Spatial modes in one-dimensional models for capillary jets.
One-dimensional (1D) models are widely employed to simplify the analysis of axisymmetric capillary jets. These models postulate that, for slender deformations of the free surface, the radial profile of the axial velocity can be approximated as uniform (viscous slice, averaged, and Cosserat models) or parabolic (parabolic model). In classical works on spatial stability analysis with 1D models, considerable misinterpretation was generated about the modes yielded by each model. The already existing physical analysis of three-dimensional (3D) axisymmetric spatial modes enables us to relate these 1D spatial modes to the exact 3D counterparts. To do so, we address the surface stimulation problem, which can be treated as linear, by considering the effect of normal and tangential stresses to perturb the jet. A Green's function for a spatially local stimulation having a harmonic time dependence provides the general formalism to describe any time-periodic stimulation. The Green's function of this signaling problem is known to be a superposition of the spatial modes, but in fact these modes are of fundamental nature, i.e., not restricted to the surface stimulation problem. The smallness of the wave number associated with each mode is the criterion to validate or invalidate the 1D approaches. The proposed axial-velocity profiles (planar or parabolic) also have a remarkable influence on the outcomes of each 1D model. We also compare with the classical 3D results for (i) conditions for absolute instability, and (ii) the amplitude of the unstable mode resulting from both normal and tangential surface stress stimulation. Incidentally, as a previous task, we need to re-deduce 1D models in order to include eventual stresses of various possible origins (electrohydrodynamic, thermocapillary, etc.) applied on the free surface, which were not considered in the previous general formulations.


Implicit emotion perception in schizophrenia.
Explicit but not implicit facial emotion perception has been shown to be impaired in schizophrenia. In this study, we used newly developed technology in social neuroscience to examine implicit emotion processing. It has been shown that when people look at faces, they automatically infer social traits, and these trait judgments rely heavily on facial features and subtle emotion expressions even with neutral faces. Eighty-one individuals with schizophrenia or schizoaffective disorder and 62 control subjects completed a computer task with 30 well-characterized neutral faces. They rated each face on 10 trait judgments: attractive, mean, trustworthy, intelligent, dominant, fun, sociable, aggressive, emotionally stable and weird. The degree to which trait ratings were predicted by objectively-measured subtle emotion expressions served as a measure of implicit emotion processing. Explicit emotion recognition was also examined. Trait ratings were significantly predicted by subtle facial emotional expressions in controls and patients. However, impairment in the implicit emotion perception of fear, happiness, anger and surprise was found in patients. Moreover, these deficits were associated with poorer everyday problem-solving skills and were relatively independent of explicit emotion recognition. Implicit emotion processing is impaired in patients with schizophrenia or schizoaffective disorder. Deficits in implicit and explicit emotion perception independently contribute to the patients' poor daily life skills. More research is needed to fully understand the role of implicit and explicit processes in the functional deficits of patients, in order to develop targeted and useful remediation interventions.


There are critical reasons for not further delaying the implementation of the new ICD-10 coding system.
On April 17, 2012, the Department of Health and Human Services (HHS) published a rule proposing postponement of the implementation date for the International Classification of Diseases, 10th Edition diagnosis codes (ICD-10-CM) and procedure codes (ICD-10-PCS) by one year to October 1, 2014. An article in Health Affairs titled "There Are Important Reasons For Delaying the Implementation Of The New ICD-10 Coding System" asserts that the ICD-10-CM conversion will be "expensive, arduous, disruptive, and of limited direct clinical benefit." Contrary to the conclusions in this article, implementation of the ICD-10-CM and ICD-10-PCS code sets will provide major advantages over the existing ICD-9-CM code set. Implementation is long overdue and will provide significant cost benefits. Any further implementation delay will increase the cost of the transition as well as perpetuate the costs and negative consequences associated with continued reliance on imprecise diagnosis and procedure information.


Intrapopulation variability in mineralization density at the human femoral mid-shaft.
One of several microstructural variables known to affect the mechanical properties of bone is the degree of mineralization of bone matrix. The aim of this study was to examine mineralization density, and its variability with age and sex, from a biomechanical perspective. Histological sections, prepared from mid-shaft femora obtained at autopsy from 40 individuals, were imaged using quantitative backscattered electron microscopy. Each cross-section montage was divided into 48 segments according to anatomical position. Mean grey-level values were quantified for each segment. One-way ANOVA with Tukey HSD post hoc tests were used to test for differences in mineralization between segments, age groups and sexes. Results showed a decrease in overall degree of mineralization density with adult age, but an increase in its coefficient of variation. Degree of mineralization was significantly lower in the periosteal third of the cortex, particularly in the antero-lateral aspect. This pattern was most prevalent amongst the youngest individuals in the sample. Whereas males between ages 45-64 years had a higher average degree of mineralization than females, the opposite was true of the older age group. Mineralization significantly decreased between middle and older age groups in males, but not in females. Despite limited consistencies in the location of high and low average mineralization bone through the cortex, the degree of interindividual variation, even within a single age and sex group, overwhelmed population level trends. The patterns of variability identified in this study are consistent with results of an analysis of collagen fibre orientation using the same sample material.


The Long-Term Persistence of Borrelia burgdorferi Antigens and DNA in the Tissues of a Patient with Lyme Disease.
Whether Borrelia burgdorferi, the causative agent of Lyme disease, can persist for long periods in the human body has been a controversial question. The objective of this study was to see if we could find B. burgdorferi in a Lyme disease patient after a long clinical course and after long-term antibiotic treatment. Therefore, we investigated the potential presence of B. burgdorferi antigens and DNA in human autopsy tissues from a well-documented serum-, PCR-, and culture-positive Lyme disease patient, a 53-year-old female from northern Westchester County in the lower Hudson Valley Region of New York State, who had received extensive antibiotic treatments during extensive antibiotic treatments over the course of her 16-year-long illness. We also asked what form the organism might take, with special interest in the recently found antibiotic-resistant aggregate form, biofilm. We also examined the host tissues for the presence of inflammatory markers such as CD3+ T lymphocytes. Autopsy tissue sections of the brain, heart, kidney, and liver were analyzed by histological and immunohistochemical methods (IHC), confocal microscopy, fluorescent in situ hybridization (FISH), polymerase chain reaction (PCR), and whole-genome sequencing (WGS)/metagenomics. We found significant pathological changes, including borrelial spirochetal clusters, in all of the organs using IHC combined with confocal microscopy. The aggregates contained a well-established biofilm marker, alginate, on their surfaces, suggesting they are true biofilm. We found B. burgdorferi DNA by FISH, polymerase chain reaction (PCR), and an independent verification by WGS/metagenomics, which resulted in the detection of B. burgdorferi sensu stricto specific DNA sequences. IHC analyses showed significant numbers of infiltrating CD3+ T lymphocytes present next to B. burgdorferi biofilms. In summary, we provide several lines of evidence that suggest that B. burgdorferi can persist in the human body, not only in the spirochetal but also in the antibiotic-resistant biofilm form, even after long-term antibiotic treatment. The presence of infiltrating lymphocytes in the vicinity of B. burgdorferi biofilms suggests that the organism in biofilm form might trigger chronic inflammation.


A designated odor-language integration system in the human brain.
Odors are surprisingly difficult to name, but the mechanism underlying this phenomenon is poorly understood. In experiments using event-related potentials (ERPs) and functional magnetic resonance imaging (fMRI), we investigated the physiological basis of odor naming with a paradigm where olfactory and visual object cues were followed by target words that either matched or mismatched the cue. We hypothesized that word processing would not only be affected by its semantic congruency with the preceding cue, but would also depend on the cue modality (olfactory or visual). Performance was slower and less precise when linking a word to its corresponding odor than to its picture. The ERP index of semantic incongruity (N400), reflected in the comparison of nonmatching versus matching target words, was more constrained to posterior electrode sites and lasted longer on odor-cue (vs picture-cue) trials. In parallel, fMRI cross-adaptation in the right orbitofrontal cortex (OFC) and the left anterior temporal lobe (ATL) was observed in response to words when preceded by matching olfactory cues, but not by matching visual cues. Time-series plots demonstrated increased fMRI activity in OFC and ATL at the onset of the odor cue itself, followed by response habituation after processing of a matching (vs nonmatching) target word, suggesting that predictive perceptual representations in these regions are already established before delivery and deliberation of the target word. Together, our findings underscore the modality-specific anatomy and physiology of object identification in the human brain.


Collaborative models for the joint production of core health technology assessments: negative and positive aspects for the joint work of different European agencies.
The purpose of the European network for Health Technology Assessment (EUnetHTA) is to make HTA agencies collaborate sharing methods and tools thus avoiding duplication of evaluative efforts and allowing resource savings. From 2010 to 2012, the activities of the network were carried out through EUnetHTA Joint Action 1 and Work Package 4 Strand B aimed at producing two Core HTAs with two main objectives: to test the Web based Core model and the collaborative working models. Our objective in this article is to give an historical record of the Work Package activities highlighting what worked and what did not in the collaboration of researchers' groups coming from different agencies. A retrospective description of all the steps for the joint production of the two Core HTAs is provided starting from the first step of selecting technologies of common interest. Primary researchers' views on the whole process have been collected through a semi-structured telephonic interview supported by a questionnaire. Coordinators views were gathered during internal meetings and validated. Majority of respondents thought topic selection procedure was not clear and well managed. About collaborative models, small groups were seen to enable more exchange, whatever the model. According to coordinators, loss of expertise and experience during the production process, different languages, and novelty of the Online Tool were main barriers. Lessons learned from this first experience in Joint Action 1 paved the path for the collaboration in Joint Action 2, as it allowed enhancements and changes in models of collaborations and coordination.


