Entropy Production beyond the Thermodynamic Limit from Single-Molecule Stretching Simulations.
Single-molecular systems are a test bed to analyze to what extent thermodynamics applies when the size of the system is drastically reduced. Isometric and isotensional single-molecule stretching experiments and their theoretical interpretations have shown the lack of a thermodynamic limit at those scales and the nonequivalence between their corresponding statistical ensembles. This disparity between thermodynamic results obtained in both experimental protocols can also be observed in entropy production, as previous theoretical results have shown. In this work, we present results from molecular dynamics simulations of stretching of a typical polymer, polyethylene-oxide, where this framework is applied to obtain friction coefficients associated with stretching at the two different statistical ensembles for two different system sizes, from which the entropy production follows. In the smallest system, they are different up to a factor of 2, and for the bigger system, the difference is smaller, as predicted. In this way, we provide numerical evidence that a thermodynamic description is still meaningful for the case of single-molecule stretching.


Emotion modulation of the body-selective areas in the developing brain.
Emotions are strongly conveyed by the human body and the ability to recognize emotions from body posture or movement is still developing through childhood and adolescence. To date, very few studies have explored how these behavioural observations are paralleled by functional brain development. Furthermore, currently no studies have explored the development of emotion modulation in these areas. In this study, we used functional magnetic resonance imaging (fMRI) to compare the brain activity of 25 children (age 6-11), 18 adolescents (age 12-17) and 26 adults while they passively viewed short videos of angry, happy or neutral body movements. We observed that when viewing dynamic bodies generally, adults showed higher activity than children bilaterally in the body-selective areas; namely the extra-striate body area (EBA), fusiform body area (FBA), posterior superior temporal sulcus (pSTS), as well as the amygdala (AMY). Adults also showed higher activity than adolescents, but only in the right hemisphere. Crucially, however, we found that there were no age differences in the emotion modulation of activity in these areas. These results indicate, for the first time, that despite activity selective to body perception increasing across childhood and adolescence, emotion modulation of these areas in adult-like from 7 years of age.


Elevated transferrin saturation, health-related quality of life and telomere length.
We sought to examine the relationship between elevated transferrin saturation (TS) and measures of health status (telomere length and patient-reported health-related quality of life) to assess whether elevated TS is associated with negative patient outcomes beyond increased risk for morbidity and mortality, using a cross-sectional analysis of the Hemochromatosis and Iron Overload Screening Study supplemented with assays for leukocyte telomere length in adults ≥25 years old (n = 669). Among individuals with elevated TS (≥45 % for women and ≥50 % for men), who also had a usual source of care, only 5.2 % reported ever being told by a doctor that they had an elevated iron condition. In a fully adjusted general linear regression model controlling for demographic characteristics as well as health conditions associated with iron overload, elevated TS versus non-elevated TS was associated with worse general health status (60.4 vs. 63.8, P < 0.05), mental health status (76.5 vs. 82.2, P < 0.0001) and shorter telomere length (241.4 vs. 261.3, P < 0.05). Increased surveillance of elevated TS may be in order as elevated TS is associated with decreased health status and very few patients with elevated TS are aware of their condition.


Emergency department patient preferences for waiting for a bed.
Many EDs have difficulty transferring admitted patients to inpatient beds in a timely manner because of access block. We assessed ED patient preferences for waiting location. Admitted ED patients at Royal Perth Hospital, Perth, Western Australia, Australia were surveyed over a 4 week period. Patients were questioned about their preferences for waiting location (ED cubicle, ED corridor, ward corridor, no preference). Patients were also asked what they felt was the maximum acceptable time for waiting for a ward bed. We also assessed if patient expectations were met with regards to their waiting times. A total of 400 patients were surveyed. Of all, 121 patients (30.2%) had no preference for waiting location and 215 patients (53.8%) preferred ED cubicles. If the waiting location option was between EDs and ward corridors, 185 patients (46.2%) had no preference. Of the 215 patients who had a preference, 72.1% preferred to wait in a ward corridor (95% CI 65.5-77.8%) and 27.9% preferred the ED corridor (95% CI 22.1-34.5%). Fifty-seven per cent of patients expected to get to their ward bed within 6 h. Seventy-two point one per cent (95% CI 66.3%-77.2%) of patients did not have their expectations met for bed waiting times. Patients would prefer to wait in ward corridors for their ward bed if there was no ED cubicle available. Waiting in the ED corridor is their least preferred option. Patients usually expect to get to their ward bed within 3 h. However, with high levels of access block, patient expectations for waiting times for a bed are usually not met. These findings could be used to drive system changes that are more patient-focussed.


Home Dialysis Utilization Among Racial and Ethnic Minorities in the United States at the National, Regional, and State Level.
♦ BACKGROUND: United States Renal Data System (USRDS) data from 2014 show that African Americans (AA) are underrepresented in the home dialysis population, with 6.4% versus 9.2% utilization in the general populace. This racial disparity may be inaccurately ascribed to the nation as a whole if regional and inter-state variability exists. This investigation sought to examine home dialysis utilization by minority Medicare beneficiary populations across the US nationally, regionally, and by individual state. ♦ METHODS: The 2012 Medicare 100% Outpatient Standard Analytic File was used to identify all Medicare fee-for-service (FFS) patients, with state of residence and race, receiving an outpatient dialysis facility bill type. Peritoneal dialysis (PD) and home hemodialysis (HHD) patients were identified using revenue and condition codes and were defined by having at least one claim during the year that met criteria for the category. Beneficiaries were counted once for each modality used that year. A home dialysis utilization ratio (UR) was calculated as the ratio of the proportion of a minority on PD or HHD within a geographic division to the proportion of Caucasians on PD or HHD within the same geographic division. A UR less than 1.00 indicated under-representation while a UR over 1.00 indicated over-representation. Utilization ratios were compared using a Poisson regression model. ♦ RESULTS: A total of 369,164 Medicare FFS dialysis patients were identified. Within the total cohort, AA were the most underrepresented minority on PD (UR 0.586; 95% confidence interval [CI]: 0.585 - 0.586; p < 0.0001), followed by Hispanics (UR 0.744; 95% CI 0.743 - 0.744; p < 0.0001). The underutilization of PD by AA and Hispanics could not be ascribed to any region of the US, as all regions of the US had UR < 1.00. Only Massachusetts had a UR > 1.00 for AA on PD. Peritoneal dialysis UR values for Asians and those self-identified as Other were 0.954; 95% CI 0.953 - 0.954 and 0.932; 95% CI 0.931 - 0.932, respectively. Nationally, all minorities utilized HHD less than Caucasians. However, more variability existed, with Asians utilizing more HHD than Caucasians in the Midwest. ♦ CONCLUSIONS: Although regional and interstate variability exists, there is near universal under-representation of AA and Hispanics in the home dialysis population, while Asians and Other demonstrate more interregional and interstate variability.


Why Medicare Advantage Plans Pay hospitals traditional Medicare prices.
The policy community generally has assumed Medicare Advantage (MA) plans negotiate hospital payment rates similar to those for commercial insurance products and well above those in traditional Medicare. After surveying senior hospital and health plan executives, we found, however, that MA plans nominally pay only 100-105 percent of traditional Medicare rates and, in real economic terms, possibly less. Respondents broadly identified three primary reasons for near-payment equivalence: statutory and regulatory provisions that limit out-of-network payments to traditional Medicare rates, de facto budget constraints that MA plans face because of the need to compete with traditional Medicare and other MA plans, and a market equilibrium that permits relatively lower MA rates as long as commercial rates remain well above the traditional Medicare rates. We explored a number of policy implications not only for the MA program but also for the problem of high and variable hospital prices in commercial insurance markets.


The SIFK score: a validated predictive model for arthroplasty progression after subchondral insufficiency fractures of the knee.
The purpose of this study was to create a predictive model utilizing baseline demographic and radiographic characteristics for the likelihood that a patient with subchondral insufficiency fracture of the knee will progress to knee arthroplasty with emphasis on clinical interpretability and usability. A retrospective review of baseline and final radiographs in addition to MRIs were reviewed for evaluation of insufficiency fractures and associated injuries. Patient and radiographic factors were used in building predictive models for progression to arthroplasty with Train: Validation: Test subsets. Multiple models were compared with emphasis on clinical utility. Total of 249 patients with a mean age of 64.6 (SD 10.5) years were included. Knee arthroplasty rate was 27% at mean of 4 years of follow-up. Lasso Regression was non-inferior to other models and was chosen for ease of interpretability. In order of importance, predictors for progression to arthroplasty included lateral meniscus extrusion, Kellgren-Lawrence Grade 4, SIFK on MFC, lateral meniscus root tear, and medial meniscus extrusion. The final SIFK Score stratified patients into low-, medium-, and high-risk categories with arthroplasty rates of 8.8%, 40.4%, and 78.9% (p < 0.001) and an area under the curve of 82.5%. In this validated model, lateral meniscus extrusion, K-L Grade 4, SIFK on MFC, lateral meniscus root tear, and medial meniscus extrusion were the most important factors in predicting progression to arthroplasty (in that order). This model assists in patient treatment and counseling in providing prognostic information based on patient-specific risk factors by classifying them into a low-, medium-, and high-risk categories. This model can be used both by medical professionals treating musculoskeletal injuries in guiding patient decision making. Level III.


Structural relationships between human erythrocyte sialoglycoproteins beta and gamma and abnormal sialoglycoproteins found in certain rare human erythrocyte variants lacking the Gerbich blood-group antigen(s).
The human erythrocyte membrane sialoglycoproteins beta and gamma are important for the maintenance of the discoid shape of the normal erythrocyte. In this paper we show that the human erythrocyte sialoglycoproteins beta and gamma (hereafter called beta and gamma) are structurally related. Rabbit antisera produced against purified beta and beta 1 and rendered specific to the cytoplasmic portion of these proteins also react with the cytoplasmic portion of gamma. Some human anti-Gerbich (Ge) sera react with the extracellular portion of both beta and gamma. This reactivity is shown to be directed towards a common epitope on beta and gamma. However, most anti-Ge sera do not react with beta, but react with an extracellular epitope only present on gamma. All individuals who lack the Ge antigens lack beta and gamma. In some cases abnormal sialoglycoproteins are present in the erythrocytes, and these are shown to be structurally related to beta and gamma. Rabbit antisera raised against the purified abnormal sialoglycoprotein from a Ge-negative erythrocyte type reacted with the cytoplasmic portion of both beta and gamma. Unlike normal beta and gamma, the abnormal sialoglycoproteins found in Ge-negative erythrocytes migrate as a diffuse band on SDS/polyacrylamide-gel electrophoresis. Studies using endoglycosidases suggest that the diffuse nature of these bands results from carbohydrate heterogeneity and that the abnormal sialoglycoproteins contain N-glycosidically linked oligosaccharides with repeating lactosamine units. Such polylactosamine chains are not present on normal beta or gamma.


