinical manifestations of the disease range from asymptomatic infection to fatal disease; the common signs and symptoms include eosinophilia, fever, periorbital edema, and myalgia. Trichinellosis surveillance has documented a steady decline in the reported incidence of the disease in the United States. In recent years, proportionally fewer cases have been associated with consumption of commercial pork products, and more are associated with meat from wild game such as bear. 2008-2012. Trichinellosis has been a nationally notifiable disease in the United States since 1966 and is reportable in 48 states, New York City, and the District of Columbia. The purpose of national surveillance is to estimate incidence of infection, detect outbreaks, and guide prevention efforts. Cases are defined by clinical characteristics and the results of laboratory testing for evidence of Trichinella infection. Food exposure histories are obtained at the local level either at the point of care or through health department interview. States notify CDC of cases electronically through the National Notifiable Disease Surveillance System (available at http://wwwn.cdc.gov/nndss). In addition, states are asked to submit a standardized supplementary case report form that captures the clinical and epidemiologic information needed to meet the surveillance case definition. Reported cases are summarized weekly and annually in MMWR. During 2008-2012, a total of 90 cases of trichinellosis were reported to CDC from 24 states and the District of Columbia. Six (7%) cases were excluded from analysis because a supplementary case report form was not submitted or the case did not meet the case definition. A total of 84 confirmed trichinellosis cases, including five outbreaks that comprised 40 cases, were analyzed and included in this report. During 2008-2012, the mean annual incidence of trichinellosis in the United States was 0.1 cases per 1 million population, with a median of 15 cases per year. Pork products were associated with 22 (26%) cases, including 10 (45%) that were linked with commercial pork products, six (27%) that were linked with wild boar, and one (5%) that was linked with home-raised swine; five (23%) were unspecified. Meats other than pork were associated with 45 (54%) cases, including 41 (91%) that were linked with bear meat, two (4%) that were linked with deer meat, and two (4%) that were linked with ground beef. The source for 17 (20%) cases was unknown. Of the 51 patients for whom information was reported on the manner in which the meat product was cooked, 24 (47%) reported eating raw or undercooked meat. The risk for Trichinella infection associated with commercial pork has decreased substantially in the United States since the 1940s, when data collection on trichinellosis cases first began. However, the continued identification of cases related to both pork and nonpork sources indicates that public education about trichinellosis and the dangers of consuming raw or undercooked meat still is needed. Changes in domestic pork production and public health education regarding the safe preparation of pork have contributed to the reduction in the incidence of trichinellosis in the United States; however, consumption of wild game meat such as bear continues to be an important source of infection. Hunters and consumers of wild game meat should be educated about the risk associated with consumption of raw or undercooked meat.


Chronic high-dose creatine feeding does not attenuate left ventricular remodeling in rat hearts post-myocardial infarction.
In heart failure, cardiac energy metabolism is compromised. The failing myocardium is characterized by reduced contents of both phosphorylated (phosphocreatine) and non-phosphorylated (free) creatine content as well as decreased energy reserve via creatine kinase (creatine kinase reaction velocity). These changes may contribute to cardiac dysfunction. The purpose of the present study was to determine whether chronic feeding with high-dose dietary creatine prevents the derangement of energy metabolism and the development of left ventricular remodeling in a rat model of heart failure, i.e. post-myocardial infarction (MI). Rats were subjected to sham operation or left coronary artery ligation. Surviving rats were fed with 0% (untreated) or 3% creatine (related to weight of diet) for 8 weeks. Creatine feeding increased serum creatine levels significantly approximately 2-fold. Thereafter, hearts were isolated, perfused and left ventricular pressure-volume curves obtained. Steady state and dynamic (CK reaction velocity) high-energy phosphate metabolism was determined with 31P NMR spectroscopy. In both MI groups (treated n = 8, untreated n = 7), pressure-volume curves were shifted right- and downward compared to both sham groups (treated n = 5, untreated n = 7), i.e. creatine had no effect on left ventricular remodeling. Likewise, similar reductions of phosphocreatine, free creatine and creatine kinase reaction velocity (untreated sham 12.0 +/- 0.7 mmol/lxs; untreated MI 7.8 +/- 0.7*; treated sham 13.6 +/- 1.0; treated MI 7.2 +/- 1.1*; *p < 0.025 sham vs. MI) were found in both MI groups. Chronic creatine feeding of post-MI rats is ineffective in preventing the functional and energetic derangements occurring post-MI. Inspite of increased serum creatine levels, neither the normal nor the failing heart accumulates additional creatine.


Gross pathology, blood chemistry, lipid and peroxide contents in rainbow trout ( Oncorhynchus mykiss Walbaum) affected by experimental Arcobacter cryaerophilus infection at low water temperature.
Arcobacter cryaerophilus was isolated from naturally infected rainbow trout ( Oncorhynchus mykiss Walbaum), and its pathogenicity was tested by intramuscular injection using healthy 1-year-old rainbow trout under cold-water conditions (at 5 degrees C). The lethal dosage of 50% end point (LD 50 ) for A. cryaerophilus was calculated as 7.79 x 10 5 viable cells. Experimental infection caused gross clinical abnormalities such as fallen scales, exophthalmia, oedema in injection region and at the base of fins, pale gills, kidney necrosis, hyperaemic areas in pale liver, haemorrhagic spots in heart, elongated spleen and swollen gallbladder. Activities of aspartate aminotransferase and alkaline phosphatase, and concentrations of glucose, total protein, albumin, cholesterol, triglyceride and calcium in the serum of the experimentally infected rainbow trout were significantly decreased compared with the healthy fish. Positive correlations were observed among blood parameters. Total lipid weights increased in the brain, muscle and liver tissues of infected fish and dropped in the gill and spleen tissues. Lipid peroxide contents in the brain, liver, kidney, spleen, muscle and gill tissues of infected rainbow trout were significantly higher than in healthy animals. The present work shows that A. cryaerophilus can be moderately virulent for rainbow trout at low water temperature, and changes in lipid and lipid peroxide contents of tissues and blood indices can highlight barely detectable effects of A. cryaerophilus infection in rainbow trout under laboratory conditions. However, the application of these indices in farm biomonitoring using rainbow trout will need more detailed studies and a careful consideration of the environmental parameters.