Post hoc Analysis for Detecting Individual Rare Variant Risk Associations Using Probit Regression Bayesian Variable Selection Methods in Case-Control Sequencing Studies.
Rare variants (RVs) have been shown to be significant contributors to complex disease risk. By definition, these variants have very low minor allele frequencies and traditional single-marker methods for statistical analysis are underpowered for typical sequencing study sample sizes. Multimarker burden-type approaches attempt to identify aggregation of RVs across case-control status by analyzing relatively small partitions of the genome, such as genes. However, it is generally the case that the aggregative measure would be a mixture of causal and neutral variants, and these omnibus tests do not directly provide any indication of which RVs may be driving a given association. Recently, Bayesian variable selection approaches have been proposed to identify RV associations from a large set of RVs under consideration. Although these approaches have been shown to be powerful at detecting associations at the RV level, there are often computational limitations on the total quantity of RVs under consideration and compromises are necessary for large-scale application. Here, we propose a computationally efficient alternative formulation of this method using a probit regression approach specifically capable of simultaneously analyzing hundreds to thousands of RVs. We evaluate our approach to detect causal variation on simulated data and examine sensitivity and specificity in instances of high RV dimensionality as well as apply it to pathway-level RV analysis results from a prostate cancer (PC) risk case-control sequencing study. Finally, we discuss potential extensions and future directions of this work.


Correlation of Serum Vitamin D Level with Mortality in Patients with Sepsis.
Sepsis is the leading cause of mortality in the critically ill. Recently, it has been found in many studies that many trace elements and nutrients do have an effect on human body and if supplemented can improve the prognosis in patients with sepsis. Primary objective: Whether low Vitamin D is associated with mortality. Secondary objective: To find out association of low Vitamin D levels and morbidity in terms of length of hospital and Intensive Care Unit (ICU) stay. Following ethical approval, consent will be sought from either the patient or assent from a near relative. Successive patients admitted to the medical emergency and ICU at tertiary care health center who fulfill the following criteria for sepsis, within a 24 h time window, were included in the study. Among 88 patients evaluated in our study 15 patients (18.2%) were found to have adequate Vitamin D levels and seven patients (8%) were found insufficient and rest 52 patients (73.9%) were found deficient in Vitamin D. Age of the patients ranged between 18 and 82 years with mean (±standard deviation) 45.02 ± 17.69 years. Mean Vitamin D level was found significantly higher among patients with positive outcome than those with unfavorable outcome (expiry) (t = 2.075, P = 0.04). On comparison of the length of hospital stay (morbidity) with Vitamin D levels, we found statistically significant inverse relation between Vitamin D levels and length of hospital stay. Vitamin D deficiency leads to increased risk of mortality in the critically ill along with prolonged hospital stay.


Early laparoscopic cholecystectomy is the appropriate management for acute gangrenous cholecystitis.
Treatment of severe acute cholecystitis by laparoscopic cholecystectomy remains controversial because of technical difficulties and high rates of complications. We determined whether early laparoscopic cholecystectomy is appropriate for acute gangrenous cholecystitis. The medical records of 116 patients with acute gangrenous cholecystitis admitted to the Korea University Guro Hospital between January 2005 and December 2009 were reviewed. The early operation group, those patients who had cholecystectomies within 4 days of the diagnosis, was compared with the delayed operation group, who had cholecystectomies 4 days after the diagnosis. Of the 116 patients, 57 were in the early operation group and 59 were in the delayed operation group. There were no statistical differences between the groups with respect to gender, age, body mass index, operative methods, major complications, duration of symptoms, mean operative time (98 vs 107 minutes), or postoperative hospital stay. However, the total hospital stay was significantly longer in the delayed operation group. More patients underwent preoperative percutaneous cholecystostomy in the delayed operation group (3.5 vs 15.3%). Early laparoscopic cholecystectomy for acute gangrenous cholecystitis is safe and feasible. There is no advantage to postponing an urgent operation in patients with acute gangrenous cholecystitis.


The identifiability of covarion models in phylogenetics.
Covarion models of character evolution describe inhomogeneities in substitution processes through time. In phylogenetics, such models are used to describe changing functional constraints or selection regimes during the evolution of biological sequences. In this work the identifiability of such models for generic parameters on a known phylogenetic tree is established, provided the number of covarion classes does not exceed the size of the observable state space. ;Generic parameters' as used here means all parameters except possibly those in a set of measure zero within the parameter space. Combined with earlier results, this implies both the tree and generic numerical parameters are identifiable if the number of classes is strictly smaller than the number of observable states.


Lifelong bilingualism and neural reserve against Alzheimer's disease: a review of findings and potential mechanisms.
Alzheimer's disease (AD) is a progressive brain disorder that initially affects medial temporal lobe circuitry and memory functions. Current drug treatments have only modest effects on the symptomatic course of the disease. In contrast, a growing body of evidence suggests that lifelong bilingualism may delay the onset of clinical AD symptoms by several years. The purpose of the present review is to summarize evidence for bilingualism as a reserve variable against AD and discuss potential underlying neurocognitive mechanisms. Evidence is reviewed suggesting that bilingualism may delay clinical AD symptoms by protecting frontostriatal and frontoparietal executive control circuitry rather than medial temporal lobe memory circuitry. Cellular and molecular mechanisms that may contribute to bilingual cognitive reserve effects are discussed, including those that may affect neuronal metabolic functions, dynamic neuronal-glial interactions, vascular factors, myelin structure and neurochemical signaling. Future studies that may test some of these potential mechanisms of bilingual CR effects are proposed.


Rationale for and Design of the PARADIGM Study: Randomized Phase III Study of mFOLFOX6 Plus Bevacizumab or Panitumumab in Chemotherapy-naïve Patients With RAS (KRAS/NRAS) Wild-type, Metastatic Colorectal Cancer.
It remains unclear whether an anti-VEGF or anti-EGFR antibody with standard doublet chemotherapy is the optimal first-line treatment in patients with RAS (KRAS/NRAS) wild-type metastatic colorectal cancer (mCRC). Here we outline the PARADIGM study (NCT02394795), designed to evaluate the superiority of panitumumab over bevacizumab, in combination with oxaliplatin/5-fluorouracil/leucovorin (mFOLFOX6) in patients with RAS wild-type chemotherapy-naïve mCRC. Eligible patients are aged 20 to 79 years with an ECOG performance status of 0-1 and histologically/cytologically confirmed RAS wild-type mCRC. A total of 800 patients are to be randomly assigned (1:1 ratio) to mFOLFOX6 plus panitumumab (n = 400) or bevacizumab (n = 400) and stratified according to institution, age (20-64 vs. 65-79 years), and liver metastases (present vs. absent). Each treatment regimen includes oxaliplatin 85 mg/m2, l-leucovorin 200 mg/m2, and 5-fluorouracil (5-FU) I.V. 400 mg/m2 on day 1; 5-FU continuous I.V. 2400 mg/m2 on days 1 to 3; and either panitumumab 6 mg/kg or bevacizumab 5 mg/kg on day 1 every 2 weeks. The primary endpoint is overall survival forming the basis to detect a hazard ratio of 0.76 with a 1-sided type I error rate of 0.025 and 80% power. Secondary efficacy endpoints include progression-free survival, response rate, duration of response, and curative resection rate. A comprehensive biomarker analysis (NCT02394834) using archival tumor tissue and circulating tumor DNA samples collected at different time points (pretreatment and confirmed progressive disease) will investigate potential biomarkers related to primary and secondary resistance. The first patient was enrolled in May 2015 and the study is anticipated to complete in 2020.


Early improvement in rhytides and skin laxity following treatment with a combination fractional laser emitting two wavelengths sequentially.
Carbon dioxide laser resurfacing remains the gold standard for the treatment of photoaged skin. Today, however, fewer patients will tolerate the postoperative downtime associated with the use of this device. Fractional photothermolysis was designed to overcome the disadvantages associated with ablative resurfacing. Prototype fractional lasers (Fraxel, Reliant Technologies Inc.) have required the use of blue tracking dye to give evenly spaced microtreatment zones, and treatments are associated with moderate levels of discomfort because of microtreatment zone depths reaching nearly 1000 microm. Newer technologies have evolved that do not require tracking dye, and are less painful than older prototypes because microtreatment zones are more superficial (100 to 300 microm) than that of the Fraxel laser. Newer devices offer advances in treating facial rhytides and skin laxity through the use of 2 laser wavelengths (1320 nm/1440 nm) emitted sequentially through a specialized diffractive lens array that produces high-intensity microtreatment zones surrounded by deeper low level heating. One to 3 treatments with this combination fractional laser device were performed on 16 Caucasian females with static periocular rhytides or skin laxity affecting the nasolabial crease. There was a 3-week period between treatments. Improvement was noted in both areas after a small number of treatments. The technology behind fractional lasers is rapidly evolving, and new devices offer significant advances over older prototypes.