Methylation of cancer related genes in tumor and peripheral blood DNA from the same breast cancer patient as two independent events.
Recently it has been suggested that acquisition of methylation of the BRCA1 promoter detectable in peripheral blood (PB) DNA, could give raise to development of breast cancer. In this study, we aimed to investigate a relationship between methylation of three breast cancer related genes in PB DNA, and tumor specific (somatic) methylation of these genes in the same individual. We have examined methylation status of the BRCA1, APC and RASSF1A promoter regions in a panel of 75 breast tumor and PB DNA samples from the same individual. In our study group, 4.0% of the patients displayed methylation of BRCA1 and APC in both tumor and the corresponding PB DNA. At the same time despite of marked methylation in tumor DNA, no methylation of BRCA1 and APC was seen in PB DNA of 4.3% and 2.7% of the patients respectively. The RASSF1A promoter did not show methylation in PB DNA. Our results show that for at least a subset of cancer patients methylation of certain cancer related genes in PB DNA does not seem to be directly linked to somatic methylation of the same genes in tumor DNA, and therefore may only be specific to PB DNA.


Effect of Trinucleotide Repeat Expansion on the Expression of TCF4 mRNA in Fuchs' Endothelial Corneal Dystrophy.
CTG trinucleotide repeat (TNR) expansion is frequently found in transcription factor 4 (TCF4) in Fuchs' endothelial corneal dystrophy (FECD), though the effect of TNR expansion on FECD pathophysiology remains unclear. The purpose of this study was to evaluate the effect of TNR expansion on TCF4 expression in corneal endothelium of patients with FECD. Peripheral blood DNA and Descemet membrane with corneal endothelium were obtained from 203 German patients with FECD. The CTG TNR repeat length in TCF4 was determined by short tandem repeat (STR) assays and Southern blotting using genomic DNA. Genotyping of rs613872 in TCF4 was performed by PCR. TCF4 mRNA levels in corneal endothelium were evaluated by quantitative PCR using three different probes. Control corneal endothelial samples were obtained from 35 non-FECD subjects. The STR assay and Southern blotting showed that 162 of the 203 patients with FECD (80%) harbored CTG trinucleotide repeat lengths larger than 50. Quantitative PCR using all three probes demonstrated that TCF4 mRNA is significantly upregulated in the corneal endothelium of patients with FECD, regardless of the presence of TNR expansion. However, the length of the TNR tended to show a positive correlation with TCF4 expression level. No correlation was shown between the genotype of TCF4 SNP, rs613872, and the level of TCF4 expression. Our findings showed that TCF4 mRNA is upregulated in the corneal endothelium of patients with FECD. Further studies on the effects of TCF4 upregulation on corneal endothelial cell function will aid in understanding the pathophysiology of FECD.


Structure of the rat gonadotropin releasing hormone (rGnRH) gene promoter and functional analysis in hypothalamic cells.
The gonadotropin releasing hormone (GnRH) gene encodes a protein which plays a critical role in mammalian reproductive physiology. Its expression is predominantly restricted to the hypothalamus although it has also been described in the placenta. To begin to determine the promoter elements important for tissue specific expression and to examine the mechanisms of developmental and hormonal regulation of the rat GnRH (rGnRH) gene, we cloned the rGnRH gene from a rat liver genomic DNA library. The nucleotide sequence of greater than 3 kb of 5'-flanking region was determined. The transcriptional initiation site in rat hypothalamic tissue and a mouse hypothalamic cell line were mapped by primer extension analysis and found to be different. In addition, transient transfection studies demonstrated that multiple regions of the distal promoter are important for tissue specific and basal promoter activity in hypothalamic cells. Furthermore, in these cells a potent activation region resides between -3026 and -1031 bp and suppressor region between -1031 and -903 bp upstream of the transcriptional start site. We conclude that different portions of the 5'-flanking region, which are activating and suppressing in nature, are critical for hypothalamic expression of the rGnRH gene.


Effect of protein and lactulose on the production of gamma-aminobutyric acid by faecal Escherichia coli.
The value of lactulose treatment in hepatic encephalopathy is widely recognised but its mode of action remains controversial. Much evidence supports a role for gamma-aminobutyric acid in hepatic encephalopathy, and lactulose could alter its bacterial production in the gut. Using the rat synaptic membrane assay and gas chromatography mass spectrometry, the production of gamma-aminobutyric acid by faecal Escherichia coli, with and without the addition of albumin, haemoglobin, whole blood, and lactulose under aerobic and anaerobic conditions was determined. Using an inorganic medium, maximal gamma-aminobutyric acid production occurred after a culture period of between 25 and 50 hours. The concentration after 30 hours of aerobic culture at 37 degrees C by a single strain was mean (SEM), 101 (5) mumol/l (99% confidence intervals 87-114 mumol/l; n = 8; interassay coefficient of variation 14.7%). gamma-aminobutyric acid production was significantly increased by the addition of albumin and haemoglobin. Under anerobic conditions, it was one fifth of that produced aerobically, but the addition of albumin and haemoglobin increased production by greater than 700%. Lactulose did not significantly attenuate gamma-aminobutyric acid production under aerobic or anaerobic conditions. gamma-aminobutyric acid determined by the rat synaptic membrane assay showed a highly significant correlation (r = 0.99) with that detected by gas chromatography mass spectrometry. These data confirm that gamma-aminobutyric acid is produced by faecal E coli and that protein enhances its production considerably, and suggest that lactulose does not exert its therapeutic effect by attenuating gamma-aminobutyric acid production.


Nonlinear parameters of surface EMG in schizophrenia patients depend on kind of antipsychotic therapy.
We compared a set of surface EMG (sEMG) parameters in several groups of schizophrenia (SZ, n = 74) patients and healthy controls (n = 11) and coupled them with the clinical data. sEMG records were quantified with spectral, mutual information (MI) based and recurrence quantification analysis (RQA) parameters, and with approximate and sample entropies (ApEn and SampEn). Psychotic deterioration was estimated with Positive and Negative Syndrome Scale (PANSS) and with the positive subscale of PANSS. Neuroleptic-induced parkinsonism (NIP) motor symptoms were estimated with Simpson-Angus Scale (SAS). Dyskinesia was measured with Abnormal Involuntary Movement Scale (AIMS). We found that there was no difference in values of sEMG parameters between healthy controls and drug-naïve SZ patients. The most specific group was formed of SZ patients who were administered both typical and atypical antipsychotics (AP). Their sEMG parameters were significantly different from those of SZ patients taking either typical or atypical AP or taking no AP. This may represent a kind of synergistic effect of these two classes of AP. For the clinical data we found that PANSS, SAS, and AIMS were not correlated to any of the sEMG parameters. with nonlinear parameters of sEMG it is possible to reveal NIP in SZ patients, and it may help to discriminate between different clinical groups of SZ patients. Combined typical and atypical AP therapy has stronger effect on sEMG than a therapy with AP of only one class.


Integrating count and detection-nondetection data to model population dynamics.
There is increasing need for methods that integrate multiple data types into a single analytical framework as the spatial and temporal scale of ecological research expands. Current work on this topic primarily focuses on combining capture-recapture data from marked individuals with other data types into integrated population models. Yet, studies of species distributions and trends often rely on data from unmarked individuals across broad scales where local abundance and environmental variables may vary. We present a modeling framework for integrating detection-nondetection and count data into a single analysis to estimate population dynamics, abundance, and individual detection probabilities during sampling. Our dynamic population model assumes that site-specific abundance can change over time according to survival of individuals and gains through reproduction and immigration. The observation process for each data type is modeled by assuming that every individual present at a site has an equal probability of being detected during sampling processes. We examine our modeling approach through a series of simulations illustrating the relative value of count vs. detection-nondetection data under a variety of parameter values and survey configurations. We also provide an empirical example of the model by combining long-term detection-nondetection data (1995-2014) with newly collected count data (2015-2016) from a growing population of Barred Owl (Strix varia) in the Pacific Northwest to examine the factors influencing population abundance over time. Our model provides a foundation for incorporating unmarked data within a single framework, even in cases where sampling processes yield different detection probabilities. This approach will be useful for survey design and to researchers interested in incorporating historical or citizen science data into analyses focused on understanding how demographic rates drive population abundance.


Do Differences in Work Disability Duration Between Men and Women Vary by Province in Canada?
Purpose Research has shown that there are important sex and gender-based differences in the work disability duration of men and women. This research is often limited to single jurisdictions, using different outcome measures, and therefore has limited generalisability of findings. This study examined if differences between work disability of men and women differed by province and by duration of work disability. Methods Cohorts of injured workers in the Canadian provinces of British Columbia (BC), Manitoba (MB) and Ontario (ON) were analysed using workers' compensation data for work-related injuries occurring between 2007 and 2011. Work disability duration was measured using cumulative days in receipt of disability benefits paid during one-year post-injury. Poisson models with restricted cubic splines tested whether differences between men and women in the likelihood of transitioning off disability benefits varied by duration of work disability in each province, adjusting for confounders. Results Men transitioned off disability benefits faster than women for claim durations of up to two to four months, after which women transitioned off disability benefits faster until ten months. Differences between men and women were consistent across all jurisdictions. For claims longer than ten months, men transitioned off work disability benefits faster than women in BC and ON, but there were no significant differences between men and women in MB. Conclusions Differences in the work disability duration between men and women vary by province and duration of work disability. Claims management processes need to be sensitive to differences that men and women face and the timing of interventions.


