Critical Care Nurses' Experiences With Spiritual Care: The SPIRIT Study.
Little is known about the effect of chaplains on critical care nurses who are caring for critically ill patients and their families. To understand nurses' experiences when they make a referral to the Spiritual Care Department for a patient or the family of a patient who is dying or deceased. Specific aims were to explore spiritual care's effect on nurses and how nurses understand the role of spiritual care in practice. A qualitative descriptive study using in-person, semistructured interviews in a 21-bed medical-surgical intensive care unit in a teaching hospital. Purposeful sampling identified nurses who had at least 5 years of experience and had cared for at least 5 patients who died on their shift and at least 5 patients for whom they initiated a spiritual care referral. Interviews were digitally recorded and anonymized; conventional content analysis was used to analyze transcripts. Three investigators independently coded 5 transcripts and developed the preliminary coding list. As analysis proceeded, investigators organized codes into categories and themes. A total of 25 nurses were interviewed. The central theme that emerged was presence, described through 3 main categories: the value of having chaplains present in the intensive care unit and their role, nurses' experiences working with chaplains, and nurses' experiences providing spiritual care. Nurses considered spiritual care essential to holistic care and valued the support chaplains provide to patients, families, and staff in today's spiritually diverse society.


Microchannel-based surface-enhanced Raman spectroscopy for integrated microfluidic analysis.
We have demonstrated a microchannel-based, surface-enhanced Raman spectroscopy (SERS) sensing approach for integrated microfluidic analysis developed using standard micro-fabrication technology. Our approach allows high-sensitivity SERS sensing with a comparatively low-excitation optical power intensity and large cross-sectional microchannel for biological cell analysis. Utilizing a microchannel with a cross section of 100 × 70 μm(2), we achieved a detection limit smaller than 10 nM for rhodamine 6G at an excitation power intensity of 132 W/cm(2), avoiding any possible heating effects on the sample under investigation. There is great potential for further improvement in the sensitivity of this microchannel-based SERS detection.


Management of Blood Pressure in Patients With Chronic Kidney Disease Not Receiving Dialysis: Synopsis of the 2021 KDIGO Clinical Practice Guideline.
The Kidney Disease: Improving Global Outcomes (KDIGO) 2021 clinical practice guideline for the management of blood pressure (BP) in patients with chronic kidney disease (CKD) not receiving dialysis is an update of the KDIGO 2012 guideline on the same topic and reflects new evidence on the risks and benefits of BP-lowering therapy among patients with CKD. It is intended to support shared decision making by health care professionals working with patients with CKD worldwide. This article is a synopsis of the full guideline. The KDIGO leadership commissioned 2 co-chairs to convene an international Work Group of researchers and clinicians. After a Controversies Conference in September 2017, the Work Group defined the scope of the evidence review, which was undertaken by an evidence review team between October 2017 and April 2020. Evidence reviews were done according to the Cochrane Handbook. The GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach was used to guide the development of the recommendations and rate the strength and quality of the evidence. Practice points were included to provide guidance when evidence was insufficient to make a graded recommendation. The guideline was revised after public consultation between January and March 2020. The updated guideline comprises 11 recommendations and 20 practice points. This synopsis summarizes key recommendations pertinent to the diagnosis and management of high BP in adults with CKD, excluding those receiving kidney replacement therapy. In particular, the synopsis focuses on recommendations for standardized BP measurement and a target systolic BP of less than 120 mm Hg, because these recommendations differ from some other guidelines.


BluePyOpt: Leveraging Open Source Software and Cloud Infrastructure to Optimise Model Parameters in Neuroscience.
At many scales in neuroscience, appropriate mathematical models take the form of complex dynamical systems. Parameterizing such models to conform to the multitude of available experimental constraints is a global non-linear optimisation problem with a complex fitness landscape, requiring numerical techniques to find suitable approximate solutions. Stochastic optimisation approaches, such as evolutionary algorithms, have been shown to be effective, but often the setting up of such optimisations and the choice of a specific search algorithm and its parameters is non-trivial, requiring domain-specific expertise. Here we describe BluePyOpt, a Python package targeted at the broad neuroscience community to simplify this task. BluePyOpt is an extensible framework for data-driven model parameter optimisation that wraps and standardizes several existing open-source tools. It simplifies the task of creating and sharing these optimisations, and the associated techniques and knowledge. This is achieved by abstracting the optimisation and evaluation tasks into various reusable and flexible discrete elements according to established best-practices. Further, BluePyOpt provides methods for setting up both small- and large-scale optimisations on a variety of platforms, ranging from laptops to Linux clusters and cloud-based compute infrastructures. The versatility of the BluePyOpt framework is demonstrated by working through three representative neuroscience specific use cases.


Mapping the landscape of human dopamine D2/3 receptors with [11C]raclopride.
The dopamine D2/3 system is fundamental for sensory, motor, emotional, and cognitive aspects of behavior. Small-scale human histopathological and animal studies show high density of D2/3 dopamine receptors (D2/3DR) in striatum, but also demonstrate the existence of such receptors across cortical and limbic regions. Assessment of D2/3DR BPND in the extrastriatal regions with [11C]raclopride has long been considered unreliable due to the relatively low density of D2/3DR outside the striatum. We describe the distribution and interregional links of D2/3DR availability measured with PET and [11C]raclopride across the human brain in a large sample (N = 176; age range 64-68 years). Structural equation modeling revealed that D2/3DR availability can be organized according to anatomical (nigrostriatal, mesolimbic, mesocortical) and functional (limbic, associative, sensorimotor) dopamine pathways. D2/3DR availability in corticolimbic functional subdivisions showed differential associations to corresponding striatal subdivisions, extending animal and pharmacological work. Our findings provide evidence on the dimensionality and organization of [11C]raclopride D2/3DR availability in the living human brain that conforms to known dopaminergic pathways.