Cardiomegaly and vasoactive hormones in rats with chronic myocardial infarction: long-term effects of chlorothiazide.
1. The effects of prolonged chlorothiazide treatment of left ventricular failure on cardiac hypertrophy, circulating vasoactive hormones and exchangeable body sodium were examined in rats with chronic myocardial infarction induced by left coronary artery ligation. Chlorothiazide therapy commenced either immediately or 2 weeks after infarction. For 4 weeks, the rats were given either chlorothiazide (50 mg day-1 kg-1) in their drinking water or drinking water alone. 2. Cardiac weight increased in untreated rats with infarction in comparison with sham-operated controls, indicating the presence of chronic left ventricular dysfunction, although exchangeable body sodium, plasma renin activity, plasma vasopressin and plasma osmolality remained unchanged. 3. Chlorothiazide raised haematocrit and plasma renin activity equally in rats with and without infarction, although exchangeable body sodium, plasma vasopressin and plasma osmolality were not changed by the treatment. Plasma atrial natriuretic peptide was 2-fold higher in rats with infarction and this response was not affected by chlorothiazide treatment. Chlorothiazide therapy did not prevent or reverse cardiac hypertrophy. 4. Chronic diuretic therapy in this experimental model of heart failure did not reduce extracellular sodium, plasma vasopressin or the extent of ventricular hypertrophy, possibly because the condition was associated with activation of the renin-angiotensin system.


Medical educators' social acts of explaining passing underperformance in students: a qualitative study.
Passing underperformance in students is ubiquitous across health and social care educators and is intimately related to the subsequent welfare of patients: underperforming students may become underperforming practitioners. This paper aims to examine how medical educators construct passing underperformance through an analysis of their social act of explaining such behaviours in peer-group settings. Ten focus groups were conducted with 70 medical educators across two UK schools with different curricular/assessment styles (England, Scotland). A qualitative content analysis of how educators explained their behaviours of passing underperformance was undertaken using the psychological concepts of proximality and distalness according to: (1) Malle's F.Ex. coding framework for behavioural explanations, and (2) participants' use of pronouns. 149 explanations of passing underperformance were identified: 72 for participants' own behaviour, 77 for others' behaviour. When explaining their own behaviour, participants used the proximal pronoun I 37% (n = 27) of the time and the distancing pronouns we/you 51% (n = 37) of the time. More Causal History of Reasons (38%; n = 27) and Enabling Factors (29%; n = 21) than Reasons (33%; n = 24) were cited. A similar pattern was found for explaining others' behaviour. Thus, medical educators used linguistic form, explanation mode and informational content within peer-group discussions to distance themselves from intentionality for their action of passing underperformance and highlighted desirable characteristics of themselves and medical educators in general. Faculty development programmes should develop assessors' awareness of how implicit factors within their talk can legitimise a culture of passing underperformance and explore the steps for cultural change.


Cardiac surgery for patients with heart failure due to structural heart disease in Uganda: access to surgery and outcomes.
Few data are available on heart failure (HF) in sub-Saharan Africa. We aimed to provide a current picture of HF aetiologies in urban Uganda, access to heart surgery, and outcomes. We prospectively collected clinical and echocardiographic data from 272 consecutive patients referred for suspected heart disease to a tertiary hospital in Kampala during seven non-governmental organisation (NGO) missions from 2009 to 2013. We focused the analysis on 140 patients who fulfilled standardised criteria of HF by echocardiography. Rheumatic heart disease (RHD) was the leading cause of HF in 44 (31%) patients. Among the 50 children included (age ≤ 16 years), congenital heart disease (CHD) was the first cause of HF (30 patients, 60%), followed by RHD (16 patients, 32%). RHD was the main cause of HF (30%) among the 90 adults. All 85 patients with RHD and CHD presented with an indication for heart surgery, of which 74 patients were deemed fit for intervention. Surgery was scheduled in 38 patients with RHD [86%, median age 19 years (IQR: 12-31)] and in 36 patients with CHD [88%, median age 4 years (IQR 1-5)]. Twenty-seven candidates (32%) were operated on after a median waiting time of 10 months (IQR 6-21). Sixteen (19%) had died after a median of 38 months (IQR 5-52); 19 (22%) were lost to follow up. RHD still represents the leading cause of HF in Uganda, in spite of cost-efficient prevention strategies. The majority of surgical candidates, albeit young, do not have access to treatment and present high mortality rates.


Untreated peristomal skin complications among long-term colorectal cancer survivors with ostomies.
This ethnography of family caregiving explored why peristomal skin complications are common and undertreated among colorectal cancer survivors with intestinal ostomies. Data were collected through in-depth interviews with 31 cancer survivors and their family caregivers, fieldwork, structured assessments, and medical records review, and analyzed with qualitative theme and matrix analyses. Survivors who received help changing the skin barrier around their stoma had fewer obstacles to detection and treatment of peristomal skin complications. Half of the survivors received unpaid help with ostomy care, and all such help came from spouses. Married couples who collaborated in ostomy care reported that having assistance in placing the ostomy appliance helped with preventing leaks, detecting skin changes, and modifying ostomy care routines. In addition, survivors who struggled to manage ostomy care independently reported more obstacles to alleviating and seeking treatment for skin problems. Oncology nurses can improve treatment of peristomal skin problems by asking patients and caregivers about ostomy care and skin problems, examining the peristomal area, and facilitating routine checkups with a wound, ostomy, and continence nurse.


Good's syndrome, a rare form of acquired immunodeficiency associated with thymomas.
Good's syndrome (GS) or thymomaassociated immunodeficiency is a rare clinical entity that should be ruled out in patients with thymoma who develop severe, recurrent bacterial infections and opportunistic viral and fungal infections. There are no treatment protocols established, hence, early recognition is imperative to avoid complications. We report the case of a 42-year-old female, known for a previous thymectomy for giant thymoma who has suffered for a long time from recurrent pulmonary and urinary tract infections and cold sores. In March 2016 she referred to our unit complaining of fever, cough, chest pain, and cold sores due to Herpes simplex virus (HSV), confirmed serologically as HSV-1. Chest X-ray showed left pneumonia due to Streptococcus pneumoniae. She started antibiotics (amoxicillin/clavulanic acid associated with azithromycin) with gradual improvement. Given her history she was studied for an underlying immunodeficiency: IgG, IgA, and IgM were significantly low or absent, as well as all IgG subclasses; blood and bone marrow aspirate leucocyte immunophenotyping showed complete absence of B lymphocytes and reduced CD4+ T cells. In light of: i) thymoma; ii) B lymphocyte deficit; iii) hypogammaglobulinemia; iv) recurrent infections, GS was diagnosed and pre-emptive immunoglobulin treatment, associated with HSV and Pneumocystis jiroveci prophylaxis (Acyclovir for HSV and Sulfamethoxazole- Trimethoprim for P. jiroveci) were started. Since then the patient has no longer presented any infectious episodes.


Molecular characterization and expression analysis of the superoxide dismutase gene from Streptococcus agalactiae.
We have cloned and sequenced a 3103-bp DNA fragment carrying the gene encoding the Mn-SOD from Streptococcus agalactiae NEM318 serotype III. This DNA fragment contained four orfs that have the same polarity of transcription. Orf1 was truncated by molecular cloning and the corresponding 228-aa-long polypeptide did not exhibit any significant homology with other cognate proteins. Orf2 encodes a protein of 345 aa that displays some similarity (29% identity) with the YqeN peptide of Bacillus subtilis, the function of which is unknown. Orf3 encodes the 202-aa-long Mn-SOD which was functionally expressed in Escherichia coli. Orf4 was also truncated by molecular cloning and encodes 99 aa of the N-terminal moiety of a protein that displays significant homology (40% f identity) with the antiterminator LicT of B. subtilis. Transcriptional analysis revealed that the sodA gene of S. agalactiae NEM318 was transcribed monocistronically from a promoter, the activity of which is neither regulated by pH, O2, nor CO2 concentrations of the culture medium. Analysis by high resolution agarose gel electrophoresis of the AluI DNA polymorphism of the sodA locus in wild-type strains of S. agalactiae belonging to serogroups I, II, or III revealed no detectable difference.


Antioxidant property of an active component purified from the leaves of paraquat-tolerant Rehmannia glutinosa.
Acteoside extracted from the leaves of Rehmannia glutinosa was examined to determine the mechanism(s) of its antioxidant properties. The deoxyribose assay system showed that acteoside has a high redox potential as electron donor, which generates hydroxyl radicals in an Fe3+-dependent manner similar to ascorbic acid. However, the antioxidant properties of acteoside differ from those of ascorbic acid in that the superoxide anion-mediated reduction of nitroblue tetrazolium was actively inhibited by acteoside but not by ascorbic acid. Acteoside protected cells against glucose oxidase-mediated cytotoxicity and apoptosis in a dose-dependent manner. In addition, acteoside had immune stimulating effects, as shown by the acteoside-mediated increase in the level of DNA synthesis, viability, and cytokine secretion in mouse splenocytes. Moreover, acteoside inhibited the gelatinolytic activity of MMP proteins in a dose-dependent manner. Considering these results and the fact that acteoside is a water-soluble natural product, acteoside might have potential as a preventative treatment for oxidative stress-mediated diseases and have possibilities in the cosmetic industry.