Hyperleukocytosis and leukostasis: management of a medical emergency.
Hyperleukocytosis is defined as a white blood cell count greater than 100,000/mL in patients affected by acute leukemia and often it is associated with increased morbidity and mortality, that can be up to 40% if unrecognized. Areas covered: Risk factors include younger age, myelomonocytic or monocytic/monoblastic morphology, microgranular variant of acute promyelocitic leukemia and T-cell ALL, and some cytogenetic abnormalities. Poor prognosis due to high early death rate secondary to leukostasis. The mechanisms at the origin of leukostasis are still poorly understood. The management of acute hyperleukocytosis and leukostasis involves supportive measures and reducing the number of circulating leukemic blast cells, with careful monitoring of fluid balance, control of uric acid production and control of urine pH to prevent tumour lysis syndrome. Expert commentary: Several studies have been performed to ameliorate the outcome of this setting of patients. The high number of leukocytes may cause 3 main complications: disseminated intravascular coagulation (DIC), tumor lysis syndrome (TLS), and leukostasis. Although hyperleukocytosis and tumour lysis syndrome are still a challenge for clinicians, a better prognosis for these conditions is emerging in the last years.


Multiple myeloma exhibits novel dependence on GLUT4, GLUT8, and GLUT11: implications for glucose transporter-directed therapy.
Multiple myeloma is one of numerous malignancies characterized by increased glucose consumption, a phenomenon with significant prognostic implications in this disease. Few studies have focused on elucidating the molecular underpinnings of glucose transporter (GLUT) activation in cancer, knowledge that could facilitate identification of promising therapeutic targets. To address this issue, we performed gene expression profiling studies involving myeloma cell lines and primary cells as well as normal lymphocytes to uncover deregulated GLUT family members in myeloma. Our data demonstrate that myeloma cells exhibit reliance on constitutively cell surface-localized GLUT4 for basal glucose consumption, maintenance of Mcl-1 expression, growth, and survival. We also establish that the activities of the enigmatic transporters GLUT8 and GLUT11 are required for proliferation and viability in myeloma, albeit because of functionalities probably distinct from whole-cell glucose supply. As proof of principle regarding the therapeutic potential of GLUT-targeted compounds, we include evidence of the antimyeloma effects elicited against both cell lines and primary cells by the FDA-approved HIV protease inhibitor ritonavir, which exerts a selective off-target inhibitory effect on GLUT4. Our work reveals critical roles for novel GLUT family members and highlights a therapeutic strategy entailing selective GLUT inhibition to specifically target aberrant glucose metabolism in cancer.


COVID-19-related Multisystem Inflammatory Syndrome in a Young Adult.
A condition called multisystem inflammatory syndrome in children (MIS-C), related to past SARS-CoV-2 infection, has been described in a series of cases. There is a growing body of evidence suggesting a similar entity in adults (MIS-A). We report a case of a young adult with a hyperinflammatory systemic syndrome with end-organ lesions and a recent SARS-CoV-2 infection. The patient developed end-organ lesions in the respiratory, cardiovascular, digestive, haematological and mucocutaneous systems. A wide diagnostic work-up did not find any specific aetiology (autoimmunity, neoplastic or infectious). There was evidence of past SARS-CoV-2 infection with positive autoimmune titres (positive IgG). A presumptive diagnosis of MIS-A was made and treatment with corticosteroids was introduced with improvement. COVID-19-related multisystem inflammatory syndrome in adults is still an unknown entity with no diagnostic criteria or treatment guidelines. Much of what is known is inferred from what we already know about MIS-C. There have been several reported cases with severity ranging from mild to severe. The mechanisms behind this condition are still largely unknown. More evidence is needed to establish diagnosis and treatment. COVID-19-related multisystem inflammatory syndrome in adults is a new entity with few case reports.Awareness is important for early diagnosis and treatment.


Production of granulocyte colony-stimulating factor in vitro by monocytes from preterm and term neonates.
We postulated that defective generation of granulocyte colony-stimulating factor (G-CSF) by cells of newborn infants might underlie their deficiencies in upregulating neutrophil production and function during bacterial infection. To test this, we isolated monocytes from the blood of preterm neonates, term neonates, and adults and, after stimulation with various concentrations of interleukin-1 alpha (IL-1 alpha) or lipopolysaccharide (LPS), quantified G-CSF concentrations in cell supernatants and G-CSF mRNA in cell lysates. When stimulated with plateau concentrations of IL-1 alpha for 24 hours, G-CSF concentrations were higher in supernatants of adult cells (8,699 +/- 5,529 pg/10(6) monocytes) than in those from term infants (2,557 +/- 442 pg, P < .05) or from preterm infants (879 +/- 348 pg, P < .05 v adults). When stimulated with plateau concentrations of LPS, supernatants of monocytes from preterm neonates had less G-CSF than did those from term neonates or adults. G-CSF mRNA content was low in cells from preterm infants, higher in those from term infants, and highest in those from adults. On the basis of the in vitro studies, we speculated that serum G-CSF concentrations might be less elevated in neutropenic neonates than in neutropenic adults. Indeed, serum concentrations were relatively low in all nonneutropenic subjects; 92 +/- 34 pg/mL (mean +/- SEM) in 10 preterm neonates, 114 +/- 21 pg/mL in 16 term neonates, and 45 +/- 13 pg/mL in 11 healthy adults. Serum concentrations were not elevated in 7 neutropenic neonates (39 +/- 17 pg/mL) but were in 8 neutropenic adults (2101 +/- 942 pg/mL, P < .05 v healthy adults). Other studies suggested that the lower G-CSF production in neonates is not counterbalanced by a heightened sensitivity of G-CSF--responsive progenitors to G-CSF. Therefore, we speculate that newborn infants, particularly those delivered prematurely, generate comparatively low quantities of G-CSF after inflammatory stimulation, and that this might constitute part of the explanation for their defective upregulation of neutrophil production and function during infection.


Instantaneous threat escape and differentiated refuge demand among zooplankton taxa.
Most animals, including aquatic crustacean zooplankton, perform strong avoidance movements when exposed to a threat, such as ultraviolet radiation (UVR). We here show that the genera Daphnia and Bosmina instantly adjust their vertical position in the water in accordance with the present UVR threat, i.e., seek refuge in deeper waters, whereas other taxa show less response to the threat. Moreover, Daphnia repeatedly respond to UVR pulses, suggesting that they spend more energy on movement than more stationary taxa, for example, during days with fluctuating cloud cover, illustrating nonlethal effects in avoiding UVR threat. Accordingly, we also show that the taxa with the most contrasting behavioral responses differ considerably in photoprotection, suggesting different morphological and behavioral strategies in handling the UVR threat. In a broader context, our studies on individual and taxa specific responses to UVR provide insights into observed spatial and temporal distribution in natural ecosystems.


On the role of cross-immunity and vaccines on the survival of less fit flu-strains.
A pathogen's route to survival involves various mechanisms including its ability to invade (host's susceptibility) and its reproductive success within an invaded host ("infectiousness"). The immunological history of an individual often plays an important role in reducing host susceptibility or it helps the host mount a faster immunological response de facto reducing infectiousness. The cross-immunity generated by prior infections to influenza A strains from the same subtype provide a significant example. The results of this paper are based on the analytical study of a two-strain epidemic model that incorporates host isolation (during primary infection) and cross-immunity to study the role of invasion mediated cross-immunity in a population where a precursor related strain (within the same subtype, i.e. H3N2, H1N1) has already become established. An uncertainty and sensitivity analysis is carried out on the ability of the invading strain to survive for given cross-immunity levels. Our findings indicate that it is possible to support coexistence even in the case when invading strains are "unfit", that is, when the basic reproduction number of the invading strain is less than one. However, such scenarios are possible only in the presence of isolation. That is, appropriate increments in isolation rates and weak cross-immunity can facilitate the survival of less fit strains. The development of "flu" vaccines that minimally enhance herd cross-immunity levels may, by increasing genotype diversity, help facilitate the generation and survival of novel strains.


Using health status to measure NHS performance: another step into the dark for the health reform in England.
The National Health Service in England is moving away from targets based on processes of care and focusing on patient outcomes. This vision is operationalised in the recently published NHS Outcomes Framework, which includes the generalised use of Patient Reported Outcomes (health status and quality of life) as measures of population health at the provider level. This is the first time that such a bold initiative is attempted in the UK and it is not without risks. In this article we elaborate on our experience on the use of Patient Reported Outcomes and identify challenges and likely implications of this approach and suggest less disruptive alternatives.


Collective information processing and pattern formation in swarms, flocks, and crowds.
The spontaneous organization of collective activities in animal groups and societies has attracted a considerable amount of attention over the last decade. This kind of coordination often permits group-living species to achieve collective tasks that are far beyond single individuals' capabilities. In particular, a key benefit lies in the integration of partial knowledge of the environment at the collective level. In this contribution, we discuss various self-organization phenomena in animal swarms and human crowds from the point of view of information exchange among individuals. In particular, we provide a general description of collective dynamics across species and introduce a classification of these dynamics not only with respect to the way information is transferred among individuals but also with regard to the knowledge processing at the collective level. Finally, we highlight the fact that the individual's ability to learn from past experiences can have a feedback effect on the collective dynamics, as experienced with the development of behavioral conventions in pedestrian crowds.


Interactions of GGA3 with the ubiquitin sorting machinery.
The Golgi-localized, gamma-ear-containing, Arf-binding (GGA) proteins constitute a family of clathrin adaptors that are mainly associated with the trans-Golgi network (TGN) and mediate the sorting of mannose 6-phosphate receptors. This sorting is dependent on the interaction of the VHS domain of the GGAs with acidic-cluster-dileucine signals in the cytosolic tails of the receptors. Here we demonstrate the existence of another population of GGAs that are associated with early endosomes. RNA interference (RNAi) of GGA3 expression results in accumulation of the cation-independent mannose 6-phosphate receptor and internalized epidermal growth factor (EGF) within enlarged early endosomes. This perturbation impairs the degradation of internalized EGF, a process that is normally dependent on the sorting of ubiquitinated EGF receptors (EGFRs) to late endosomes. Protein interaction analyses show that the GGAs bind ubiquitin. The VHS and GAT domains of GGA3 are responsible for this binding, as well as for interactions with TSG101, a component of the ubiquitin-dependent sorting machinery. Thus, GGAs may have additional roles in sorting of ubiquitinated cargo.