Regulation of Energy Expenditure by Brainstem GABA Neurons.
Homeostatic control of core body temperature is essential for survival. Temperature is sensed by specific neurons, in turn eliciting both behavioral (i.e., locomotion) and physiologic (i.e., thermogenesis, vasodilatation) responses. Here, we report that a population of GABAergic (Vgat-expressing) neurons in the dorsolateral portion of the dorsal raphe nucleus (DRN), hereafter DRNVgat neurons, are activated by ambient heat and bidirectionally regulate energy expenditure through changes in both thermogenesis and locomotion. We find that DRNVgat neurons innervate brown fat via a descending projection to the raphe pallidus (RPa). These neurons also densely innervate ascending targets implicated in the central regulation of energy expenditure, including the hypothalamus and extended amygdala. Optogenetic stimulation of different projection targets reveals that DRNVgat neurons are capable of regulating thermogenesis through both a "direct" descending pathway through the RPa and multiple "indirect" ascending pathways. This work establishes a key regulatory role for DRNVgat neurons in controlling energy expenditure.


Protein tyrosine phosphatase-1B regulates the tyrosine phosphorylation of the adapter Grb2-associated binder 1 (Gab1) in the retina.
Gab1 (Grb2-associated binder 1) is a key coordinator that belongs to the insulin receptor substrate-1 like family of adaptor molecules and is tyrosine phosphorylated in response to various growth factors, cytokines, and numerous other molecules. Tyrosine phosphorylated Gab1 is able to recruit a number of signaling effectors including PI3K, SHP2 and PLC-γ. In this study, we characterized the localization and regulation of tyrosine phosphorylation of Gab1 in the retina. Our immuno localization studies suggest that Gab1 is expressed in rod photoreceptor inner segments. We found that hydrogen peroxide activates the tyrosine phosphorylation of Gab1 ex vivo and hydrogen peroxide has been shown to inhibit the protein tyrosine phosphatase PTP1B activity. We found a stable association between the D181A substrate trap mutant of PTP1B and Gab1. Our studies suggest that PTP1B interacts with Gab1 through Tyrosine 83 and this residue may be the major PTP1B target residue on Gab1. We also found that Gab1 undergoes a light-dependent tyrosine phosphorylation and PTP1B regulates the phosphorylation state of Gab1. Consistent with these observations, we found an enhanced Gab1 tyrosine phosphorylation in PTP1B deficient mice and also in retinas treated ex vivo with a PTP1B specific allosteric inhibitor. Our laboratory has previously reported that retinas deficient of PTP1B are resistant to light damage compared to wild type mice. Since Gab1 is negatively regulated by PTP1B, a part of the retinal neuroprotective effect we have observed previously in PTP1B deficient mice could be contributed by Gab1 as well. In summary, our data suggest that PTP1B regulates the phosphorylation state of retinal Gab1 in vivo.


New linear lipopeptides produced by Pseudomonas cichorii SF1-54 are involved in virulence, swarming motility, and biofilm formation.
Pseudomonas cichorii is the causal agent of lettuce midrib rot, characterized by a dark-brown to green-black discoloration of the midrib. Formation of necrotic lesions by several plant-pathogenic pseudomonads is associated with production of phytotoxic lipopeptides, which contribute to virulence. Therefore, the ability of P. cichorii SF1-54 to produce lipopeptides was investigated. A cell-free culture filtrate of SF1-54 showed surfactant, antimicrobial, and phytotoxic activities which are typical for lipopeptides. High-performance liquid chromatography analysis of P. cichorii SF1-54 culture filtrate revealed the presence of seven compounds with lipopeptide characteristics. Two related lipopeptides, named cichofactin A and B, were studied in more detail: they are linear lipopeptides with a decanoic and dodecanoic lipid chain, respectively, connected to the N-terminus of an eight-amino-acid peptide moiety. Both cichofactins are new members of the syringafactin lipopeptide family. Furthermore, two nonribosomal peptide synthethase-encoding genes, cifA and cifB, were identified as responsible for cichofactin biosynthesis. A cifAB deletion mutant no longer produced cichofactins and was impaired in swarming motility but showed enhanced biofilm formation. Upon spray inoculation on lettuce, the cichofactin-deficient mutant caused significantly less rotten midribs than the wild type, indicating that cichofactins are involved in pathogenicity of P. cichorii SF1-54. Further analysis revealed that P. cichorii isolates vary greatly in swarming motility and cichofactin production.


Mimic nature, beyond nature: facile synthesis of durable superhydrophobic textiles using organosilanes.
Low mechanical stability of superhydrophobic surfaces is the bottle neck we are facing for their practical applications. Here we report facile fabrication of durable superhydrophobic textiles by dip coating in a nanocomposite solution of fluoro-free organosilanes. The kind of organosilane, molar ratio of organosilane in the precursor and water concentration as well as the dip coating parameters (e.g., concentration of nanocomposite, ultrasonication and curing time) have great influences on the superhydrophobicity and abrasion stability of the coated textiles. The superhydrophobic textiles show excellent mechanical, chemical and environmental stability under the optimal conditions. No obvious changes in contact angle can be seen during various stability tests. Water drops stay nearly spherical in shape on the samples and could easily roll off the samples after various stability tests. In addition, the slightly reduced superhydrophobicity can be easily repaired by dip coating again in the same nanocomposite solution. Moreover, this simple approach can be easily applied to various substrates and scaled up. The excellent stability of the superhydrophobic textiles and the simple dip coating procedure pave the way for their practical applications in various fields such as oil/water separation.