Prevalence, quantification and antimicrobial resistance of Campylobacter spp. on chicken neck-skins at points of slaughter in 5 major cities located on 4 continents.
Quantitative data on Campylobacter contamination of food are lacking, notably in developing countries. We assessed Campylobacter contamination of chicken neck-skins at points of slaughter in 5 major cities in Africa (Dakar in Senegal, Yaounde in Cameroon), Oceania (Noumea in New Caledonia), the Indian Ocean (Antananarivo in Madagascar) and Asia (Ho Chi Minh City (HCMC) in Vietnam. One hundred and fifty slaughtered chickens were collected in each of the 5 major cities from semi-industrial abattoirs or markets (direct slaughter by the seller), and 65.5% (491/750) were found to be Campylobacter-positive. Two cities, Yaounde and Noumea, demonstrated high prevalence Campylobacter detection rates (92.7% and 96.7% respectively) in contrast with HCMC (15.3%). Four species were identified among 633 isolates, namely C. jejuni (48.3%), C. coli (37.3%), C. lari (11.7%) and C. upsaliensis (1%). HCMC was the only city with C. lari isolation as was Antananarivo for C. upsaliensis. C. coli was highly prevalent only in Yaounde (69.5%). Among the 491 samples positive in Campylobacter detection, 329 were also positive with the enumeration method. The number of Campylobacter colony-forming units (CFU) per gram of neck-skin in samples positive in enumeration was high (mean of the log(10): 3.2 log(10) CFU/g, arithmetic mean: 7900CFU/g). All the cities showed close enumeration means except HCMC with a 1.81 log(10) CFU/g mean for positive samples. Semi-industrial abattoir was linked to a significant lower count of Campylobacter contamination than direct slaughter by the seller (p=0.006). On 546 isolates (546/633, 86.3%) tested for antibiotic susceptibility, resistance to erythromycin, ampicillin and ciprofloxacin was observed for respectively 11%, 19% and 50%. HCMC was the city where antibiotic resistant rates were the highest (95%, p=0.014). Considering the 329 positive chickens in Campylobacter enumeration, the mean number of resistant isolates to at least 2 different antibiotic families (19.8%), may be estimated ca. 1500CFU/g; the corresponding mean of the log(10) would be 2.5 log(10)CFU/g. As chickens are sold at slaughter and brought directly at home to be cooked, these data suggest a high probability of cross-contamination. A substantial proportion of isolates are drug-resistant, which could lead to potential public health issues. Health authorities should consider measures to reduce Campylobacter contamination of chicken during farming and at slaughter, and to provide appropriate food hygiene education. Further studies are needed in particular to investigate food-handling practices in domestic kitchens.


Three mechanisms underlie KCNQ2/3 heteromeric potassium M-channel potentiation.
The non-inactivating potassium M-current exerts a strong influence on neuronal excitability. The channels responsible for this current are made up of KCNQ subunits, and mutations in most of these produce human pathologies. Notably, in terms of excitation, mutations in either KCNQ2 or KCNQ3 lead to benign neonatal familial convulsions. Although a mere reduction of 25% in KCNQ2/3 function can increase excitability to epileptogenic levels, the potentiation of these subunits has anti-epileptogenic effects. After KCNQ2/3 heteromerization, current levels can augment as much as 10-fold, and we have discovered that there are three processes underlying this potentiation. First, there is an increase in the number of channels inserted in the membrane after heteromerization of the C-terminal region. Second, the N-terminal domain from KCNQ2 exerts a negative influence on the current level. Finally, Ala 315 of KCNQ3, a residue located in the inner vestibule after the selectivity filter, plays a critical role in preventing current flow in KCNQ3 homomeric channels, whereas it is permissive in heteromers in combination with Thr at the equivalent 276 position of KCNQ2.


Strengthening the evidence-base of integrated care for people with multi-morbidity in Europe using Multi-Criteria Decision Analysis (MCDA).
Evaluation of integrated care programmes for individuals with multi-morbidity requires a broader evaluation framework and a broader definition of added value than is common in cost-utility analysis. This is possible through the use of Multi-Criteria Decision Analysis (MCDA). This paper presents the seven steps of an MCDA to evaluate 17 different integrated care programmes for individuals with multi-morbidity in 8 European countries participating in the 4-year, EU-funded SELFIE project. In step one, qualitative research was undertaken to better understand the decision-context of these programmes. The programmes faced decisions related to their sustainability in terms of reimbursement, continuation, extension, and/or wider implementation. In step two, a uniform set of decision criteria was defined in terms of outcomes measured across the 17 programmes: physical functioning, psychological well-being, social relationships and participation, enjoyment of life, resilience, person-centeredness, continuity of care, and total health and social care costs. These were supplemented by programme-type specific outcomes. Step three presents the quasi-experimental studies designed to measure the performance of the programmes on the decision criteria. Step four gives details of the methods (Discrete Choice Experiment, Swing Weighting) to determine the relative importance of the decision criteria among five stakeholder groups per country. An example in step five illustrates the value-based method of MCDA by which the performance of the programmes on each decision criterion is combined with the weight of the respective criterion to derive an overall value score. Step six describes how we deal with uncertainty and introduces the Conditional Multi-Attribute Acceptability Curve. Step seven addresses the interpretation of results in stakeholder workshops. By discussing our solutions to the challenges involved in creating a uniform MCDA approach for the evaluation of different programmes, this paper provides guidance to future evaluations and stimulates debate on how to evaluate integrated care for multi-morbidity.


Individualized prognosis of cognitive decline and dementia in mild cognitive impairment based on plasma biomarker combinations.
We developed models for individualized risk prediction of cognitive decline in mild cognitive impairment (MCI) using plasma biomarkers of β-amyloid (Aβ), tau and neurodegeneration. A total of 573 patients with MCI from the Swedish BioFINDER study and the Alzheimer's Disease Neuroimaging Initiative (ADNI) were included in the study. The primary outcomes were longitudinal cognition and conversion to Alzheimer's disease (AD) dementia. A model combining tau phosphorylated at threonine 181 (P-tau181) and neurofilament light (NfL), but not Aβ42/Aβ40, had the best prognosis performance of all models (area under the curve = 0.88 for 4-year conversion to AD in BioFINDER, validated in ADNI), was stronger than a basic model of age, sex, education and baseline cognition, and performed similarly to cerebrospinal fluid biomarkers. A publicly available online tool for individualized prognosis in MCI based on our combined plasma biomarker models is introduced. Combination of plasma biomarkers may be of high value to identify individuals with MCI who will progress to AD dementia in clinical trials and in clinical practice.


Multiple sites and synergism in the binding of inhibitors to microsomal aminopeptidase.
The active site of microsomal aminopeptidase has been probed by studying the inhibition of the enzyme in the simultaneous presence of two ligands. The results have been analyzed with the Yonetani-Theorell plot to quantitate the degree of interaction between the two inhibitors. As expected, the enzyme contains a strong binding site for the alpha-amino group and the hydrophobic side chain of specific substrates. In addition, however, the enzyme can interact with another amine and a second hydrophobic group. Evidence suggests that this extra amine may bind to the zinc in an unprotonated form and that one of the hydrophobic sites is located in the vicinity. Another unexpected finding in this work is a strong synergism between the binding of ammonia and that of zinc ligands such as hydroxamates. This synergism may reflect an induced-fit mechanism that brings the catalytically important zinc atom into the optimal state only in the presence of specific substrates.


Within-mat variability in anatoxin-a and homoanatoxin-a production among benthic Phormidium (cyanobacteria) strains.
Benthic Phormidium mats can contain high concentrations of the neurotoxins anatoxin-a and homoanatoxin-a. However, little is known about the co-occurrence of anatoxin-producing and non-anatoxin-producing strains within mats. There is also no data on variation in anatoxin content among toxic genotypes isolated from the same mat. In this study, 30 Phormidium strains were isolated from 1 cm(2) sections of Phormidium-dominated mats collected from three different sites. Strains were grown to stationary phase and their anatoxin-a, homoanatoxin-a, dihydroanatoxin-a and dihydrohomoanatoxin-a concentrations determined using liquid chromatography-mass spectrometry. Each strain was characterized using morphological and molecular (16S rRNA gene sequences) techniques. Eighteen strains produced anatoxin-a, dihydroanatoxin-a or homoanatoxin-a. Strains isolated from each mat either all produced toxins, or were a mixture of anatoxin and non-anatoxin-producing genotypes. Based on morphology these genotypes could not be separated. The 16S rRNA gene sequence comparisons showed a difference of at least 17 nucleotides among anatoxin and non-anatoxin-producing strains and these formed two separate sub-clades during phylogenetic analysis. The total anatoxin concentration among toxic strains varied from 2.21 to 211.88 mg kg(-1) (freeze dried weight), representing a 100 fold variation in toxin content. These data indicate that both the relative abundance of anatoxin and non-anatoxin-producing genotypes, and variations in anatoxin producing capability, can influence the overall toxin concentration of benthic Phormidium mat samples.