Interictal to ictal transition in human temporal lobe epilepsy: insights from a computational model of intracerebral EEG.
In human partial epilepsies and in experimental models of chronic and/or acute epilepsy, the role of inhibition and the relationship between the inhibition and excitation and epileptogenesis has long been questioned. Besides experimental methods carried out either in vitro (human or animal tissue) or in vivo (animals), pathophysiologic mechanisms can be approached by direct recording of brain electrical activity in human epilepsy. Indeed, in some clinical presurgical investigation methods like stereoelectroencephalography, intracerebral electrodes are used in patients suffering from drug resistant epilepsy to directly record paroxysmal activities with excellent temporal resolution (in the order of 1 millisecond). The study of neurophysiologic mechanisms underlying such depth-EEG activities is crucial to progress in the understanding of the interictal to ictal transition. In this study, the authors relate electrophysiologic patterns typically observed during the transition from interictal to ictal activity in human mesial temporal lobe epilepsy (MTLE) to mechanisms (at a neuronal population level) involved in seizure generation through a computational model of EEG activity. Intracerebral EEG signals recorded from hippocampus in five patients with MTLE during four periods (during interictal activity, just before seizure onset, during seizure onset, and during ictal activity) were used to identify the three main parameters of a model of hippocampus EEG activity (related to excitation, slow dendritic inhibition and fast somatic inhibition). The identification procedure used optimization algorithms to minimize a spectral distance between real and simulated signals. Results demonstrated that the model generates very realistic signals for automatically identified parameters. They also showed that the transition from interictal to ictal activity cannot be simply explained by an increase in excitation and a decrease in inhibition but rather by time-varying ensemble interactions between pyramidal cells and local interneurons projecting to either their dendritic or perisomatic region (with slow and fast GABAA kinetics). Particularly, during preonset activity, an increasing dendritic GABAergic inhibition compensates a gradually increasing excitation up to a brutal drop at seizure onset when faster oscillations (beta and low gamma band, 15 to 40 Hz) are observed. These faster oscillations are then explained by the model feedback loop between pyramidal cells and interneurons targeting their perisomatic region. These findings obtained from model identification in human temporal lobe epilepsy are in agreement with some results obtained experimentally, either on animal models of epilepsy or on the human epileptic tissue.


Online dietary intake estimation: reproducibility and validity of the Food4Me food frequency questionnaire against a 4-day weighed food record.
Advances in nutritional assessment are continuing to embrace developments in computer technology. The online Food4Me food frequency questionnaire (FFQ) was created as an electronic system for the collection of nutrient intake data. To ensure its accuracy in assessing both nutrient and food group intake, further validation against data obtained using a reliable, but independent, instrument and assessment of its reproducibility are required. The aim was to assess the reproducibility and validity of the Food4Me FFQ against a 4-day weighed food record (WFR). Reproducibility of the Food4Me FFQ was assessed using test-retest methodology by asking participants to complete the FFQ on 2 occasions 4 weeks apart. To assess the validity of the Food4Me FFQ against the 4-day WFR, half the participants were also asked to complete a 4-day WFR 1 week after the first administration of the Food4Me FFQ. Level of agreement between nutrient and food group intakes estimated by the repeated Food4Me FFQ and the Food4Me FFQ and 4-day WFR were evaluated using Bland-Altman methodology and classification into quartiles of daily intake. Crude unadjusted correlation coefficients were also calculated for nutrient and food group intakes. In total, 100 people participated in the assessment of reproducibility (mean age 32, SD 12 years), and 49 of these (mean age 27, SD 8 years) also took part in the assessment of validity. Crude unadjusted correlations for repeated Food4Me FFQ ranged from .65 (vitamin D) to .90 (alcohol). The mean cross-classification into "exact agreement plus adjacent" was 92% for both nutrient and food group intakes, and Bland-Altman plots showed good agreement for energy-adjusted macronutrient intakes. Agreement between the Food4Me FFQ and 4-day WFR varied, with crude unadjusted correlations ranging from .23 (vitamin D) to .65 (protein, % total energy) for nutrient intakes and .11 (soups, sauces and miscellaneous foods) to .73 (yogurts) for food group intake. The mean cross-classification into "exact agreement plus adjacent" was 80% and 78% for nutrient and food group intake, respectively. There were no significant differences between energy intakes estimated using the Food4Me FFQ and 4-day WFR, and Bland-Altman plots showed good agreement for both energy and energy-controlled nutrient intakes. The results demonstrate that the online Food4Me FFQ is reproducible for assessing nutrient and food group intake and has moderate agreement with the 4-day WFR for assessing energy and energy-adjusted nutrient intakes. The Food4Me FFQ is a suitable online tool for assessing dietary intake in healthy adults.


National climate policies across Europe and their impacts on cities strategies.
Globally, efforts are underway to reduce anthropogenic greenhouse gas emissions and to adapt to climate change impacts at the local level. However, there is a poor understanding of the relationship between city strategies on climate change mitigation and adaptation and the relevant policies at national and European level. This paper describes a comparative study and evaluation of cross-national policy. It reports the findings of studying the climate change strategies or plans from 200 European cities from Austria, Belgium, Estonia, Finland, France, Germany, Ireland, Italy, Netherlands, Spain and the United Kingdom. The study highlights the shared responsibility of global, European, national, regional and city policies. An interpretation and illustration of the influences from international and national networks and policy makers in stimulating the development of local strategies and actions is proposed. It was found that there is no archetypical way of planning for climate change, and multiple interests and motivations are inevitable. Our research warrants the need for a multi-scale approach to climate policy in the future, mainly ensuring sufficient capacity and resource to enable local authorities to plan and respond to their specific climate change agenda for maximising the management potentials for translating environmental challenges into opportunities.


The Effect of Passive Heat Stress and Exercise-Induced Dehydration on the Compensatory Reserve During Simulated Hemorrhage.
Compensatory reserve represents the proportion of physiological responses engaged to compensate for reductions in central blood volume before the onset of decompensation. We hypothesized that compensatory reserve would be reduced by hyperthermia and exercise-induced dehydration, conditions often encountered on the battlefield. Twenty healthy males volunteered for two separate protocols during which they underwent lower-body negative pressure (LBNP) to hemodynamic decompensation (systolic blood pressure <80 mm Hg). During protocol #1, LBNP was performed following a passive increase in core temperature of ∼1.2°C (HT) or a normothermic time-control period (NT). During protocol #2, LBNP was performed following exercise during which: fluid losses were replaced (hydrated), fluid intake was restricted and exercise ended at the same increase in core temperature as hydrated (isothermic dehydrated), or fluid intake was restricted and exercise duration was the same as hydrated (time-match dehydrated). Compensatory reserve was estimated with the compensatory reserve index (CRI), a machine-learning algorithm that extracts features from continuous photoplethysmograph signals. Prior to LBNP, CRI was reduced by passive heating [NT: 0.87 (SD 0.09) vs. HT: 0.42 (SD 0.19) units, P <0.01] and exercise-induced dehydration [hydrated: 0.67 (SD 0.19) vs. isothermic dehydrated: 0.52 (SD 0.21) vs. time-match dehydrated: 0.47 (SD 0.25) units; P <0.01 vs. hydrated]. During subsequent LBNP, CRI decreased further and its rate of change was similar between conditions. CRI values at decompensation did not differ between conditions. These results suggest that passive heating and exercise-induced dehydration limit the body's physiological reserve to compensate for further reductions in central blood volume.


Heritabilities, proportions of heritabilities explained by GWAS findings, and implications of cross-phenotype effects on PR interval.
Electrocardiogram (ECG) measurements are a powerful tool for evaluating cardiac function and are widely used for the diagnosis and prediction of a variety of conditions, including myocardial infarction, cardiac arrhythmias, and sudden cardiac death. Recently, genome-wide association studies (GWASs) identified a large number of genes related to ECG parameter variability, specifically for the QT, QRS, and PR intervals. The aims of this study were to establish the heritability of ECG traits, including indices of left ventricular hypertrophy, and to directly assess the proportion of those heritabilities explained by GWAS variants. These analyses were conducted in a large, Dutch family-based cohort study, the Erasmus Rucphen Family study using variance component methods implemented in the SOLAR (Sequential Oligogenic Linkage Analysis Routines) software package. Heritability estimates ranged from 34% for QRS and Cornell voltage product to 49% for 12-lead sum. Trait-specific GWAS findings for each trait explained a fraction of their heritability (17% for QRS, 4% for QT, 2% for PR, 3% for Sokolow-Lyon index, and 4% for 12-lead sum). The inclusion of all ECG-associated single nucleotide polymorphisms explained an additional 6% of the heritability of PR. In conclusion, this study shows that, although GWAS explain a portion of ECG trait variability, a large amount of heritability remains to be explained. In addition, larger GWAS for PR are likely to detect loci already identified, particularly those observed for QRS and 12-lead sum.


Disodium cromoglycate in the treatment of chronic proctitis.
The effect of topical disodium cromoglycate (DSCG) has been examined in 30 patients with chronic active proctitis using a double-blind crossover trial. Each treatment period was four weeks and patients were given DSCG 200 mg by enema twice daily and 100 mg orally three times each day. Twenty-six patients completed the trial successfully, 14 responded to DSCG treatment, two improved with placebo, and 10 responded to neither. Patients who responded to DSCG had significantly more eosinophils in their rectal biopsies than those who failed to respond and in some instances the counts were very high. The findings support the hypothesis than an allergic reaction is important in the pathogenesis of proctitis.


Single molecule FRET characterization of large ribozyme folding.
A procedure to investigate the folding of group II intron by single molecule Fluorescence Resonance Energy Transfer (smFRET) using total internal reflection fluorescence microscopy (TIRFM) is described in this chapter. Using our previous studies on the folding and dynamics of a large ribozyme in the presence of metal ions (i.e., Mg(2+) and Ca(2+)) and/or the DEAD-box protein Mss116 as an example, we here describe step-by-step procedures to perform experiments. smFRET allows the investigation of individual molecules, thus, providing kinetic and mechanistic information hidden in ensemble averaged experiments.