Patterns of pectin methylesterase transcripts in developing stem nodules of Sesbania rostrata.
Differential display was applied to the early stages of the interaction between the tropical legume Sesbania rostrata and its microsymbiont Azorhizobium caulinodans ORS571. An upregulated clone that is similar to pectin methylesterase-encoding genes was isolated (Srpmel). The full-length sequence of Srpme1 was used to localize PME transcripts in situ during S. rostrata stem-nodule development. Several expression patterns were distinguished, hinting at general roles in vascular tissue development and cell division or expansion and at symbiosis-specific functions, such as uninfected cell differentiation.


CHD chromatin remodelers and the transcription cycle.
It is well established that ATP-dependent chromatin remodelers modulate DNA access of transcription factors and RNA polymerases by "opening" or "closing" chromatin structure. However, this view is far too simplistic. Recent findings have demonstrated that these enzymes not only set the stage for the transcription machinery to act but are actively involved at every step of the transcription process. As a consequence, they affect initiation, elongation, termination and RNA processing. In this review we will use the CHD family as a paradigm to illustrate the progress that has been made in revealing these new concepts.


In utero Programming of Allergic Susceptibility.
Around 30-40% of the world's population will experience allergy, the most common and earliest-onset noncommunicable disease. With a steady rise in the incidence of allergic disease over recent decades, up to 18% of children will suffer a respiratory, food or skin allergy before their 18th birthday. There is compelling evidence that the risk of developing allergy is influenced by early life events and particularly in utero exposures. A comprehensive literature review was undertaken which outlines prenatal risk factors and potential mechanisms underlying the development of allergy in childhood. Exposures including maternal cigarette smoking, preterm birth and Caesarean delivery are implicated in predisposing infants to the later development of allergy. In contrast, restricted growth in utero, a healthy maternal diet and a larger family size are protective, but the mechanisms here are unclear and require further investigation. To ameliorate the allergy pandemic in young children, we must define prenatal mechanisms that alter the programming of the fetal immune system and also identify specific targets for antenatal interventions.


Prognostic Value of Right Ventricular Ejection Fraction Assessed by Transthoracic 3D Echocardiography.
Cardiac magnetic resonance is the gold standard for the evaluation of right ventricular (RV) volumes, but it is impractical to perform in every patient. Although reference values of RV volumes and RV ejection fraction by 3D transthoracic echocardiography (3DTTE) have been established, their prognostic values have not been elucidated yet. We hypothesized that RV ejection fraction measured by 3DTTE (3DRVEF) predicts future cardiovascular events. In protocol 1, we determined the accuracy of RV volumes and RV ejection fraction measurements by 3DTTE against cardiac magnetic resonance in 60 subjects. In protocol 2, 3DRVEF was measured in 446 patients with various cardiovascular diseases. Study subjects were followed up to record cardiac death and major adverse cardiovascular events. In protocol 1, 3DTTE-determined RV end-diastolic volume, end-systolic volume, and RV ejection fraction had good correlations to those by cardiac magnetic resonance (r=0.74-0.90). In protocol 2, 38 cardiac deaths and 88 major adverse cardiovascular events occurred during a median follow-up of 4.1 years. Univariable Cox proportional analysis revealed that 3DRVEF was associated with both cardiac death (P<0.0001) and major adverse cardiovascular event (P<0.0001). 3DRVEF remained as an independent predictor for cardiac death (P<0.0001) and major adverse cardiovascular event (P<0.0001) even in a stepwise multivariable Cox proportional hazard analysis. Classification and regression-tree analysis demonstrated that 3DRVEF played an important role for risk stratification. 3DTTE-determined RV ejection fraction was independently associated with cardiac outcomes in patients with diverse backgrounds. 3DRVEF offered incremental value over clinical risk factors and the other echocardiographic parameters including left ventricular systolic and diastolic function for predicting future adverse outcome.


Constitutional democracy and technology in the age of artificial intelligence.
Given the foreseeable pervasiveness of artificial intelligence (AI) in modern societies, it is legitimate and necessary to ask the question how this new technology must be shaped to support the maintenance and strengthening of constitutional democracy. This paper first describes the four core elements of today's digital power concentration, which need to be seen in cumulation and which, seen together, are both a threat to democracy and to functioning markets. It then recalls the experience with the lawless Internet and the relationship between technology and the law as it has developed in the Internet economy and the experience with GDPR before it moves on to the key question for AI in democracy, namely which of the challenges of AI can be safely and with good conscience left to ethics, and which challenges of AI need to be addressed by rules which are enforceable and encompass the legitimacy of democratic process, thus laws. The paper closes with a call for a new culture of incorporating the principles of democracy, rule of law and human rights by design in AI and a three-level technological impact assessment for new technologies like AI as a practical way forward for this purpose.This article is part of a theme issue 'Governing artificial intelligence: ethical, legal, and technical opportunities and challenges'.


Invasive micropapillary breast carcinoma: a retrospective study of classification by pathological parameters.
Micropapillary breast carcinoma has been recognized as a morphologically and biologically distinct form of breast carcinoma. Although data suggest that patient outcomes in cases of micropapillary breast carcinoma do not differ significantly from other breast carcinomas, the impact that a micropapillary component might have on the pathological work-up of a case of breast carcinoma remains an important point of discussion (especially as pertaining to the risk of lymphovascular disease). In this study, we perform an extensive retrospective study of the pathological parameters of seven years of breast surgical pathology cases to explore the relationship that micropapillary morphology might have with other important pathological parameters of a breast cancer case work-up (e.g. tumour size, lymphovascular invasion, lymph node status). We also analyze our data set to see if a micropapillary component would influence hierarchical classification by pathological parameters. Micropapillary features correlated with a higher frequency of ER positivity and lymphovascular invasion; there was no statistical difference between those cases with and without a micropapillary component from the perspective of other clinicopathological parameters, however. The presence of micropapillary features did influence classification, however, and produced a distinct cluster amidst comparison of other pathological variables.