Nonstationary filtered shot-noise processes and applications to neuronal membranes.
Filtered shot noise processes have proven to be very effective in modeling the evolution of systems exposed to shot noise sources and have been applied to a wide variety of fields ranging from electronics through biology. In particular, they can model the membrane potential V(m) of neurons driven by stochastic input, where these filtered processes are able to capture the nonstationary characteristics of V(m) fluctuations in response to presynaptic input with variable rate. In this paper we apply the general framework of Poisson point processes transformations to analyze these systems in the general case of nonstationary input rates. We obtain exact analytic expressions, as well as different approximations, for the joint cumulants of filtered shot noise processes with multiplicative noise. These general results are then applied to a model of neuronal membranes subject to conductance shot noise with a continuously variable rate of presynaptic spikes. We propose very effective approximations for the time evolution of the V(m) distribution and a simple method to estimate the presynaptic rate from a small number of V(m) traces. This work opens the perspective of obtaining analytic access to important statistical properties of conductance-based neuronal models such as the first passage time.


Solvation in Space-time: Pretransition Effects in Trajectory Space.
We demonstrate pretransition effects in space-time in trajectories of systems in which the dynamics displays a first-order phase transition between distinct dynamical phases. These effects are analogous to those observed for thermodynamic first-order phase transitions, most notably the hydrophobic effect in water. Considering the (infinite temperature) East model as an elementary example, we study the properties of "space-time solvation" by examining trajectories where finite space-time regions are conditioned to be inactive in an otherwise active phase. We find that solvating an inactive region of space-time within an active trajectory shows two regimes in the dynamical equivalent of solvation free energy: an "entropic" small solute regime in which uncorrelated fluctuations are sufficient to evacuate activity from the solute, and an "energetic" large solute regime which involves the formation of a solute-induced inactive domain with an associated active-inactive interface bearing a dynamical interfacial tension. We also show that as a result of this dynamical interfacial tension there is a dynamical analog of the hydrophobic collapse that drives the assembly of large hydrophobes in water. We discuss the general relevance of these results to the properties of dynamical fluctuations in systems with slow collective relaxation such as glass formers.


One-Pot Parallel Synthesis of Alkyl Sulfides, Sulfoxides, and Sulfones.
A simple and cost-effective one-pot parallel synthesis approach to sulfides, sulfoxides, and sulfones from thiourea was elaborated. The method combines two procedures optimized to the parallel synthesis conditions: alkylation of thiourea with alkyl chlorides and mono or full oxidation of in situ generated sulfides with H2O2 or H2O2-(NH4)2MoO4. The experimental set up required commonly used lab equipment: conventional oven and ultrasonic bath; the work up includes filtration or extraction with chloroform. The method was evaluated on an 81 member library of drug-like sulfides, sulfoxides, and sulfones yielding the compounds on a 30-300 mg scale. A small-scale synthesis of 2-(benzhydrylsulfinyl)acetamide (modafinil) utilizing our approach resulted in similar efficiency to the published procedures.


An exploration of the disease burden due to Cryptosporidium in consumed surface water for sub-Saharan Africa.
The protozoan pathogen Cryptosporidium is an important cause of diarrhoeal disease, but in many contexts its burden remains uncertain. The Global Waterborne Pathogen model for Cryptosporidium (GloWPa-Crypto) predicts oocyst concentrations in surface water at 0.5 by 0.5° (longitude by latitude) resolution, allowing us to assess the burden specifically associated with the consumption of contaminated surface water at a large scale. In this study, data produced by the GloWPa-Crypto model were used in a quantitative microbial risk assessment (QMRA) for sub-Saharan Africa, one of the regions most severely affected by diarrhoeal disease. We first estimated the number of people consuming surface water in this region and assessed both direct consumption and consumption from a piped (treated) supply. The disease burden was expressed in disability adjusted life years (DALYs). We estimate an annual number of 4.3 × 107 (95% uncertainty interval [UI] 7.4 × 106-5.4 × 107) cases which represent 1.6 × 106 (95% UI 3.2 × 105-2.3 × 106) DALYs. Relative disease burden (DALYs per 100,000 persons) varies widely, ranging between 1.3 (95% UI 0.1-5.7) for Senegal and 1.0 × 103 (95% UI 4.2 × 102-1.4 × 103) for Eswatini. Countries that carry the highest relative disease burden are primarily located in south and south-east sub-Saharan Africa and are characterised by a relatively high HIV/AIDS prevalence. Direct surface water consumption accounts for the vast majority of cases, but the results also point towards the importance of stable drinking water treatment performance. This is, to our knowledge, the first study to utilise modelled data on pathogen concentrations in a large scale QMRA. It demonstrates the potential value of such data in epidemiological research, particularly regarding disease aetiology.


A first-principles study of pressure-induced phase transformation in a rare-earth formate framework.
Among the panoply of exciting properties that metal-organic frameworks (MOFs) exhibit, fully reversible pressure-induced phase transformations (PIPTs) are particularly interesting as they intrinsically relate to the flexibility of MOFs. Recently, a number of MOFs have been reported to exhibit this feature, which is attributed to bond rearrangement with applied pressure. However, the experimental assessment of whether a given MOF exhibits PIPT or not requires sophisticated instruments as well as detailed structural investigations. Can we capture such low pressure transformations through simulations is the question we seek to answer in this paper. For this, we have performed first-principles calculations based on the density functional theory, on a MOF, [tmenH2][Y(HCOO)4]2 (tmenH2(2+) = N,N,N',N'-tetramethylethylenediammonium). The estimated lattice constants for both the parent and product phases of the PIPT agree well with the earlier experimental results available for the same MOF with erbium. Importantly, the results confirm the observed PIPT, and thus provide theoretical corroborative evidence for the experimental findings. Our calculations offer insights into the energetics involved and reveal that the less dense phase is energetically more stable than the denser phase. From detailed analyses of the two phases, we correlate the changes in bonding and electronic structure across the PIPT with elastic and electronic conduction behavior that can be verified experimentally, to develop a deeper understanding of the PIPT in MOFs.


[Opening Status of the Korea Midwifery Birthing Centers and Development of Midwifery Practice Guideline].
This study was to investigate the operational status of the midwifery birthing centers (MBCs) and midwives' job status (Phase 1) and to develop midwifery practice guidelines (MPG) (Phase 2) in Korea. In the first phase, the subjects were 15 midwives who operated 11 of 14 MBCs that were opened as of August 2018. The questionnaire consisted of items to measure the operational status of the MBC and midwives' job status. In the second phase, the MPG was developed from literature review, interviews with five midwives opening their MBCs, surveys with 74 midwives, and a validity evaluation conducted by seven experts. The distribution of operating MBCs was five in Gyunggi-do, two each in Seoul and Incheon, one each in Busan, Chungcheongbuk-do, Gyeongsangbuk-do, Gyeongsangnam-do and Jeju-do. The mean age of midwives was 54.3 and all were female. In 2017, a total of 762 births including 81 homebirths were performed by midwives. The job performance was highest in the order of neonatal care 3.81, childbirth care 3.56, and postpartal care 3.53, respectively. The MPG included seven areas of prenatal care, childbirth care, postpartal care, neonatal care, primary health care, law/ethics, and administration, with 56 tasks and 166 task elements. This study provides the valid basic data for the operational status of the MBC and the midwives' job status. The MPG describes the midwife's job and may be used as basic data for preparing policies for the development of midwifery practice in Korea.


Quantum dot-sensitized solar cells based on directly adsorbed zinc copper indium sulfide colloids.
Heavy metal-based quantum dots (QDs) have been demonstrated to behave as efficient sensitizers in QD-sensitized solar cells (QDSSCs), as attested by the countless studies and encouraging efficiencies reported so far. However, their intrinsic toxicity has arisen as a major issue for the prospects of commercialization. Here, we examine the potential of environmentally friendly zinc copper indium sulfide (ZCIS) QDs for the fabrication of liquid-junction QDSSCs by means of photoelectrochemical measurements. A straightforward approach to directly adsorb ZCIS QDs on TiO2 from a colloidal dispersion is presented. Incident photon-to-current efficiency (IPCE) spectra of sensitized photoanodes show a marked dependence on adsorption time, with longer times leading to poorer performances. Cyclic voltammograms point to a blockage of the channels of the mesoporous TiO2 film by the agglomeration of QDs as the main reason for the decrease in efficiency. Photoanodes were also subjected to the ZnS treatment. Its effects on electron recombination with the electrolyte are analyzed through electrochemical impedance spectroscopy and photopotential measurements. The corresponding results bring out the role of the ZnS coating as a barrier layer in preventing electron leakage toward the electrolyte, as argued in other QD-sensitized systems. The beneficial effect of the ZnS coating is ultimately reflected in the power conversion efficiency of complete devices, reaching values of 2%. In a more general vein, through these findings, we aim to call the attention to the potentiality of this quaternary alloy, virtually unexplored as a light harvester for sensitized devices.


Why primary care practices should become digital health information hubs for their patients.
Two interesting health care trends are currently occurring: 1) patient-facing technologies, such as personal health records, patient portals, and mobile health apps, are being adopted at rapid rates, and 2) primary care, which includes family practice, is being promoted as essential to reducing health care costs and improving health care outcomes. While these trends are notable and commendable, both remain subject to significant fragmentation and incentive misalignments, which has resulted in significant data coordination and value generation challenges. In particular, patient-facing technologies designed to increase care coordination, often fall prey to the very digital fragmentation issues they are supposed to overcome. Additionally, primary care providers are treating patients that may have considerable health information histories, but generating a single view of such multi-source data is nearly impossible. We contribute to this debate by proposing that primary care practices become digital health information hubs for their patients. Such hubs would offer health data coordination in a medically professional setting with the benefits of expert, trustworthy advice coupled with active patient engagement. We acknowledge challenges including: costs, information quality and provenance, willingness-to-share information and records, willingness-to-use (by both providers and patients), primary care scope creep, and determinations of technical and process effectiveness. Even with such potential challenges, we strongly believe that more debate is needed on this topic prior to full implementation of various health information technology incentives and reform programs currently being designed and enacted throughout the world. Ultimately, if we do not provide a meaningful way for the full spectrum of health information to be used by both providers and patients, especially early in the health care continuum, effectively improving health outcomes may remain elusive. We view the primary care practice as a central component of digital information coordination, especially when considering the current challenges of digital health information fragmentation. Given these fragmentation issues and the emphasis on primary care as central to improving health and lower overall health care costs, we suggest that primary care practices should embrace their evolving role and should seek to become digital health information hubs for their patients.