Cyclin D3 promotes pancreatic β-cell fitness and viability in a cell cycle-independent manner and is targeted in autoimmune diabetes.
Type 1 diabetes is an autoimmune condition caused by the lymphocyte-mediated destruction of the insulin-producing β cells in pancreatic islets. We aimed to identify final molecular entities targeted by the autoimmune assault on pancreatic β cells that are causally related to β cell viability. Here, we show that cyclin D3 is targeted by the autoimmune attack on pancreatic β cells in vivo. Cyclin D3 is down-regulated in a dose-dependent manner in β cells by leukocyte infiltration into the islets of the nonobese diabetic (NOD) type 1 diabetes-prone mouse model. Furthermore, we established a direct in vivo causal link between cyclin D3 expression levels and β-cell fitness and viability in the NOD mice. We found that changes in cyclin D3 expression levels in vivo altered the β-cell apoptosis rates, β-cell area homeostasis, and β-cell sensitivity to glucose without affecting β-cell proliferation in the NOD mice. Cyclin D3-deficient NOD mice exhibited exacerbated diabetes and impaired glucose responsiveness; conversely, transgenic NOD mice overexpressing cyclin D3 in β cells exhibited mild diabetes and improved glucose responsiveness. Overexpression of cyclin D3 in β cells of cyclin D3-deficient mice rescued them from the exacerbated diabetes observed in transgene-negative littermates. Moreover, cyclin D3 overexpression protected the NOD-derived insulinoma NIT-1 cell line from cytokine-induced apoptosis. Here, for the first time to our knowledge, cyclin D3 is identified as a key molecule targeted by autoimmunity that plays a nonredundant, protective, and cell cycle-independent role in β cells against inflammation-induced apoptosis and confers metabolic fitness to these cells.


LMCD1 antisense RNA 1 is a newly identified long noncoding RNA.
Long noncoding RNAs (lncRNAs) are one of the interesting fields in cancer researches. LncRNAs are generally dysregulated in many diseases. LMCD1 antisense RNA 1 (LMCD1-AS1) is a newly identified lncRNA with protumorigenic functions on tumor cells. LMCD1-AS1 expression is increased in hepatocellular carcinoma (HCC). LMCD1-AS1 is a sponge of miR-106b-5p activity. LMCD1-AS1 modulates the survival of osteosarcoma via targeting miR-106b-5p. LMCD1-AS1 and Sp1 are highly expressed in osteosarcoma. SP1 can bind to the promoter region of LMCD1-AS1, resulting in its overexpression in osteosarcoma. GLI2 is shown to bind to the LMCD1-AS1 promoter and is transcriptionally activated by LMCD1-AS1. LMCD1 acts as a miR-1287-5p sponge to increase GLI2 expression. LMCD1 is abundantly expressed in kidney tissue. Moreover, it is functionally involved in protein-protein interactions with transcriptional co-repressor activity, including regulation of the calcineurin-NFAT signaling cascade known to play a critical role in recovery from acute kidney injury (AKI). The E2F1/LMCD1-AS1/miR-345-5p/COL6A3 axis is a newly identified regulatory mechanism, which has a function in cholangiocarcinoma (CCA) tumorigenesis and progression and provides potential therapeutic targets for CCA. Also, LMCD1-AS1 functions in thyroid cancer (THCA) development. LMCD1-AS1 is overexpressed in THCA cells, and LMCD1-AS1 knockdown suppresses the malignant phenotypes of THCA cells. In THCA development, LMCD1-AS1 exerts protumorigenic function through sponging miR-1287-5p to increase GLI2 expression, constituting a feedback loop of LMCD1-AS1/miR-1287-5p/GLI2. In this review, the author focuses on the molecular mechanisms of newly identified long noncoding RNA LMCD1 antisense RNA 1 (LMCD1-AS1).


Synaptotagmin C2A loop 2 mediates Ca2+-dependent SNARE interactions essential for Ca2+-triggered vesicle exocytosis.
Synaptotagmins contain tandem C2 domains and function as Ca(2+) sensors for vesicle exocytosis but the mechanism for coupling Ca(2+) rises to membrane fusion remains undefined. Synaptotagmins bind SNAREs, essential components of the membrane fusion machinery, but the role of these interactions in Ca(2+)-triggered vesicle exocytosis has not been directly assessed. We identified sites on synaptotagmin-1 that mediate Ca(2+)-dependent SNAP25 binding by zero-length cross-linking. Mutation of these sites in C2A and C2B eliminated Ca(2+)-dependent synaptotagmin-1 binding to SNAREs without affecting Ca(2+)-dependent membrane binding. The mutants failed to confer Ca(2+) regulation on SNARE-dependent liposome fusion and failed to restore Ca(2+)-triggered vesicle exocytosis in synaptotagmin-deficient PC12 cells. The results provide direct evidence that Ca(2+)-dependent SNARE binding by synaptotagmin is essential for Ca(2+)-triggered vesicle exocytosis and that Ca(2+)-dependent membrane binding by itself is insufficient to trigger fusion. A structure-based model of the SNARE-binding surface of C2A provided a new view of how Ca(2+)-dependent SNARE and membrane binding occur simultaneously.


Training faculty in nontechnical skill assessment: national guidelines on program requirements.
To develop guidelines for a faculty training program in nontechnical skill assessment in surgery. Nontechnical skills in the operating room are critical for patient safety. The successful integration of these skills into workplace-based assessment is dependent upon the availability of faculty who are able to teach and assess them. At present, no guidelines exist regarding the training requirements for such faculty in surgical contexts. The development of the guidelines was carried out in several stages: stage 1-a detailed literature review on current training for nontechnical skill assessors; stage 2-semistructured interviews with a multidisciplinary panel (consisting of clinicians and psychologists/human factors specialists) of experts in surgical nontechnical skills; and stage 3-interview findings fed into an Expert Consensus Panel (ECP) Delphi approach to establish consensus regarding training requirements for faculty assessing nontechnical skills in surgery. The ECP agreed that training in nontechnical skill assessment should be delivered by a multidisciplinary team consisting of clinicians and psychologists/human factors specialists. The ECP reached consensus regarding who should be targeted to be trained as faculty (including proficiency and revalidation requirements). Consensus was reached on 7 essential training program content elements (including training in providing feedback/debriefing) and 8 essential methods of evaluating the effectiveness of a "train-the-trainers" program. This study provides evidence-based guidelines that can be used to guide the development and evaluation of programs to educate faculty in the training and assessment of nontechnical skills. Uptake of these guidelines could accelerate the development of surgical expertise required for safe and high-quality patient care.


Mass Casualty Incidents in the Underground Mining Industry: Applying the Haddon Matrix on an Integrative Literature Review.
Underground mining is associated with obvious risks that can lead to mass casualty incidents. Information about such incidents was analyzed in an integrated literature review. A literature search (1980-2015) identified 564 modern-era underground mining reports from countries sharing similar occupational health legislation. These reports were condensed to 31 reports after consideration of quality grading and appropriateness to the aim. The Haddon matrix was used for structure, separating human factors from technical and environmental details, and timing. Most of the reports were descriptive regarding injury-creating technical and environmental factors. The influence of rock characteristics was an important pre-event environmental factor. The organic nature of coal adds risks not shared in hard-rock mines. A sequence of mechanisms is commonly described, often initiated by a human factor in interaction with technology and step-wise escalation to involve environmental circumstances. Socioeconomic factors introduce heterogeneity. In the Haddon matrix, emergency medical services are mainly a post-event environmental issue, which were not well described in the available literature. The US Quecreek Coal Mine incident of 2002 stands out as a well-planned rescue mission. Evaluation of the preparedness to handle underground mining incidents deserves further scientific attention. Preparedness must include the medical aspects of rescue operations. (Disaster Med Public Health Preparedness. 2018;12:138-146).


Supraventricular tachycardia. ECG diagnosis and anatomy.
This paper reviews the anatomical substrates responsible for the induction and maintenance of supraventricular tachycardia and discusses the ECG findings associated with these tachycardias. The normal anatomy of the supraventricular conducting system, particularly within the atria, is complex with conduction proceeding along preferential pathway, which are in turn determined in part by the anisotropic properties of the atrial myocardium. There appear to be at least dual inputs to the atrioventricular node, a posteriorly situated slow pathway and an anterior fast pathway. It is sometimes possible to relate ECG findings directly to anatomical substrates; for example, in some cases of atrial tachycardia the site of the atrial focus (left or right, superior or inferior) can be determined by the polarity of the P wave. The anatomical substrates responsible for intra-atrial re-entry, atrial flutter and atrial fibrillation relate to anatomical barriers to impulse propagation and areas of slow conduction. In atrial flutter the crista terminalis, Eustachian valve, inferior vena cava, coronary sinus os, and tricuspid annulus have been identified as anatomical barriers to conduction around which a macro re-entrant circuit within the right atrium may conduct, usually in a counter-clockwise direction. Clockwise direction of conduction, and other mechanisms of tachycardia, occur in some of the less typical forms of atrial fluter. Atrial fibrillation is caused by multiple wavelets which randomly conduct through the atrial myocardium and are responsible for the irregular 'fibrillation waves' on the ECG. Supraventricular tachycardia presents as a narrow complex tachycardia unless pre-existing or rate-related bundle branch block is present. Less common causes for a broad complex tachycardia occurring in supraventricular tachycardia include an accessory atrioventricular or atriofascicular pathway conducting antegradely during tachycardia, or accessory pathway participation as a bystander during supraventricular tachycardia. ECG features which can help to distinguish between atrioventricular nodal re-entrant tachycardia and atrioventricular re-entrant tachycardia include: (1) the presence of a delta wave during sinus rhythm which is highly suggestive of atrioventricular re-entrant tachycardia as the mechanism of supraventricular tachycardia; (2) the finding of a pseudo s (lead II) or pseudo r' (lead V1) during tachycardia in atrioventricular nodal re-entrant tachycardia; (3) lengthening of the tachycardia cycle length in cases of atrioventricular re-entrant tachycardia when bundle branch block occurs ipsilateral to the accessory pathway and (4) the finding of QRS alternans during tachycardia which is suggestive of atrioventricular re-entrant tachycardia. "Long RP' tachycardia may be caused by an atrial tachycardia due to an inferiorly situated area of abnormal automaticity, atypical atrioventricular nodal re-entrant tachycardia with slow retrograde conduction, or atrioventricular re-entrant tachycardia with an accessory pathway conducting slowly from ventricle to atrium during tachycardia.


Protein complexes in cells by AI-assisted structural proteomics.
Accurately modeling the structures of proteins and their complexes using artificial intelligence is revolutionizing molecular biology. Experimental data enable a candidate-based approach to systematically model novel protein assemblies. Here, we use a combination of in-cell crosslinking mass spectrometry and co-fractionation mass spectrometry (CoFrac-MS) to identify protein-protein interactions in the model Gram-positive bacterium Bacillus subtilis. We show that crosslinking interactions prior to cell lysis reveals protein interactions that are often lost upon cell lysis. We predict the structures of these protein interactions and others in the SubtiWiki database with AlphaFold-Multimer and, after controlling for the false-positive rate of the predictions, we propose novel structural models of 153 dimeric and 14 trimeric protein assemblies. Crosslinking MS data independently validates the AlphaFold predictions and scoring. We report and validate novel interactors of central cellular machineries that include the ribosome, RNA polymerase, and pyruvate dehydrogenase, assigning function to several uncharacterized proteins. Our approach uncovers protein-protein interactions inside intact cells, provides structural insight into their interaction interfaces, and is applicable to genetically intractable organisms, including pathogenic bacteria.