A comparative study of the effect of arterial and venous occlusion after various periods of ischemia.
The author attempted to quantify any additional tissue damage resulting from one hour of venous occlusion after controlled periods of ischemia in skeletal muscle, compared to equal time periods of ischemia. The rat quadriceps muscle was used. pH and temperature were monitored during the experiment and the damage was evaluated on histochemical sections. Of the other two parameters monitored in this study, the pH recovery rate during reperfusion best reflected tissue perfusion and served as a predictor for the extent of tissue damage, when global ischemia or the combination of ischemia and postischemic venous stasis did not exceed five hours. Apart from the nonstained lethally damaged areas, interstitial tissue edema and cellular infiltration were constant findings in all muscles that sustained ischemia or ischemia and subsequent venous occlusion. However, both findings were more pronounced in the muscles that underwent venous obstruction. Muscle fibers were more edematous after venous occlusion, compared to ischemic muscles. Thrombosed veins and collapsed arteries, surrounded by excessive edema and inflammatory reaction, were common in muscles after ischemia and venous occlusion. Comparing the difference in percent of lethal damage from one hour of postischemic venous stasis versus the damage from additional ischemia of equal duration, findings demonstrated comparable damage when reperfusion was established in less than five hours.


Impact of Donor Age on Recipient Survival in Adult-to-Adult Living-donor Liver Transplantation.
To investigate the influence of donor age on recipient outcome after living-donor partial liver transplantation (LDLT). Donor age is a well-known prognostic factor in deceased donor liver transplantation; however, its role in LDLT remains unclear. We retrospectively analyzed 315 consecutive cases of primary adult-to-adult LDLT in our center between April 2006 and March 2014. Recipients were divided into 5 groups according to the donor age: D-20s (n = 60); D-30s (n = 72); D-40s (n = 57); D-50s (n = 94); and D-60s (n = 32). The recipient survival and the association with various clinical factors were investigated. Recipient survival proportions were significantly higher in D-20s compared with all the other groups (P = 0.008, < 0.001, < 0.001, and = 0.006, vs D-30s, -40s, -50s, and -60s, respectively), whereas there was no association between recipient survival and their own age. There are 3 typical relationships between donors and recipients in adult-to-adult LDLT: from child-to-parent, between spouses/siblings, and from parent-to-child. The overall survival in child-to-parent was significantly higher than in spouses/siblings (P = 0.002) and in parent-to-child (P = 0.005), despite significantly higher recipient age in child-to-parent [59 (42-69) years, P < 0.001]. Contrastingly, parent-to-child exhibited the lowest survival, despite the youngest recipient age [26 (20-43) years, P < 0.001]. In addition, younger donor age exhibited significantly better recipient survival both in hepatitis C virus-related and in non-hepatitis C virus diseases. Univariate and multivariate analyses both demonstrated that donor age and graft-type (right-sided livers) are independent prognostic factors for recipient survival. Donor age is an independent, strong prognostic factor in adult-to-adult LDLT.


Elimination of the O-linked glycosylation site at Thr 104 results in the generation of a soluble human-transferrin receptor.
The transferrin receptor (TfR) is the plasma membrane protein responsible for the binding and internalization of the major iron-transport protein, transferrin. The function of the single O-linked oligosaccharide near the transmembrane domain of the TfR at amino acid Thr 104 is unknown. To elucidate the effect of the O-linked carbohydrate on TfR function, the oligosaccharide was eliminated by replacing Thr 104 with Asp and the mutated cDNA was expressed in a cell line lacking endogenous TfR. Elimination of the oligosaccharide at Thr 104 results in a form of the receptor that is susceptible to cleavage. A 78-kD soluble TfR that can bind transferrin is released into the growth medium. The intact mutant TfR is not grossly altered in its structure and does not differ significantly from the wild-type human receptor in many respects: (1) It shows the same distribution between the plasma membrane and intracellular compartments; (2) the binding constant for transferrin is similar to that of the wild-type TfR; and (3) it is not rapidly degraded. Protein-sequence analysis of the soluble form indicates that the sequence begins at amino acid 101 of the intact receptor. This is the same cleavage site reported for a soluble form of normal receptor found in human serum. Substitution of Gly, Glu, or Met at position 104 also results in increased cleavage of the TfR and suggests that elimination of the O-linked carbohydrate at position 104 enhances the susceptibility of TfR to cleavage and may mimic a naturally occurring process previously described as being related to erythropoiesis.


Regulation of the Epstein-Barr virus C promoter by AUF1 and the cyclic AMP/protein kinase A signaling pathway.
EBNA2 is an Epstein-Barr virus (EBV)-encoded protein that regulates the expression of viral and cellular genes required for EBV-driven B-cell immortalization. Elucidating the mechanisms by which EBNA2 regulates viral and cellular gene expression is necessary to understand EBV-induced B-cell immortalization and viral latency in humans. EBNA2 targets to the latency C promoter (Cp) through an interaction with the cellular DNA binding protein CBF1 (RBPJk). The EBNA2 enhancer in Cp also binds another cellular factor, C promoter binding factor 2 (CBF2), whose protein product(s) has not yet been identified. Within the EBNA2 enhancer in Cp, we have previously identified the DNA sequence required for CBF2 binding and also determined that this element is required for efficient activation of Cp by EBNA2. In this study, the CBF2 activity was biochemically purified and microsequenced. The peptides sequenced were identical to the hnRNP protein AUF1. Antibodies against AUF1 but not antibodies to related hnRNP proteins reacted with CBF2 in gel mobility shift assays. In addition, stimulation of the cellular cyclic AMP (cAMP)/protein kinase A (PKA) signal transduction pathway results in an increase in detectable CBF2/AUF1 binding activity extracted from stimulated cells. Furthermore, the CBF2 binding site was able to confer EBNA2 responsiveness to a heterologous promoter when transfected cells were treated with compounds that activate PKA or by cotransfection of plasmids expressing a constitutively active catalytic subunit of PKA. EBNA2-mediated stimulation of the latency Cp is also increased in similar cotransfection assays. These results further support an important role for CBF2 in mediating EBNA2 transactivation; they identify the hnRNP protein AUF1 as a major component of CBF2 and are also the first evidence of a cis-acting sequence other than a CBF1 binding element that is able to confer responsiveness to EBNA2.