Validity, responsiveness and the minimal clinically important difference for the de Morton Mobility Index (DEMMI) in an older acute medical population.
The de Morton Mobility Index (DEMMI) is a new mobility instrument that overcomes the limitations of existing instruments. It is the first mobility instrument that accurately measures the mobility of all older adults. The aim of this study was to provide a detailed report of investigations of the validity, responsiveness to change and minimal clinically important difference (MCID) of the DEMMI during its development in an older acute medical population. This study was conducted using a head to head comparison design in two independent samples of older acute medical patients (development sample, n = 86; validation sample, n = 106). Consecutive patients (≥ 65 years) were assessed using the DEMMI, Barthel Index (BI) and Hierarchical Assessment of Balance and Mobility (HABAM) within 48 hours of hospital admission and discharge. Convergent and discriminant validity were investigated using Spearman's rho and known groups validity was investigated using a independent t test to compare DEMMI scores for patients who were discharged to home compared to inpatient rehabilitation. Criterion and distribution based methods were employed for estimating instrument responsiveness to change and the MCID. Significant moderate to high correlations were identified between DEMMI and BI scores (r = 0.76 and r = 0.68) and DEMMI and HABAM scores (r = 0.91 and r = 0.92) in both samples. In both samples, DEMMI scores for patients who were discharged to home were significantly higher than for patients discharged to inpatient rehabilitation and provided evidence of known groups validity. Patients who were discharged to inpatient rehabilitation (n = 8) had a mean DEMMI score of 50.75 (sd = 11.29) at acute hospital discharge compared to patients who were discharged to home (n = 70) with a mean DEMMI score of 62.14 (sd = 18.41). MCID estimates were similar across samples using distribution and criterion based methods. The MCID for the DEMMI was 10 points on the 100 point interval scale. The DEMMI was significantly more responsive to change than the BI using criterion and distribution based methods in the validation sample. This study has validated the DEMMI in two independent samples of older acute medical patients. Estimates of its responsiveness and MCID have also been established. This study confirms that the DEMMI overcomes the limitations of the BI and HABAM and provides an advanced method for objectively assessing mobility for older acute medical patients.


Efficacy of two vaccine formulations against contagious bovine pleuropneumonia (CBPP) in Kenyan indigenous cattle.
A live, attenuated vaccine is currently the only viable option to control of CBPP in Africa. It has been suggested that simple modifications to current vaccines and protocols might improve efficacy in the field. In this report we compared the current vaccine formulation with a buffered preparation that maintains Mycoplasma viability at ambient temperature for a longer time. Groups of animals were vaccinated with the two formulations and compared with non vaccinated groups. Half of the animals in each group were challenged 3 months post vaccination, the other half after 16 months. Protection levels were measured using the pathology index, calculated from post mortem scores of lesions from animals killed during the course of clinical disease. In the challenge at 3 months post vaccination, the protection levels were 52% and 77% for the modified and current vaccine preparations, respectively. At 16 months post vaccination, the protection levels were 56% and 62% for the modified and current vaccine preparations, respectively. These findings indicate that there are no differences in protection levels between the two vaccines. Because of its longer half life after reconstitution, the modified vaccine might be preferred in field situations where the reconstituted vaccine is likely not to be administered immediately.


TiO2 nanoparticles induced hippocampal neuroinflammation in mice.
Titanium dioxide nanoparticles (TiO2 NPs) have been used in various medical and industrial areas. However, the impacts of these nanoparticles on neuroinflammation in the brain are poorly understood. In this study, mice were exposed to 2.5, 5, or 10 mg/kg body weight TiO2 NPs for 90 consecutive days, and the TLRs/TNF-α/NF-κB signaling pathway associated with the hippocampal neuroinflammation was investigated. Our findings showed titanium accumulation in the hippocampus, neuroinflammation and impairment of spatial memory in mice following exposure to TiO2 NPs. Furthermore, TiO2 NPs significantly activated the expression of Toll-like receptors (TLR2, TLR4), tumor necrosis factor-α, nucleic IκB kinase, NF-κB-inducible kinase, nucleic factor-κB, NF-κB2(p52), RelA(p65), and significantly suppressed the expression of IκB and interleukin-2. These findings suggest that neuroinflammation may be involved in TiO2 NP-induced alterations of cytokine expression in mouse hippocampus. Therefore, more attention should be focused on the application of TiO2 NPs in the food industry and their long-term exposure effects, especially in the human central nervous system.


Hanbury Brown and Twiss interferometry with twisted light.
The rich physics exhibited by random optical wave fields permitted Hanbury Brown and Twiss to unveil fundamental aspects of light. Furthermore, it has been recognized that optical vortices are ubiquitous in random light and that the phase distribution around these optical singularities imprints a spectrum of orbital angular momentum onto a light field. We demonstrate that random fluctuations of intensity give rise to the formation of correlations in the orbital angular momentum components and angular positions of pseudothermal light. The presence of these correlations is manifested through distinct interference structures in the orbital angular momentum-mode distribution of random light. These novel forms of interference correspond to the azimuthal analog of the Hanbury Brown and Twiss effect. This family of effects can be of fundamental importance in applications where entanglement is not required and where correlations in angular position and orbital angular momentum suffice. We also suggest that the azimuthal Hanbury Brown and Twiss effect can be useful in the exploration of novel phenomena in other branches of physics and astrophysics.


The role of egg-nest contrast in the rejection of brood parasitic eggs.
Hosts of avian brood parasites can avoid the reproductive costs of raising genetically unrelated offspring by rejecting parasitic eggs. The perceptual cues and controls mediating parasitic egg discrimination and ejection are well studied: hosts are thought to use differences in egg color, brightness, maculation, size and shape to discriminate between their own and foreign eggs. Most theories of brood parasitism implicitly assume that the primary criteria to which hosts attend when discriminating eggs are differences between the eggs themselves. However, this assumption is confounded by the degree to which chromatic and achromatic characteristics of the nest lining co-vary with egg coloration, so that egg-nest contrast per se might be the recognition cue driving parasitic egg detection. Here, we systematically tested whether and how egg-nest contrast itself contributes to foreign egg discrimination. In an artificial parasitism experiment, we independently manipulated egg color and nest lining color of the egg-ejector American robin (Turdus migratorius), a host of the obligate brood parasitic brown-headed cowbird (Molothrus ater). We hypothesized that the degree of contrast between foreign eggs and the nest background would affect host egg rejection behavior. We predicted that experimentally decreasing egg-nest chromatic and achromatic contrast (i.e. rendering parasitic eggs more cryptic against the nest lining) would decrease rejection rates, while increasing egg-nest contrast would increase rejection rates. In contrast to our predictions, egg-nest contrast was not a significant predictor of egg ejection patterns. Instead, egg color significantly predicted responses to parasitism. We conclude that egg-egg differences are the primary drivers of egg rejection in this system. Future studies should test for the effects of egg-nest contrast per se in predicting parasitic egg recognition in other host-parasite systems, including those hosts building enclosed nests and those parasites laying cryptic eggs, as an alternative to hypothesized effects of egg-egg contrast.


Serum BDNF levels in patients with gambling disorder are associated with the severity of gambling disorder and Iowa Gambling Task indices.
Background and aims Gambling disorder (GD) shares many similarities with substance use disorders (SUDs) in clinical, neurobiological, and neurocognitive features, including decision-making. We evaluated the relationships among, GD, decision-making, and brain-derived neurotrophic factor (BDNF), as measured by serum BDNF levels. Methods Twenty-one male patients with GD and 21 healthy sex- and age-matched control subjects were evaluated for associations between serum BDNF levels and the Problem Gambling Severity Index (PGSI), as well as between serum BDNF levels and Iowa Gambling Task (IGT) indices. Results The mean serum BDNF levels were significantly increased in patients with GD compared to healthy controls. A significant correlation between serum BDNF levels and PGSI scores was found when controlling for age, depression, and duration of GD. A significant negative correlation was obtained between serum BDNF levels and IGT improvement scores. Discussion These findings support the hypothesis that serum BDNF levels constitute a dual biomarker for the neuroendocrine changes and the severity of GD in patients. Serum BDNF level may serve as an indicator of poor decision-making performance and learning processes in GD and help to identify the common physiological underpinnings between GD and SUDs.


Digital camera simulation.
We describe a simulation of the complete image processing pipeline of a digital camera, beginning with a radiometric description of the scene captured by the camera and ending with a radiometric description of the image rendered on a display. We show that there is a good correspondence between measured and simulated sensor performance. Through the use of simulation, we can quantify the effects of individual digital camera components on system performance and image quality. This computational approach can be helpful for both camera design and image quality assessment.