Impact of dose-distribution uncertainties on rectal ntcp modeling. II: Uncertainty implications.
A trial of nonescalated conformal versus conventional radiotherapy treatment of prostate cancer has been carried out at the Royal Marsden NHS Trust (RMH) and Institute of Cancer Research (ICR), demonstrating a significant reduction in the rate of rectal bleeding reported for patients treated using the conformal technique. The rate of bleeding has been shown to fall significantly as the extent of rectal wall receiving a planned dose-level in excess of 57 Gy is reduced. Dose-distributions delivered to the rectal wall over the course of radiotherapy treatment inevitably differ from planned distributions. In a previous paper estimates were obtained of the uncertainties in some planned rectal dose-distribution parameters generated by patient setup error, rectal wall movement and the variable degree of rectal wall distension. Here these uncertainties are combined to obtain estimates of the total planning uncertainties in rectal dose-distribution parameters thought likely, on the basis of mechanistic biological modeling, to correlate strongly with the complication rate. Working from these totaled uncertainty values, together with values of patient-to-patient and technique-to-technique differences in planned dose-distribution parameters, it can be inferred that the rectal dose-distribution uncertainties: (i) Have only a marginal impact on fits of a normal tissue complication probability (ntcp) model to RMH/ICR dose-distribution and grade 1, 2, 3 bleeding data (slightly flattening observed volume-response curves); (ii) only slightly reduce the power of a 2 x 100 patient trial of conformal versus conventional prostate radiotherapy to detect a significantly lower rate of grade 1,2,3 rectal bleeding amongst conformally treated patients; (iii) do not diminish the information content of individual planned patient dose-distribution data to the point where the fitting of technique-averaged data would provide as sensitive a test of the existence of a volume effect as the fitting of individual patient data.


Soluble thrombopoietin receptor (Mpl) and granulocyte colony-stimulating factor receptor directly stimulate proliferation of primitive hematopoietic progenitors of mice in synergy with steel factor or the ligand for Flt3/Flk2.
In an effort to establish the specificity of the thrombopoietin (TPO) effects on murine multipotential progenitors, we tested the effects of soluble TPO receptor (sTPOR; sMpl) on multilineage colony formation that was supported by a combination of TPO and steel factor (SF). Surprisingly, sTPOR did not suppress colony formation from primitive progenitors. This led to the discovery that sTPOR synergizes with SF or Flt3/Flk2 ligand (FL) to support the formation of various types of hematopoietic colonies including multilineage colonies. The colonies supported by the combination of sTPOR and SF were capable of expressing both myeloid and B-lymphoid potentials. Studies using micromanipulation and serum-free culture showed that the effects of sTPOR and SF on the primitive progenitors are direct, not mediated by contaminating stromal cells, and not dependent on factors present in the serum. TPOR belongs to the cytokine receptor group that includes granulocyte colony-stimulating factor receptor (G-CSFR) and erythropoietin receptor (EPOR). Therefore, we tested the effects of sG-CSFR and sEPOR on primitive progenitors. sG-CSFR, but not sEPOR, was able to synergize with SF or FL in supporting the proliferation of primitive progenitors. The direct effects of the soluble receptors appear to be mediated through interactions with their respective membrane-bound receptors expressed on the primitive hematopoietic progenitors.


Fiber loop mirror-based optical transmissivity and optical phase retardation measurement architecture.
We introduce and experimentally demonstrate a fiber-connectorized optical system based on the use of a fiber-loop mirror (FLM) to study both the optical transmissivity and the optical phase retardation of a material. Our approach to investigating the optical transmissivity of a test sample is by initially adjusting the optical powers at both FLM output ports to the extremum. A reference and the test sample are then placed one by one at one of the FLM output ports. For the optical phase retardation measurement, we propose placing a test sample inside the FLM and analyzing the ratio of the normalized optical powers from the two FLM output ports in order to eliminate the effect of unwanted optical losses. Our experimental proof of concept using three known zero-order wave plates as our test samples shows promising results that agree very well with our theoretical analysis. Key features include robustness, low optical loss, low polarization dependent loss, and ease of implementation.


Surveillance of device associated infections and mortality in a major intensive care unit in the Republic of Cyprus.
Device-associated health care-associated infections (DA-HAI) pose a threat to patient safety, particularly in the intensive care unit. The aim of this study was to assess the incidence of DA-HAIs, mortality and crude excess mortality at a General Hospital's Intensive Care Unit (ICU) in the Republic of Cyprus for 1 year period. A prospective cohort, active DA-HAIs surveillance study with the use of Health Acquired Infections (HAIs) ICU Protocol (v1.01 standard edition) as provided by ECDC/NHSN for the active DA-HAIs surveillance study was conducted. The study sample included 198 ICU patients admitted during the research period and hospitalized for over 48 h. The Ventilator-Associated Pneumonia (VAP), Central Line-Associated Bloodstream Infection (CLABSI), and Catheter-Associated Urinary Tract Infection (CAUTI) rates, length of stay (LOS), mortality, and crude excess mortality were calculated. CLABSI was the most frequent DA-HAI with 15.9 incidence rate per 1000 Central Venus Catheter (CVC) days. The VAP rate, was 10.1 per 1000 ventilator days and the CAUTI rate was 2.7 per 1000 urinary catheter days. Device associated infections were found to be significantly associated with the length of ICU stay (p < 0.001), the CVC days (p < 0.001), ventilator days (p < 0.001), and urinary catheter days (p < 0.001). The excess mortality was 22.1% for those who acquired a DA-HAI (95% CI, 2-42.2%) compared to the patients who remained DA-HAI free. Mortality of patients with VAP infection was 2.3 times higher (RR = 2.33 95% CI, 1.07-5.05) than those patients admitted without a HAI and subsequently did not acquire a DA-HAI. The most frequently isolated pathogen was Staphylococcus epidermidis (13.9%) and Candida albicans (13.9%). Higher DA-HAIs rates and device utilization than the international benchmarks were found in this study, calling into question the safety of preventative practices employed in this unit.


New approaches to spatially analyse primary health care usage patterns in rural South Africa.
To develop indices to quantitatively assess and understand the spatial usage patterns of health facilities in the Hlabisa district of South Africa. We mapped and interviewed more than 23 000 homesteads (approximately 200 000 people) in Hlabisa district, South Africa and spatially analysed their modal primary health usage patterns using a geographical information system. We generated contour maps of health service use and quantified the relationship between clinic catchments and distance-defined catchments using inclusion and exclusion error. We propose the distance usage index (DUI) as an overall spatial measure of clinic usage. This index is the sum of the distances from clinic to all client homesteads divided by the sum of the distances from clinic to all homesteads within its distance-defined catchment. The index encompasses inclusion, exclusion, and strength of patient attraction for each clinic. Eighty-seven per cent of homesteads use the nearest clinic. Residents of homesteads travel an average Euclidean distance of 4.72 km to attend clinics. There is a significant logarithmic relationship between distance from clinic and their use by homesteads (r(2)=0.774, P < 0.0001). The DUI values range between 31 and 198% (mean=110%, SD=43.7) for 12 clinics and highlight clinic usage patterns across the district. The DUI is a powerful and informative composite measure of clinic usage. The results of the study have important implications for health care provision in developing countries.


HPV vaccine and adolescent males.
In 2009, the United States approved quadrivalent HPV vaccine for males 9-26 years old, but data on vaccine uptake are lacking. We determined HPV vaccine uptake among adolescent males, as well as stage of adoption and vaccine acceptability to parents and their sons. A national sample of parents of adolescent males ages 11-17 years (n=547) and their sons (n=421) completed online surveys during August and September 2010. Analyses used multivariate linear regression. Few sons (2%) had received any doses of HPV vaccine, and most parents and sons were unaware the vaccine can be given to males. Parents with unvaccinated sons were moderately willing to get their sons free HPV vaccine (mean=3.37, SD=1.21, possible range 1-5). Parents were more willing to get their sons vaccinated if they perceived higher levels of HPV vaccine effectiveness (β=0.20) or if they anticipated higher regret about their sons not getting vaccinated and later developing an HPV infection (β=0.32). Vaccine acceptability was also modest among unvaccinated sons (mean=2.98, SD=1.13, possible range 1-5). Sons were more willing to get vaccinated if they perceived higher peer acceptance of HPV vaccine (β=0.39) or anticipated higher regret about not getting vaccinated and later developing an HPV infection (β=0.22). HPV vaccine uptake was nearly nonexistent a year after permissive national recommendations were first issued for males. Vaccine acceptability was moderate among both parents and sons. Efforts to increase vaccine uptake among adolescent males should consider the important role of peer acceptance and anticipated regret.


Mechanisms of trastuzumab induced cardiotoxicity - is exercise a potential treatment?
The use of the adjuvant therapeutic antibody trastuzumab in breast cancer is associated with a range of cardiotoxic side effects despite successfully reducing the severity of outcomes cancer patients,. The most common cardiac effect, a reduction in left ventricular ejection fraction (LVEF), is a known precursor to heart failure and often requires interruption of chemotherapy to avoid endangering patients further. An understanding of trastuzumab's cardiac-specific interactions is therefore critical in devising new methods to not only avoid permanent cardiac damage, but also prolong treatment time, and therefore effectiveness, for breast cancer patients. Increasingly, the use of exercise as a treatment has been indicated across the field of cardio-oncology due to encouraging evidence that it can protect against LVEF reductions and heart failure. This review explores the mechanisms of trastuzumab-mediated cardiotoxicity, as well as the physiological effects of exercise on the heart, in order to assess the suitability of exercise intervention for breast cancer patients on trastuzumab antibody-therapy. We furthermore draw comparison to existing evidence for exercise intervention as a cardioprotective treatment in doxorubicin-induced cardiotoxicity. Although preclinical evidence seems to support exercise-based approaches also in trastuzumab-cardiotoxicity, current clinical evidence is too limited to confidently recommend it as a treatment, largely owing to issues of adherence. Future studies should therefore examine how the variety and duration of exercise can be adjusted to improve treatment effectiveness at a more personalised level.