Osteopontin promotes vascular cell adhesion and spreading and is chemotactic for smooth muscle cells in vitro.
Osteopontin is an Arg-Gly-Asp-containing acidic phosphoprotein recently shown to be upregulated in vascular smooth muscle during rat arterial neointima formation and in human atherosclerotic plaques. Functional studies showed that osteopontin promoted adhesion of both cultured aortic endothelial cells and aortic smooth muscle cells. Adhesion of vascular cells to osteopontin was dose dependent and half maximal when solutions containing 7 and 30 nmol/L osteopontin were used to coat wells for endothelial and smooth muscle cells, respectively. Smooth muscle cells adherent to osteopontin were spread after 60 minutes, whereas endothelial cells remained round, although flattened, at this time point but were spread at 90 minutes. Cell spreading on osteopontin was accompanied by the formation of focal adhesion plaques. A newly developed anti-osteopontin antibody completely inhibited adhesion of both cell types to osteopontin but not to fibronectin or vitronectin. In addition, the peptide GRGDSP blocked adhesion to osteopontin, suggesting that integrins mediate Arg-Gly-Asp-dependent adhesion. Indeed, an antibody against the alpha v beta 3 integrin neutralized adhesion of both endothelium and smooth muscle cells to osteopontin by approximately 50%, demonstrating that alpha v beta 3 is one osteopontin receptor on vascular cells. Osteopontin also promoted the migration of smooth muscle cells in a Boyden-type chamber, with half-maximal effects observed at 77 nmol/L osteopontin. Checkerboard analysis demonstrated that this stimulus was chemotactic in nature. Our findings suggest that osteopontin may be functionally important as an adhesive and chemotactic molecule for vascular cells, particularly when levels of osteopontin are dramatically increased, as is the case after arterial angioplasty and in atherosclerotic plaques.


HIV viral suppression and longevity among a cohort of children initiating antiretroviral therapy in Eastern Cape, South Africa.
There are limited data on viral suppression (VS) in children with HIV receiving antiretroviral therapy (ART) in routine care in low-resource settings. We examined VS in a cohort of children initiating ART in routine HIV care in Eastern Cape Province, South Africa. The Pediatric Enhanced Surveillance Study enrolled HIV-infected ART eligibility children zero to twelve years at five health facilities from 2012 to 2014. All children received routine HIV care and treatment services and attended quarterly study visits for up to 24 months. Time to VS among those starting treatment was measured from ART start date to first viral load (VL) result <1000 and VL <50 copies/mL using competing risk estimators (death as competing risk). Multivariable sub-distributional hazards models examined characteristics associated with VS and VL rebound following suppression among those with a VL >30 days after the VS date. Of 397 children enrolled, 349 (87.9%) started ART: 118 (33.8%) children age <12 months, 122 (35.0%) one to five years and 109 (31.2%) six to twelve years. At study enrolment, median weight-for-age z-score (WAZ) was -1.7 (interquartile range (IQR):-3.1 to -0.4) and median log VL was 5.6 (IQR: 5.0 to 6.2). Cumulative incidence of VS <1000 copies/mL at six, twelve and twenty-four months was 57.6% (95% CI 52.1 to 62.7), 78.7% (95% CI 73.7 to 82.9) and 84.0% (95% CI 78.9 to 87.9); for VS <50 copies/mL: 40.3% (95% CI 35.0 to 45.5), 63.9% (95% CI 58.2 to 69.0) and 72.9% (95% CI 66.9 to 78.0). At 12 months only 46.6% (95% CI 36.6 to 56.0) of children <12 months had achieved VS <50 copies/mL compared to 76.9% (95% CI 67.9 to 83.7) of children six to twelve years (p < 0.001). In multivariable models, children with VL >1 million copies/mL at ART initiation were half as likely to achieve VS <50 copies/mL (adjusted sub-distributional hazards 0.50; 95% CI 0.36 to 0.71). Among children achieving VS <50 copies/mL, 37 (19.7%) had VL 50 to 1000 copies/mL and 31 (16.5%) had a VL >1000 copies/mL. Children <12 months had twofold increased risk of VL rebound to VL >1000 copies/mL (adjusted relative risk 2.03, 95% CI: 1.10 to 3.74) compared with six to twelve year olds. We found suboptimal VS among South African children initiating treatment and high proportions experiencing VL rebound, particularly among younger children. Greater efforts are needed to ensure that all children achieve optimal outcomes.