On-pump beating heart mitral valve surgery without cross-clamping the aorta.
Cardiac reperfusion injury is a well-described complication occurring after ischemia or following cardioplegic arrest. Various strategies have been developed to prevent ischemic reperfusion injury. The aim of this study was to assess the efficacy and applicability of the on-pump beating heart mitral valve surgery without cross-clamping the aorta in order to prevent reperfusion injury. The prospective study (between April 2005 and December 2006) included 88 consecutive patients who underwent mitral valve surgery. The operations were carried out on a beating heart using normothermic cardiopulmonary bypass without cross-clamping the aorta, therefore perfusing the heart antegradely through the aortic root. Venting the heart from the aorta and the pulmonary vein provided adequate visualization of the operative field. Seventy-eight patients (88.6%) underwent mitral valve replacement and 10 patients (11.3%) underwent mitral valve repair with this technique. Concomitant surgery was required in 29 patients (32.9%). Twenty-five patients (28.4%) had also undergone previous open heart surgery. Mean cardiopulmonary bypass time was 57.4 +/- 18.4 minutes. Mean duration of ventilation was 12.2 +/- 3.5 hours, mean intensive care unit stay was 1.3 +/- 1.6 days, and mean hospital stay was 6.9 +/- 4.5 days. One-year survival was 96.6% for all causes of mortality. In this study, we showed that on-pump beating heart operations without cross-clamping is an acceptable surgical choice for mitral valve disease. Complication rates are low and perioperative mortality is lower than that generally reported with conventional technique.


Leptospirosis in sheep in Western Canada.
A survey of 930 ovine sera and kidneys from 33 sheep was conducted to assess the rate of leptospiral infection in sheep slaughtered in Alberta. Sera were tested for the presence of agglutinins to indigenous serovars of Leptospira interrogans. Kidneys with gross lesions were examined for the presence of leptospires by means of an indirect fluorescent antibody test (FAT) and by culture. Antibodies to serovars pomona and hardjo were present at rates of 1.0% and 0.4%, respectively, in sheep from Saskatchewan, Alberta and British Columbia. Sera from 120 feedlot lambs shipped from Oregon reacted to serovars pomona, hardjo and grippotyphosa at rates of 1.7%, 61.7% and 59.1%, respectively. Fluorescent antibody test detected serovars (presumptively) hardjo in 52% of Oregon feedlot lambs and grippotyphosa in 32% of the same group, a finding supported by the isolation of both these serovars from a pool of two fluorescent antibody test-positive kidneys. The grippotyphosa strain was highly virulent for hamsters, producing intense icterus and death. Leptospires, presumptively serovar grippotyphosa were demonstrated by fluorescent antibody test in one Alberta lamb kidney. The possibility of spreading leptospirosis by movement of breeding stock through public facilities and by assembling lambs in feedlots is discussed.


Brain size evolution in pipefishes and seahorses: the role of feeding ecology, life history and sexual selection.
Brain size varies greatly at all taxonomic levels. Feeding ecology, life history and sexual selection have been proposed as key components in generating contemporary diversity in brain size across vertebrates. Analyses of brain size evolution have, however, been limited to lineages where males predominantly compete for mating and females choose mates. Here, we present the first original data set of brain sizes in pipefishes and seahorses (Syngnathidae) a group in which intense female mating competition occurs in many species. After controlling for the effect of shared ancestry and overall body size, brain size was positively correlated with relative snout length. Moreover, we found that females, on average, had 4.3% heavier brains than males and that polyandrous species demonstrated more pronounced (11.7%) female-biased brain size dimorphism. Our results suggest that adaptations for feeding on mobile prey items and sexual selection in females are important factors in brain size evolution of pipefishes and seahorses. Most importantly, our study supports the idea that sexual selection plays a major role in brain size evolution, regardless of on which sex sexual selection acts stronger.


Development of a full micro-scale spatially offset Raman spectroscopy prototype as a portable analytical tool.
We present, for the first time, a portable full micro-Spatially Offset Raman Spectroscopy (micro-SORS) prototype permitting the in situ analysis of thin, highly turbid stratified layers at depths not accessible to conventional Raman microscopy. The technique is suitable for the characterisation of painted layers in panels, canvases and mural paintings, painted statues and decorated objects in cultural heritage or stratified polymers, and biological, catalytic and forensics samples where invasive analysis is undesirable or impossible to perform. The new device is characterised conceptually in polymer and paint layer systems. The provision of portability with full micro-SORS delivers subsurface micro-SORS capability unlocking the non-invasive and non-destructive potential of micro-SORS at its most effective form permitting it to be applied to large and non-portable objects in situ without recourse to removing micro-fragments for laboratory analysis on benchtop Raman microscopes.


A retrospective study of pediatric endoscopy as performed in an adult endoscopy unit.
Gastrointestinal endoscopy is a safe, efficient technique with minimal complications, and a useful diagnostic tool for the pediatric population. Under ideal conditions endoscopies for children should be performed by experienced pediatric endoscopists. In this study we report our experience with pediatric endoscopy at the general adult endoscopy unit in our hospital. Our goal is to quantify the number of endoscopies performed in children, as well as their indications and findings, the type of sedation or anesthesia used, and the time waiting for the test to occur. Our experience demonstrates that endoscopists in a general adult gastroenterology department, working together with pediatricians, may perform a relevant number of endoscopies in children in a fast, safe, effective manner.


Gamma and beta frequency oscillations in response to novel auditory stimuli: A comparison of human electroencephalogram (EEG) data with in vitro models.
Investigations using hippocampal slices maintained in vitro have demonstrated that bursts of oscillatory field potentials in the gamma frequency range (30-80 Hz) are followed by a slower oscillation in the beta 1 range (12-20 Hz). In this study, we demonstrate that a comparable gamma-to-beta transition is seen in the human electroencephalogram (EEG) in response to novel auditory stimuli. Correlations between gamma and beta 1 activity revealed a high degree of interdependence of synchronized oscillations in these bands in the human EEG. Evoked (stimulus-locked) gamma oscillations preceded beta 1 oscillations in response to novel stimuli, suggesting that this may be analogous to the gamma-to-beta shift observed in vitro. Beta 1 oscillations were the earliest discriminatory responses to show enhancement to novel stimuli, preceding changes in the broad-band event-related potential (mismatch negativity). Later peaks of induced beta activity over the parietal cortex were always accompanied by an underlying gamma frequency oscillation as seen in vitro. A further analogy between in vitro and human recordings was that both gamma and beta oscillations habituated markedly after the initial novel stimulus presentation.


Discriminative learning of propagation and spatial pattern for motor imagery EEG analysis.
Effective learning and recovery of relevant source brain activity patterns is a major challenge to brain-computer interface using scalp EEG. Various spatial filtering solutions have been developed. Most current methods estimate an instantaneous demixing with the assumption of uncorrelatedness of the source signals. However, recent evidence in neuroscience suggests that multiple brain regions cooperate, especially during motor imagery, a major modality of brain activity for brain-computer interface. In this sense, methods that assume uncorrelatedness of the sources become inaccurate. Therefore, we are promoting a new methodology that considers both volume conduction effect and signal propagation between multiple brain regions. Specifically, we propose a novel discriminative algorithm for joint learning of propagation and spatial pattern with an iterative optimization solution. To validate the new methodology, we conduct experiments involving 16 healthy subjects and perform numerical analysis of the proposed algorithm for EEG classification in motor imagery brain-computer interface. Results from extensive analysis validate the effectiveness of the new methodology with high statistical significance.


Effect of waxy (Low Amylose) on Fungal Infection of Sorghum Grain.
Loss of function mutations in waxy, encoding granule bound starch synthase (GBSS) that synthesizes amylose, results in starch granules containing mostly amylopectin. Low amylose grain with altered starch properties has increased usability for feed, food, and grain-based ethanol. In sorghum, two classes of waxy (wx) alleles had been characterized for absence or presence of GBSS: wx(a) (GBSS(-)) and wx(b) (GBSS(+), with reduced activity). Field-grown grain of wild-type; waxy, GBSS(-); and waxy, GBSS(+) plant introduction accessions were screened for fungal infection. Overall, results showed that waxy grains were not more susceptible than wild-type. GBSS(-) and wild-type grain had similar infection levels. However, height was a factor with waxy, GBSS(+) lines: short accessions (wx(b) allele) were more susceptible than tall accessions (undescribed allele). In greenhouse experiments, grain from accessions and near-isogenic wx(a), wx(b), and wild-type lines were inoculated with Alternaria sp., Fusarium thapsinum, and Curvularia sorghina to analyze germination and seedling fitness. As a group, waxy lines were not more susceptible to these pathogens than wild-type, supporting field evaluations. After C. sorghina and F. thapsinum inoculations most waxy and wild-type lines had reduced emergence, survival, and seedling weights. These results are valuable for developing waxy hybrids with resistance to grain-infecting fungi.