Cluster stability as a new method to assess changes in performance and its determinant factors over a season in young swimmers.
To apply a new method to identify, classify, and follow up young swimmers based on their performance and its determinant factors over a season and analyze the swimmers' stability over a competitive season with that method. Fifteen boys and 18 girls (11.8±0.7 y) part of a national talent-identification scheme were evaluated at 3 different moments of a competitive season. Performance (ie, official 100-m freestyle race time), arm span, chest perimeter, stroke length, swimming velocity, speed fluctuation, coefficient of active drag, propelling efficiency, and stroke index were selected as variables. Hierarchical and k-means cluster analysis were computed. Data suggested a 3-cluster solution, splitting the swimmers according to their performance in all 3 moments. Cluster 1 was related to better performances (talented swimmers), cluster 2 to poor performances (nonproficient swimmers), and cluster 3 to average performance (proficient swimmers) in all moments. Stepwise discriminant analysis revealed that 100%, 94%, and 85% of original groups were correctly classified for the 1st, 2nd, and 3rd evaluation moments, respectively (0.11≤Λ≤0.80; 5.64≤χ2≤63.40; 0.001<P≤.68). Membership of clusters was moderately stable over the season (stability range 46.1-75% for the 2 clusters with most subjects). Cluster stability is a feasible, comprehensive, and informative method to gain insight into changes in performance and its determinant factors in young swimmers. Talented swimmers were characterized by anthropometrics and kinematic features.


Virologic and serologic surveillance for dengue fever in Jeddah, Saudi Arabia, 1994-1999.
Dengue fever infection was first documented in Jeddah, Saudi Arabia, by virus isolation of dengue type 2 virus in 1994 at the virology laboratory of Dr. Soliman Fakeeh Hospital. Dengue virus surveillance was established after that time. Blood samples were collected from 985 patients (710 male patients and 275 female patients) with suspected cases of dengue from February 1994 to December 1999. Dengue virus isolates were obtained in 207 patients (21%; 162 male patients and 45 female patients). Dengue type 2 was the predominant serotype (138 of 207 isolates, 66.7%), followed by dengue type 1 with (56 of 207 isolates, 27%) and dengue type 3 (13 of 207 isolates, 6.3%). The largest number of isolates (186 of 207 isolates, 90%) was in 1994, a year during which there was a dengue epidemic. In the next 5 years, 1995-1999, only 21 isolates (10%) were isolated. Immunoglobulin M capture enzyme-linked immunosorbent assay was positive in 160 acute samples; 52 of them were from virus culture-positive cases and 108 (11%) from culture-negative cases. The total number of cases diagnosed by both methods was 315 (32%). The prevalence of dengue immunoglobulin G antibodies, as assessed on the basis of immunofluorescent assay, hemagglutination inhibition titers > or = 1/20, or both, in the acute samples was 314 (32%) of 985, indicating past Flavivirus infection. Two patients died, one man with dengue hemorrhagic fever and one woman with dengue shock syndrome. Both fatal dengue cases were due to infection with type 2 virus. All other cases were simple dengue fever. To our knowledge, this is the first report confirming the circulation of 3 dengue serotypes in Jeddah.


Contactless Capacitive Electrocardiography Using Hybrid Flexible Printed Electrodes.
Traditional capacitive electrocardiogram (cECG) electrodes suffer from limited patient comfort, difficulty of disinfection and low signal-to-noise ratio in addition to the challenge of integrating them in wearables. A novel hybrid flexible cECG electrode was developed that offers high versatility in the integration method, is well suited for large-scale manufacturing, is easy to disinfect in clinical settings and exhibits better performance over a comparable rigid contactless electrode. The novel flexible electrode meets the frequency requirement for clinically important QRS complex detection (0.67-5 Hz) and its performance is improved over rigid contactless electrode across all measured metrics as it maintains lower cut-off frequency, higher source capacitance and higher pass-band gain when characterized over a wide spectrum of patient morphologies. The results presented in this article suggest that the novel flexible electrode could be used in a medical device for cECG acquisition and medical diagnosis. The novel design proves also to be less sensitive to motion than a reference rigid electrode. We therefore anticipate it can represent an important step towards improving the repeatability of cECG methods while requiring less post-processing. This would help making cECG a viable method for remote cardiac health monitoring.


Beta-Caryophyllene, a CB2R Selective Agonist, Protects Against Cognitive Impairment Caused by Neuro-inflammation and Not in Dementia Due to Ageing Induced by Mitochondrial Dysfunction.
Dementia is a neurodegenerative disorder majorly evidenced by cognitive impairment. Although there are many types of dementia, the common underlying etiological factors in all the types are neuro-inflammation or aging induced apoptosis. β-caryophyllene, a cannabinoid type-2 receptor agonist, has been reported to have promising neuroprotective effects in cerebral ischemia and neuro-inflammation. In the present study, we evaluated the effects of β-caryophyllene against animal models of dementia whose etiology mimicked neuro-inflammation and aging. Two doses (50 and 100 mg/kg of body weight) of β-caryophyllene given orally were tested against AlCl3-induced dementia in male Sprague Dawley (SD) rats using the Morris water maze test. Subsequently, the effect of the drug was assessed for episodic memory in female SD rats using novel object recognition task in doxorubicin-induced neuro-inflammation and chemobrain model. Moreover, its effects were evaluated in D-galactose-induced mitochondrial dysfunction leading to dementia. β-caryophyllene, at both doses, showed significant improvement in memory when assessed using parameters like target quadrant entries, escape latency and path efficiency in the Morris water maze test for spatial memory. In the doxorubicin-induced chemobrain model, β-caryophyllene at 100 mg/kg significantly elevated acetylcholinesterase and catalase levels and lowered lipid peroxidation compared to the disease control. In the novel object recognition task, β-caryophyllene at 100 mg/kg significantly improved recognition index and discrimination index in the treated animals compared to the disease control, with a significant increase in catalase and a decrease in lipid peroxidation in both hippocampus and frontal cortex. However, in the D-galactose-induced mitochondrial dysfunction model, β-caryophyllene failed to show positive effects when spatial memory was assessed. It also failed to improve D-galactose-induced diminished mitochondrial complex I and II activities. Hence, we conclude that β-caryophyllene at 100 mg/kg protects against dementia induced by neuro-inflammation with no effect on neuronal aging induced by mitochondrial dysfunction.


Scanning electron microscopy study of small bowel biopsies in chronic diarrhoea in childhood.
In this study we have compared the results of Scanning Electron Microscopy (SEM) with Light- and Stereomicroscopy in a series of small bowel biopsies in children. In 9 cases displaying features of partial or subtotal atrophy, Light and Dissecting-Microscopy yielded similar results. The distinction between coeliac and non-coeliac chronic diarrhoea was only possible on clinical grounds, and by the immunological detection of specific antibodies. On SEM however coeliac patients showed characteristic alterations consisting of: absence of villi; prominent crypt outlets resulting in a mosaic appearance; concentric furrows running all around the openings; and downy brush feature at high power. The microvilli were loosely distributed and had an irregular pleomorphic outline; they often displayed a drumstick swelling of the tip and were bent. In contrast, non-coeliac chronic diarrhoea cases were characterized by a thick mucous layer on the mucosal surface, that made it impossible to visualize further changes. Peculiar vascular changes in lymphangiectasia and in sickle beta thalassemia could be detected only by Light Microscopy. In addition, in the lymphangiectasia case SEM allowed the detection of enteroadherent bacteria; and in the lambliasis case, of pseudomembranes. Absence of glycocalyx was noted both in controls and in patients. The results of this study point to a diagnostic utility of SEM particularly in the differential diagnosis of chronic diarrhoea; moreover they suggest that enteroadherent bacteria may not be pathogenic and that the absence of glycocalyx is not specific for allergic enteropathy as previously claimed.


Right-sided free wall accessory pathway refractory to conventional catheter ablation: lessons from 3-dimensional electroanatomic mapping.
the aim of this study was to delineate the electroanatomic substrates of right-sided free wall (RFW) accessory pathways (APs) that were refractory to conventional catheter ablation utilizing 3-dimensional (3-D) mapping. eleven patients with RFW APs that failed initial conventional catheter ablation(s) by a mean of 1.9 ± 0.5 attempts were enrolled in the study. Electroanatomic mapping of the right atrium was performed during orthodromic reciprocating tachycardia in 3 patients and right ventricular pacing in 8 patients. The earliest atrial activation site, which represented the atrial insertion of the AP, was separated from the tricuspid annulus by an average of 14.3 ± 3.9 mm, and the local activation time was 27.8 ± 17.0 ms earlier than that of the corresponding annular point. One patient exhibited an AP with wide branching on the atrial side. RF ablation with an irrigated catheter successfully interrupted AP conduction in all patients without complications. RFW APs resistant to conventional catheter ablation might be due to unique anatomic AP features such as more epicardial course at the annulus level with atrial insertion distant from the tricuspid annulus. Electroanatomic mapping is helpful to accurately localize the atrial insertion sites of these APs and facilitates catheter ablation.


Severe renal dysgenesis produced by a dominant gene.
A woman with the autosomal dominant syndrome of preauricular pits, cervical fistulae, and partial deafness gave birth to two children with preauricular pits and severe renal dysgenesis. The facies had some features of the Potter facies of renal agenesis. One child died soon after birth because of pneumothorax and immature development of the lungs. We suggest that all infants with renal agenesis or dysgenesis be examined for preauricular pits because of the high recurrence risk of renal anomalies in families with this syndrome.


Camera sensor arrangement for crop/weed detection accuracy in agronomic images.
In Precision Agriculture, images coming from camera-based sensors are commonly used for weed identification and crop line detection, either to apply specific treatments or for vehicle guidance purposes. Accuracy of identification and detection is an important issue to be addressed in image processing. There are two main types of parameters affecting the accuracy of the images, namely: (a) extrinsic, related to the sensor's positioning in the tractor; (b) intrinsic, related to the sensor specifications, such as CCD resolution, focal length or iris aperture, among others. Moreover, in agricultural applications, the uncontrolled illumination, existing in outdoor environments, is also an important factor affecting the image accuracy. This paper is exclusively focused on two main issues, always with the goal to achieve the highest image accuracy in Precision Agriculture applications, making the following two main contributions: (a) camera sensor arrangement, to adjust extrinsic parameters and (b) design of strategies for controlling the adverse illumination effects.