Developmental assistance for child and adolescent mental health in low- and middle-income countries (2007-2014): Annual trends and allocation by sector, project type, donors and recipients.
Globally, mental disorders are the leading cause of disability among children and adolescents. To date, there has been no estimate of developmental assistance supporting mental health projects that target children and adolescents (DAMH-CA). This study aimed to identify, describe and analyse DAMH-CA with respect to annual trends (2007-2014), sector, project type, recipient regions, and top donor and recipient countries, and estimate annual DAMH-CA per child/adolescent by region. Developmental assistance for all projects focused on children and adolescent mental health between 2007 and 2014 was identified on the Organisation for Economic Co-operation and Development's (OECD) Creditor Reporting System, and analysed by target population, sector, project type, donors, and recipients. The study did not include governmental or private organisation funds, nor funding for projects that targeted the community or those that included mental health but not as a primary objective. Between 2007 and 2014, 704 projects were identified, constituting US$ 88.35 million in DAMH-CA, with an average of 16.9% of annual development assistance for mental health. Three quarters of DAMH-CA was used to fund projects in the humanitarian sector, while less than 10% was directed at mental health projects within the education, HIV/AIDS, rights, and neurology sectors. DAMH-CA was predominantly invested in psychosocial support projects (US$ 63.24 million, 72%), while little in absolute and relative terms supported capacity building, prevention, promotion or research, with the latter receiving just US$ 1.2 million over the eight years (1.4% of total DAMH-CA). For 2014, DAMH-CA per child/adolescent was US$ 0.02 in Europe, less than US$ 0.01 in Asia, Africa, and Latin America and the Caribbean, and US$ 0 in Oceania. To mitigate the growing burden of mental and neurological disorders, increased financial aid must be invested in child and adolescent mental health, especially with respect to capacity building, research and prevention of mental disorder projects. The present findings can be used to inform policy development and guide resource allocation, as current developmental assistance is described by sector and project type, thereby facilitating the identification of specific areas of investment need.


Can MRI reveal phenotypes of multiple sclerosis?
The multicontrast capability of magnetic resonance imaging (MRI) is discussed in its role in the search for phenotypes of multiple sclerosis (MS). Aspects of MRI specificity, putative markers for pathogenetic components of disease and issues of spatial and temporal distribution are discussed. While particular reference is made to MS, the concepts apply to common pathological features of many neurologic diseases and to neurodegenerative disease in general. The assessment and dissociation of disease activity and disease severity, as well as the combination of varied metrics for the purposes of inferential and predictive disease modeling, are explored with respect to biomarkers and clinical outcomes. By virtue of its noninvasive nature and multicontrast capabilities depicting multiple facets of MS pathology, MRI lends itself to the systematic search of pathogenetically distinct subtypes of MS in large populations of patients. In conjunction with clinical, immunological, serological and genetic information, clusters of MS patients with distinct clinical prognosis and diverse response profiles to available and future treatments may be identified.


Activity-dependent presynaptic effect of serotonin 1B receptors on the somatosensory thalamocortical transmission in neonatal mice.
The disruptive effect of excessive serotonin (5-HT) levels on the development of cortical sensory maps is mediated by 5-HT1B receptors, as shown in barrelless monoamine oxidase A knock-out mice, in which the additional inactivation of 5-HT1B receptors restores the barrels. However, it is unclear whether 5-HT1B receptors mediate their effect on barrel formation by a trophic action or an activity-dependent effect. To test for a possible effect of 5-HT1B receptors on activity, we studied the influence of 5-HT on the thalamocortical (TC) synaptic transmission in layer IV cortical neurons. In TC slices of postnatal day 5 (P5)-P9 neonate mice, we show that 5-HT reduces monosynaptic TC EPSCs evoked by low-frequency internal capsule stimulation and relieves the short-term depression of the EPSC evoked by high-frequency stimulation. We provide evidence that 5-HT decreases the presynaptic release of glutamate: 5-HT reduces similarly the AMPA-kainate and NMDA components and the paired pulse depression of TC EPSCs. We show also that 5-HT1B receptors mediate exclusively the effect of 5-HT: first, the effect of 5-HT on the TC EPSC is correlated with the transient expression of 5-HT1B receptor mRNAs in the ventrobasal thalamic nucleus during postnatal development; second, it is mimicked by a 5-HT1B agonist; third, 5-HT has no effect in 5-HT1B receptor knock-out mice. Our results show that in the developing barrel field of the neonatal mice, 5-HT1B receptors mediate an activity-dependent regulation of the TC EPSC that could favor the propagation of high-frequency TC activity.


Limited Genetic Diversity of Hepatitis B Virus in the General Population of the Offin River Valley in Ghana.
Hepatitis B virus (HBV) infections account for approximately 780,000 deaths per year, most of which occur in the developing world. Co-infection with HBV and hepatitis delta virus (HDV) may lead to the most severe form of viral hepatitis. In Ghana, knowledge on the prevalence of HBV and HDV in the general population is scanty and the few genetic analyses of the prevailing HBV genotypes are dating back more than a decade. In the present study, 1,323 serum samples from individuals living in a rural area (Offin river valley) of Ghana were analyzed for the presence of the hepatitis B surface antigen (HBsAg). Positive sera were subsequently tested for the presence of anti-HDV antibodies. A total of 107 (8%) sera were HBsAg positive with an 8.4% prevalence of anti-HDV antibodies among the HBsAg positives. Phylogenetic analysis based on HBV pre-S/S sequences, attributed all 52 typable samples to genotype E. All belonged to serotype ayw4. While 19 sequences clustered with those from a number of African countries, the other 33 formed a separate cluster distinguished by an intergroup mean distance of 1.5% from the pan-African HBV/E cluster. Successful implementation of HBV vaccination in the region was reflected by the low HBsAg carrier rate of 1.8% among children ≤11 years.


Exposure to Contact Sports Results in Maintained Performance During Experimental Pain.
During pain, motor performance tends to decline. However, athletes who engage in contact sports are able to maintain performance despite the inherent pain that accompanies participation. This may be the result of being challenged rather than threatened by pain; adaptive coping strategies; habituation to pain; or finding pain less bothersome. This study aimed to measure performance of a novel motor task both in pain and not in pain within experienced contact athletes (n = 40), novice contact athletes (n = 40), and noncontact athletes (n = 40). Challenge and threat perceptions were manipulated during the pain condition and measures of pain tolerance, perception, coping styles, and bothersomeness were taken. Results indicated that contact athletes, regardless of experience, were able to maintain their performance during painful stimulation. Noncontact athletes, conversely, performed significantly worse during pain stimulation. In addition, contact athletes tended to be more challenged and the noncontact athletes more threatened within the pain condition. Experienced contact athletes demonstrated higher levels of pain tolerance and direct coping, and reported lower levels of pain bothersomeness and intensity than the other groups. The results suggest that even relatively brief exposure to contact sports may be enough to help maintain performance in pain. Being in a challenged state appears to be an important factor during performance in pain. Moreover, pain tolerance, intensity, and bothersomeness may differentiate novice and experienced athletes. PERSPECTIVE: Exposure to voluntary pain and challenge states are associated with adaptive responses to pain. Motor task performance may be maintained in individuals with more experience of sports-related pain.