Combined behavioural markers of cognitive biases are associated with anhedonia.
Biases towards negative information, as well as away from positive information, are associated with psychopathology. Examining biases in multiple processes has been theorised to be more predictive than examining bias in any process alone. Anhedonia is a core symptom of psychopathology and predictive of future psychopathological symptoms. Finding that combined biases are associated with anhedonia would advance knowledge of the nature of emotional processing biases and the value of objective performance-based measures for identifying early risk markers. Participants (N = 139) completed tasks that assess latency bias (dot probe) and biased recognition (two-alternative forced-choice) of emotional information, as well as an anhedonia measure. An index was computed for each task's performance reflecting biased processing of positive and negative words. Only combined biases on both tasks were associated with anhedonia. Attentional bias was positively associated with anhedonia, but only when recognition bias for emotional words was high. Thus, assessing biases in multiple domains increased sensitivity to uncover relationships between emotional processing biases and anhedonic symptoms.


On the mechanism of parathyroid hormone stimulation of calcium uptake by mouse distal convoluted tubule cells.
PTH stimulates transcellular Ca2+ absorption in renal distal convoluted tubules. The effect of PTH on membrane voltage, the ionic basis of the change in voltage, and the relations between voltage and calcium entry were determined on immortalized mouse distal convoluted tubule cells. PTH (10(-8) M) significantly increased 45Ca2+ uptake from basal levels of 2.81 +/- 0.16 to 3.88 +/- 0.19 nmol min-1 mg protein-1. PTH-induced 45Ca2+ uptake was abolished by the dihydropyridine antagonist, nifedipine (10(-5) M). PTH did not affect 22Na+ uptake. Intracellular calcium activity ([Ca2+]i) was measured in cells loaded with fura-2. Control [Ca2+]i averaged 112 +/- 21 nM. PTH increased [Ca2+]i over the range of 10(-11) to 10(-7) M. Maximal stimulation to 326 +/- 31 nM was achieved at 10(-8) M PTH. Resting membrane voltage measured with the potential sensitive dye DiO6(3) averaged -71 +/- 2 mV. PTH hyperpolarized cells by 19 +/- 4 mV. The chloride-channel blocker NPPB prevented PTH-induced hyperpolarization. PTH decreased and NPPB increased intracellular chloride, measured with the fluorescent dye SPQ. Chloride permeability was estimated by measuring the rate of 125I- efflux. PTH increased 125I- efflux and this effect was blocked by NPPB. Clamping voltage with K+/valinomycin; depolarizing membrane voltage by reducing extracellular chloride; or addition of NPPB prevented PTH-induced calcium uptake. In conclusion, PTH increases chloride conductance in distal convoluted tubule cells leading to decreased intracellular chloride activity, membrane hyperpolarization, and increased calcium entry through dihydropyridine-sensitive calcium channels.


Improving the convergence of closed and open path integral molecular dynamics via higher order Trotter factorization schemes.
Higher order factorization schemes are developed for path integral molecular dynamics in order to improve the convergence of estimators for physical observables as a function of the Trotter number. The methods are based on the Takahashi-Imada and Susuki decompositions of the Boltzmann operator. The methods introduced improve the averages of the estimators by using the classical forces needed to carry out the dynamics to construct a posteriori weighting factors for standard path integral molecular dynamics. The new approaches are straightforward to implement in existing path integral codes and carry no significant overhead. The Suzuki higher order factorization was also used to improve the end-to-end distance estimator in open path integral molecular dynamics. The new schemes are tested in various model systems, including an ab initio path integral molecular dynamics calculation on the hydrogen molecule and a quantum water model. The proposed algorithms have potential utility for reducing the cost of path integral molecular dynamics calculations of bulk systems.


Attitudes and knowledge of clinical staff regarding people who self-harm: a systematic review.
The attitudes held by clinical staff towards people who harm themselves, together with their knowledge about self-harm, are likely to influence their clinical practice and hence the experiences and outcomes of patients. Our aim was to systematically review the nature of staff attitudes towards people who engage in self-harm, including the factors that influence them, and the impact of training on attitudes, knowledge and behaviour of staff. A comprehensive search for relevant studies was performed on six electronic databases. Two independent reviewers screened titles, abstracts and full reports of studies, extracted data and gave each paper a quality rating. Qualitative and quantitative studies published in English were included. A total of 74 studies were included. Attitudes of general hospital staff, especially doctors, were largely negative, particularly towards individuals who repeatedly self-harm. Self-harm patients were viewed more negatively than other patients, except those abusing alcohol or drugs. Psychiatric staff in community and hospital settings displayed more positive attitudes than general hospital staff. Negative attitudes were more common among doctors than nursing staff although this was only true of general hospital staff. Active training led to consistent improvements in attitude and knowledge in all groups. Attitudes of general hospital staff towards self-harm patients are often negative, mirroring the experience of service users. Interventions can have a positive impact and improve the quality of patient care. Included only English language publications.


Assembly dynamics of microtubules at molecular resolution.
Microtubules are highly dynamic protein polymers that form a crucial part of the cytoskeleton in all eukaryotic cells. Although microtubules are known to self-assemble from tubulin dimers, information on the assembly dynamics of microtubules has been limited, both in vitro and in vivo, to measurements of average growth and shrinkage rates over several thousands of tubulin subunits. As a result there is a lack of information on the sequence of molecular events that leads to the growth and shrinkage of microtubule ends. Here we use optical tweezers to observe the assembly dynamics of individual microtubules at molecular resolution. We find that microtubules can increase their overall length almost instantaneously by amounts exceeding the size of individual dimers (8 nm). When the microtubule-associated protein XMAP215 (ref. 6) is added, this effect is markedly enhanced and fast increases in length of about 40-60 nm are observed. These observations suggest that small tubulin oligomers are able to add directly to growing microtubules and that XMAP215 speeds up microtubule growth by facilitating the addition of long oligomers. The achievement of molecular resolution on the microtubule assembly process opens the way to direct studies of the molecular mechanism by which the many recently discovered microtubule end-binding proteins regulate microtubule dynamics in living cells.


QT dispersion and components of the QT interval in ischaemia and infarction.
To evaluate changes in QT dispersion and components of the QT interval in patients admitted with unstable angina and acute myocardial infarction and to study the dynamics of these changes in patients with infarction. Prospective study recording electrocardiograms at 50 mm/s in patients admitted with typical cardiac chest pain. Subsequent confirmation of acute myocardial infarction according to standard criteria. Single blind analysis for QT dispersion and QT components using a digitiser and simple computer program. Results are expressed as native QT dispersion, QTc dispersion, and the QT dispersion ratio defined as QT dispersion divided by cycle length and expressed as a percentage. QT dispersion, QTc dispersion, and QT dispersion ratio were all higher in patients with acute myocardial infarction than in those with unstable angina (mean (SD) 66 (18) ms, 75 (26) ms1/2, and 8.1 (2.4)% compared with 38 (13) ms, 39 (13) ms1/2, and 4.5 (1.7) % respectively). Dynamic changes in QTc dispersion were seen after acute infarction with significant differences in the QT components occurring between the different patient groups. Levels of QT dispersion (87 (15) ms), QTc dispersion (105 (17) ms1/2), and QT dispersion ratio (11.7 (0.8)%) in the four patients with ventricular fibrillation were significantly higher. Use of QT dispersion ratio gave a narrower confidence interval. QT dispersion is increased after myocardial infarction and levels are higher in patients with ventricular fibrillation. The changes in QT dispersion are dynamic and may reflect the changing pattern of underlying ventricular recovery of ventricular excitability, which is profoundly disturbed in the earliest phase of acute infarction. Expressing QT dispersion as a percentage of cycle length (QT dispersion ratio) rather than using standard rate correction may be superior in identifying patients who develop ventricular fibrillation.


Current status of robotic partial nephrectomy.
In recent years, robotic partial nephrectomy has emerged as a technique for treatment of small renal masses alongside laparoscopic and open partial nephrectomy. Since this technique is still in a phase of adoption, many technical improvements, alterations and early experiences are published. We aim to review the recent literature, focus on recent advances in techniques and give an overview of published series. Recent series confirm the feasibility of robotic partial nephrectomy and demonstrate perioperative data and short-term oncological outcomes that are at least comparable to laparoscopic series. The development of better renorrhaphy techniques and optimal use of the robotic features to gain console surgeon independence seem to be the main focus. Also alternative hilar control, early unclamping and off-clamp techniques are being developed to lower the ischaemic effect on the kidney. The learning curve seems to be less steep than laparoscopic techniques. Robotic partial nephrectomy proves to be a well tolerated and efficacious minimally invasive option in the treatment of renal lesions. Main areas of interest are decreasing warm ischaemia time and modified renal closure techniques.


Generalized linear discriminant analysis: a unified framework and efficient model selection.
High-dimensional data are common in many domains, and dimensionality reduction is the key to cope with the curse-of-dimensionality. Linear discriminant analysis (LDA) is a well-known method for supervised dimensionality reduction. When dealing with high-dimensional and low sample size data, classical LDA suffers from the singularity problem. Over the years, many algorithms have been developed to overcome this problem, and they have been applied successfully in various applications. However, there is a lack of a systematic study of the commonalities and differences of these algorithms, as well as their intrinsic relationships. In this paper, a unified framework for generalized LDA is proposed, which elucidates the properties of various algorithms and their relationships. Based on the proposed framework, we show that the matrix computations involved in LDA-based algorithms can be simplified so that the cross-validation procedure for model selection can be performed efficiently. We conduct extensive experiments using a collection of high-dimensional data sets, including text documents, face images, gene expression data, and gene expression pattern images, to evaluate the proposed theories and algorithms.