Relationship between serum leptin levels and bone mineral density and bone metabolic markers in patients on hemodialysis.
Leptin is the protein product of the obesity gene, which is produced in fat tissue. It was originally thought to be involved only in the regulation of food intake and energy balance. We aimed to investigate the relationship of serum leptin levels with bone mineral density (BMD) and biochemical markers of bone turnover in patients on hemodialysis (HD). This study included 72 patients (43 males and 29 females), whose mean age was 55.1 ± 11.4 years, mean body mass index was 23.13 ± 2.75 kg/m 2 and mean duration on HD was 5 ± 3.4 years. The BMD values were calculated using dual-energy X-ray absorptiometry (DEXA) at the femoral neck and lumbar spine. Blood samples were taken for leptin, intact parathyroid hormone (I-PTH), bone alkaline phosphatase (BAP), calcium (Ca), phosphate (P) and albumin. The leptin levels were higher in females than in males (22.3 ± 19.6 vs 20.8 ± 23), but this difference was not significant. The serum leptin level had a strong positive correlation with Ca levels in the female patients (r = 0.659 and P = 0.01) and a negative correlation with albumin levels (r = -0.461 and P = 0.01). No correlation was found with age, BMI, duration on dialysis, BMD and serum levels of PTH, BAP and P for the entire patient group or either gender separately. The serum leptin level was significantly lower in females with PTH >300 pg/mL when compared with patients with PTH = 100-300 pg/mL (86 ± 85 vs 47 ± 48) (P = 0.011).Women with BAP <300 IU/L had significantly higher serum leptin than those with BAP 300-600 IU/L (P = 0.024). Women with Ca <8.5 mg/dL had significantly lower serum leptin levels compared with those with Ca levels of 8.5-10.5 mg/dL (P = 0.011). There was no significant difference between the two genders among variables such as age, BMI, duration on dialysis, serum leptin, I-PTH, Ca, P, BAP, albumin and BMD of the femoral neck and lumbar spine.


Safety and immunogenicity of a glycoprotein D genital herpes vaccine in healthy girls 10-17 years of age: results from a randomised, controlled, double-blind trial.
The investigational AS04-adjuvanted herpes simplex virus type 2 (HSV-2) glycoprotein D (gD2) subunit prophylactic vaccine ('HSV vaccine'; GlaxoSmithKline Vaccines) has been shown to be well tolerated in adults, but limited data exist for pre-teen and adolescent girls, a likely target population. The primary objective of this study was to compare the occurrence of serious adverse events (SAEs) over 12 months between HSV vaccine recipients and saline recipients (placebo control group) in pre-teen and adolescent girls. The immunogenicity of the HSV vaccine was also assessed. Healthy girls aged 10-17 years, stratified by age (10-15 years; 16-17 years), were randomised 2:1:1 to receive the HSV vaccine, a hepatitis A vaccine (Havrix™; HAV control) or placebo (saline) according to a 0-, 1-, 6-month schedule. Participants and study personnel not involved in the preparation or administration of vaccines were blinded to treatment. Safety and immunogenicity analyses were performed overall and by age (10-15 years; 16-17 years) and HSV serostatus. No statistically significant difference in the percentage of subjects with SAEs was observed between the HSV and saline group, or between the HSV and pooled control (HAV and saline) groups. The HSV vaccine was well tolerated, although a higher incidence of solicited local symptoms was observed in the HSV group than in the control group. Neither age nor HSV serostatus at the time of study entry had an impact on the safety profile of this vaccine. The HSV vaccine was immunogenic regardless of pre-vaccination HSV serostatus. Higher anti-gD geometric mean concentrations were observed in HSV-1 seropositive participants than in HSV-1 seronegative participants. The HSV vaccine had an acceptable safety profile, and was well tolerated and immunogenic when administered to girls aged 10-17 years regardless of age or HSV pre-vaccination serostatus.


Changes in circulating microRNA after recumbent isometric yoga practice by patients with myalgic encephalomyelitis/chronic fatigue syndrome: an explorative pilot study.
Yoga is a representative mind-body therapy. Our previous studies have demonstrated that isometric yoga (i.e. yoga programs that we developed so individuals can practice yoga poses with a self-adjustable isometric load) reduces the fatigue of patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS); however, the underlying mechanisms remain unclear. Several studies have suggested that the micro-ribonucleic acid (miRNA) expression of ME/CFS patients is different from that of healthy subjects. However, it has not to date been determined if the practice of isometric yoga can affect miRNA expression. Therefore, we sought to investigate if isometric yoga is associated with changes in the expression levels of serum miRNA of patients with ME/CFS. The study included nine patients with ME/CFS who failed to show satisfactory improvement after at least 6 months of treatment administered at our hospital. Patients practiced recumbent isometric yoga for 3 months; they met with a yoga instructor every 2 to 4 weeks and participated in daily in-home sessions. The effect of recumbent isometric yoga on fatigue was assessed by comparing pre- and post-intervention scores on the Japanese version of the 11-item Chalder fatigue scale (CFQ 11). Patient blood samples were drawn pre- and post-intervention, just prior to practicing recumbent isometric yoga with an instructor. The serum was used for miRNA array analysis with known human miRNAs. The average CFQ 11 score decreased significantly (from 25.3 ± 5.5 to 17.0 ± 5.8, p < 0.0001) after practicing recumbent isometric yoga for 3 months. The miRNA microarray analysis revealed that four miRNAs were significantly upregulated, and 42 were downregulated after the intervention period. This explorative pilot study is the first to demonstrate changes in the serum levels of several miRNAs after regular practice of recumbent isometric yoga. These miRNAs might represent biomarkers for the fatigue-relieving effects of isometric yoga of patients with ME/CFS. University Hospital Medical Information Network (UMIN CTR) 000023472. Registered Aug 4, 2016.


Signalling pathways activated by glucagon-like peptide-1 (7-36) amide in the rat heart and their role in protection against ischaemia.
Glucagon-like peptide-1 is an incretin hormone proposed to have insulinomimetic effects on peripheral insulin-sensitive tissue. We examined these effects on the heart by using isolated, perfused rat hearts and adult ventricular myocytes. During normoxic perfusion, no effects of escalating concentrations of GLP-1 on either heart rate or left ventricular developed pressure were found. With functional performance as readout, we found that GLP-1 directly protected the heart against damage incurred by global low-flow ischaemia. This protection was sensitive to the presence of iodo-acetate, implicating activation of glycolysis, and was abolished by wortmannin, indicative of PI-3-kinase as mediator of protection. In addition, GLP-1 had an infarct-sparing effect when supported by the presence of the dipeptidyl peptidase-IV inhibitor valine pyrrolidide. GLP-1 could not directly activate protein kinase B (also called Akt) or the extracellular regulated kinases Erk1/2 in hearts or cardiocytes under normoxic conditions, but phosphorylation of the AMP-activated kinase (AMPK) on Thr(172) was enhanced. I n addition, the glycolytic enzyme phosphofructokinase- 2 was activated dose dependently. During reperfusion after ischaemia, modulation of the phosphorylation of PKB/Akt as well as AMPK was evident. GLP-1 therefore directly protected the heart against low-flow ischaemia by enhancing glycolysis, probably via activation of AMP kinase and by modulating the profile of activation of the survival kinase PKB/Akt.


Urine Sample-Derived Cerebral Organoids Suitable for Studying Neurodevelopment and Pharmacological Responses.
Cerebral organoids (COs) developed from human induced pluripotent stem cells (hiPSCs) have been noticed for their potential in research and clinical applications. While skin fibroblast-derived hiPSCs are proficient at forming COs, the cellular and molecular features of COs developed using hiPSCs generated from other somatic cells have not been systematically examined. Urinary epithelial cells (UECs) isolated from human urine samples are somatic cells that can be non-invasively collected from most individuals. In this work, we streamlined the production of COs using hiPSCs reprogrammed from urine sample-derived UECs. UEC-derived hiPSC-developed COs presented a robust capacity for neurogenesis and astrogliogenesis. Although UEC-derived hiPSCs required specific protocol optimization to properly form COs, the cellular and transcriptomic features of COs developed from UEC-derived hiPSCs were comparable to those of COs developed from embryonic stem cells. UEC-derived hiPSC-developed COs that were initially committed to forebrain development showed cellular plasticity to transition between prosencephalic and rhombencephalic fates in vitro and in vivo, indicating their potential to develop into the cell components of various brain regions. The opposite regulation of AKT activity and neural differentiation was found in these COs treated with AKT and PTEN inhibitors. Overall, our data reveal the suitability, advantage, and possible limitations of human urine sample-derived COs for studying neurodevelopment and pharmacological responses.


Cognitive skills affect economic preferences, strategic behavior, and job attachment.
Economic analysis has so far said little about how an individual's cognitive skills (CS) are related to the individual's economic preferences in different choice domains, such as risk taking or saving, and how preferences in different domains are related to each other. Using a sample of 1,000 trainee truckers we report three findings. First, there is a strong and significant relationship between an individual's CS and preferences. Individuals with better CS are more patient, in both short- and long-run. Better CS are also associated with a greater willingness to take calculated risks. Second, CS predict social awareness and choices in a sequential Prisoner's Dilemma game. Subjects with better CS more accurately forecast others' behavior and differentiate their behavior as a second mover more strongly depending on the first-mover's choice. Third, CS, and in particular, the ability to plan, strongly predict perseverance on the job in a setting with a substantial financial penalty for early exit. Consistent with CS being a common factor in all of these preferences and behaviors, we find a strong pattern of correlation among them. These results, taken together with the theoretical explanation we offer for the relationships we find, suggest that higher CS systematically affect preferences and choices in ways that favor economic success.


[Identification of pathogens in ancient skeletal series: the malaria of the Medici Grand Dukes (Florence, XVI century)].
The application of paleoimmunological techniques on ancient human bone tissue allowed the identification of ancient pathogens, such as malaria by Plasmodium falciparum. Until now the immunocromatographic tests were applied only on mummified muscle. Ir this study positive results were obtained using ancient spongy bone samples belonging to the skeletal remains of four members of the Medici family of Florence who, according to archive data, died of malaria: Eleonora di Toledo (1522-1562), Giovanni (1543-1562) and don Garzia (1547-1562), and the Grand Duke Francesco I (1531-1587). These results are of particular interest not only because they confirm the historical data, but also because they demonstrate that immunological tests can be applied to bone samples, opening new paths of research for the screening of large skeletal series.