Physicochemical Stability of an Oral Suspension of Trimethoprim 20 mg/mL in Combination with Sulfadiazine 200 mg/mL in PCCA Base SuspendIt.
Trimethoprim is a diaminopyrimidine antibacterial agent that, like sulfonamides, inhibits bacterial folic acid synthesis, but at a different stage in the metabolic pathway. It has a similar spectrum of activity to the sulfonamides and is given by mouth or by injection, either alone or in conjunction with a sulfonamide, such as sulfadiazine. Sulfadiazine is a bacteriostatic antibacterial agent that interferes with folic acid synthesis in susceptible bacteria. The combination of the two drugs produces a synergistic effect against both Gram-positive and Gram-negative aerobic bacteria, by inhibiting enzymes in the folic acid pathways, which in turn inhibits bacterial thymidine synthesis. There are no published studies of the stability of the combination of trimethoprim and sulfadiazine in a liquid dosage form. An extemporaneously compounded suspension from pure drug powders or commercial tablets would provide an alternative option to meet unique patient needs. The purpose of this study was to determine the physicochemical stability of trimethoprim combined with sulfadiazine in PCCA base SuspendIt. PCCA base SuspendIt is a sugar-free, paraben-free, dye-free, and gluten-free thixotropic vehicle containing a natural sweetener obtained from the monk fruit. It thickens upon standing to minimize settling of any insoluble drug particles and becomes fluid upon shaking to allow convenient pouring during administration to the patient. A robust stability-indicating high-performance liquid chromatographic assay for the simultaneous determination of trimethoprim and sulfadiazine in SuspendIt was developed and validated. This assay was used to determine the chemical stability of both drugs in SuspendIt. Samples were prepared and stored under three different temperature conditions (5°C, 25°C, 40°C), and assayed using the high-performance liquid chromatographic assay at pre-determined intervals over an extended period of time as follows: 0, 7, 14, 30, 45, 60, 91, 120, and 182 days at each designated temperature. Physical data such as pH, viscosity, appearance, and average particle size were also monitored. The study showed that drug concentration did not go below 90% of the label claim (initial drug concentration) at room temperature and in the refrigerator. The pH values also did not change significantly. There was some variability in viscosity and average particle size. This study demonstrates that trimethoprim and sulfadiazine are physically and chemically stable in combination in SuspendIt for 182 days at room temperature and in the refrigerator, thus providing a viable, compounded alternative for both drugs in a liquid dosage form, with an extended beyond-use-date to meet patient needs.


The use of intraservice work per unit of time (IWPUT) and the building block method (BBM) for the calculation of surgical work.
We will review the contribution to the Medicare Fee Schedule (MFS) by the techniques of intensity of work per unit of time (IWPUT), the building block methodology (BBM), and the work accomplished by the American College of Surgeons General Surgery Coding & Reimbursement Committee (GSCRC) in using IWPUT/BBM to detect undervalued surgical procedures and recommend payment increases. The MFS has had a major impact on surgeons' income since its introduction in 1992 by the Centers for Medicare and Medicaid (CMS) and additionally has been adopted for use by many commercial insurers. A major component of MFS is physician work, measured as the relative value of work (RVW), which has 2 components: time and intensity. These components are incorporated by: RVW = time x intensity. This work formula can be rearranged to give the IWPUT, which has become a powerful tool to calculate the amount of RVW performed by physicians. Most procedures are valued by the total RVW in the global surgical package, which includes pre-, intra-, and postoperative care for a time after surgery. Summing these perioperative components into RVW is called the building block methodology (BBM). Using these techniques, the GSCRC increased the values for 314 surgery procedures during a recent CMS 5-year review, resulting in an increase to general surgeons of roughly 76 million dollars annually. The use of IWPUT/BBM has been instrumental to correct payment for undervalued surgical procedures. They are powerful methods to measure RVW across specialties and to solve reimbursement, compensation, and practice management problems facing surgeons.


Application of a decision rule and a D-dimer assay in the diagnosis of pulmonary embolism.
Current strategies for diagnosing pulmonary embolism (PE) include a clinical decision rule (CDR), followed by a D-dimer assay in patients with an unlikely clinical probability. We assessed the implementation of the current guidelines for the diagnosis of PE. A first questionnaire was sent to internists and pulmonologists to assess the proportion of physicians that adequately applied the guidelines. Two versions of a second questionnaire were sent presenting five hypothetical cases of which in two cases with an intermediate clinical probability an abnormal D-dimer test result was added to one version. We assessed the variation of the CDR and compared the proportions of a likely clinical probability between the two versions. A total of 65 physicians responded to the first questionnaire (response rate 75%). Half of the physicians (N=29; 46%) indicated that they use a CDR in all patients and 22 physicians (45%) indicated that they review the D-dimer result after they examined patients. Sixty-two physicians responded on the second questionnaire (response rate 36%). A shift was observed from an unlikely to a likely probability when an abnormal D-dimer test result was added to the clinical information (22% to 41%; p=0.22 and 26% to 50%; p<0.05). Our findings indicate that physicians do not use the guidelines for diagnosis of PE consistently. Furthermore, the knowledge of an abnormal D-dimer test result before seeing the patient leads to a higher CDR score. Physicians should therefore first examine patients before taking note of the D-dimer test result.


Trapped in Statelessness: Rohingya Refugees in Bangladesh.
The Rohingya people are one of the most ill-treated and persecuted refugee groups in the world, having lived in a realm of statelessness for over six generations, and who are still doing so. In recent years, more than 500,000 Rohingyas fled from Myanmar (Burma) to neighboring countries. This article addresses the Rohingya refugee crisis in Bangladesh, with special emphasis on the living conditions of this vulnerable population. We reviewed several documents on Rohingya refugees, visited a registered refugee camp (Teknaf), collected case reports, and conducted a series of meetings with stakeholders in the Cox's Bazar district of Bangladesh. A total of 33,131 registered Rohingya refugees are living in two registered camps in Cox's Bazar, and up to 80,000 additional refugees are housed in nearby makeshift camps. Overall, the living conditions of Rohingya refugees inside the overcrowded camps remain dismal. Mental health is poor, proper hygiene conditions are lacking, malnutrition is endemic, and physical/sexual abuse is high. A concerted diplomatic effort involving Bangladesh and Myanmar, and international mediators such as the Organization of Islamic Countries and the United Nations, is urgently required to effectively address this complex situation.


An investigation on endoparasites of Rana ridibunda complex (s. l.) with dermal parasite (metacercariae) in Dalaman (Turkey).
In this study, endoparasites of the Rana ridibunda specimens collected from Dalaman area, southwestern Turkey were investigated. In the intestine of 17 specimens of R. ridibunda, five different parasites, represented by three species of the trematoda (Diplodiscus sp, Pleurogenoides sp, Plagiorchis sp) and two genera of round worms (Cosmocerca sp; Foleyella sp) were recognized. The trematoda and one of the round worms were found in the rectal region whereas the other round worm species are observed in the abdominal cavity.


Intraspecific Genomic Divergence and Minor Structural Variations in Leishmania (Viannia) panamensis.
Leishmania (Viannia) panamensis is one of the most important Leishmania species associated with cutaneous leishmaniasis (CL) in Latin America. Despite its wide geographic distribution and pathogenic potential in humans and animals, the genomic variability of this species is low compared with other Leishmania species circulating in the same geographical area. No studies have reported a detailed analysis of the whole genome of L. panamensis from clinical isolates using DNA high-throughput sequencing to clarify its intraspecific genomic variability or plausible divergence. Therefore, this study aimed to evaluate the intraspecific genomic variability of L. panamensis from Colombia and Panama. A total of 22 genomes were analyzed, 19 from Colombian patients with CL and three genomes from Panama obtained from public databases. The phylogenomic analysis revealed the potential existence of three well-supported clades as evidence of intraspecific divergence. Additionally, the whole-genome analysis showed low structural variations in terms of ploidy, copy number variations, and single-nucleotide polymorphisms (SNPs). SNPs shared among all clades were identified, revealing their importance in different biological processes of L. panamensis. The findings not only expand our knowledge of intraspecific genomic variability of one of the most important Leishmania species in South America but also highlights the possible existence of different clades/lineages/subpopulations across a geographic scale.


Epigenetics underpins phenotypic plasticity of protandrous sex change in fish.
Phenotypic plasticity is an important driver of species resilience. Often mediated by epigenetic changes, phenotypic plasticity enables individual genotypes to express variable phenotypes in response to environmental change. Barramundi (Lates calcarifer) are a protandrous (male-first) sequential hermaphrodite that exhibits plasticity in length-at-sex change between geographic regions. This plasticity is likely to be mediated by changes in DNA methylation (DNAm), a well-studied epigenetic modification. To investigate the relationships between length, sex, and DNAm in a sequential hermaphrodite, here, we compare DNAm in four conserved vertebrate sex-determining genes in male and female barramundi of differing lengths from three geographic regions of northern Australia. Barramundi first mature as male and later sex change to female upon the attainment of a larger body size; however, a general pattern of increasing female-specific DNAm markers with increasing length was not observed. Significant differences in DNAm between males and females of similar lengths suggest that female-specific DNAm arises rapidly during sex change, rather than gradually with fish growth. The findings also reveal that region-specific differences in length-at-sex change are accompanied by differences in DNAm and are consistent with variability in remotely sensed sea temperature and salinity. Together, these findings provide the first in situ evidence for epigenetically and environmentally mediated sex change in a protandrous hermaphrodite and offer significant insight into the molecular and ecological processes governing the marked and unique plasticity of sex in fish.


Is obesity related to the type of dietary fatty acids? An ecological study.
Animal studies and a few clinical trials lend credibility to the hypothesis that not all types of fatty acids carry the same potential for weight gain. Only a few epidemiological studies concerning this issue are currently available and results are conflicting. The purpose of the present ecological study was to test the existence of an association between obesity prevalence and the types of fat available in 168 countries. Data on the prevalence of obesity (BMI >or= 30 kg/m2) for women over 15 years of age were obtained from the WHO Global InfoBase. Food balance sheets for the years 1998 to 2002 were obtained from the FAOSTAT database. Five-year means for energy, total fat, MUFA, PUFA, SFA and 'other fat' per capita were calculated, with their standard deviations, for each country. Bivariate correlations and a multiple linear regression model were used to test for the association between prevalence of obesity and types of fat available in these countries. Not surprisingly, dietary energy supply, SFA, PUFA and 'other fat' were positively associated with the prevalence of obesity. We also found, however, a strong negative association between MUFA availability and obesity prevalence (beta= -0.68, P<0.0001). Populations with a lower prevalence of obesity seem to consume a greater amount of MUFA. Considering the partial correlations between variables, our results suggest that in countries with higher obesity prevalence, it is the shift from MUFA to PUFA that particularly appears to be associated with the risk of obesity.