The clinical domains of psychosomatic medicine.
The psychosomatic evidence that has consolidated over the past decades provides the ideal background for dealing with the new needs that emerge in current medical practice. A review of the psychosomatic literature, using both MEDLINE and manual searches, was performed. Search terms were psychosomatic, psychosomatic medicine, mind-body medicine, and biopsychosocial. Medical journals and books in English were also searched manually. Articles, with particular reference to review articles, which were judged to be relevant to clinical practice, were selected. The following aspects were found of particular clinical interest: assessment of psychosocial factors affecting individual vulnerability (life events, chronic stress and allostatic load, well-being, and health attitudes), evaluation of psychosocial correlates of medical disease (psychiatric disturbances, psychological symptoms, illness behavior, and quality of life), application of psychological therapies to medical disease (lifestyle modification, treatment of psychiatric comorbidity, and abnormal illness behavior). A psychosomatic approach may be crucial in managing patients with unexplained somatic symptoms and in identifying psychological distress that cannot be diagnosed by psychiatric categories. Furthermore, it may contribute to recovery and rehabilitation by specific interventions.


Behavioral assessment of child-directed canine aggression.
To characterize behavioral circumstances of bites to children by dogs presented to a veterinary behavior clinic. Retrospective case series examining medical records of dogs presenting by referral to a university veterinary hospital for aggression and which had bitten a child <18 years old. Behavioral data included age of victim, familiarity with dog, and circumstances of bites. Records of bites to 111 children were examined. Children <6 years old were most commonly bitten in association with resource guarding (44%), whereas older children were most commonly bitten in association with territory guarding (23%). Similarly, food guarding was the most common circumstance for bites to familiar children (42%) and territory guarding for bites to unfamiliar children (53%). Behavioral screening of the 103 dogs examined revealed resource guarding (61%) and discipline measures (59%) as the most common stimuli for aggression. Anxiety screens revealed abnormalities in 77% of dogs. Potential contributory medical conditions were identified/suspected in 50% of dogs. When history before presentation was known, 66% of dogs had never previously bitten a child, and 19% had never bitten any human. Most dogs (93%) were neutered, and 66% of owners had taken their dogs to obedience training classes. Most children were bitten by dogs with no history of biting children. There is a high rate of behavioral abnormalities (aggression and anxiety) in this canine population. Common calming measures (neutering, training) were not routinely effective deterrents.


Cost analysis related to dose-response of spinal manipulative therapy for chronic low back pain: outcomes from a randomized controlled trial.
The purpose of this analysis is to report the incremental costs and benefits of different doses of spinal manipulative therapy (SMT) in patients with chronic low back pain (LBP). We randomized 400 patients with chronic LBP to receive a dose of 0, 6, 12, or 18 sessions of SMT. Participants were scheduled for 18 visits for 6 weeks and received SMT or light massage control from a doctor of chiropractic. Societal costs in the year after study enrollment were estimated using patient reports of health care use and lost productivity. The main health outcomes were the number of pain-free days and disability-free days. Multiple regression was performed on outcomes and log-transformed cost data. Lost productivity accounts for most societal costs of chronic LBP. Cost of treatment and lost productivity ranged from $3398 for 12 SMT sessions to $3815 for 0 SMT sessions with no statistically significant differences between groups. Baseline patient characteristics related to increase in costs were greater age (P = .03), greater disability (P = .01), lower quality-adjusted life year scores (P = .01), and higher costs in the period preceding enrollment (P < .01). Pain-free and disability-free days were greater for all SMT doses compared with control, but only SMT 12 yielded a statistically significant benefit of 22.9 pain-free days (P = .03) and 19.8 disability-free days (P = .04). No statistically significant group differences in quality-adjusted life years were noted. A dose of 12 SMT sessions yielded a modest benefit in pain-free and disability-free days. Care of chronic LBP with SMT did not increase the costs of treatment plus lost productivity.


Palivizumab use in preterm neonates.
Respiratory syncytial virus (RSV) is the leading cause of bronchiolitis in infants. Palivizumab is an immunoprophylactic agent for RSV prevention in preterm infants and those with neonatal chronic lung disease. This study examines its use across neonatal units in Ireland. A questionnaire was administered to one Consultant Neonatologist or Paediatrician in each of the 20 maternity centres in Ireland about their guidelines for Palivizumab administration. There is variation in administration of Palivizumab with little consistency found between protocols reported in terms of age and presence of chronic lung disease. Ten centres have in house protocols, 3 centres use the American Academy of Paediatrics (AAP) guidelines, 2 centres prefer the UK Joint Committee on Vaccination and Immunisation (JCVI) guidelines and 3 centres do not have a set protocol. Four participants felt its use has impacted on hospital admissions and 61% believe its use is cost effective. The budgetary implication for immunoprophylaxis with Palivizumab in Ireland is estimated at 1.5 to 2 million euros annually. Given current pharmacoeconomic constraints there is a need to implement a national protocol on RSV immunoprophylaxis.


Biogenetic models of psychopathology, implicit guilt, and mental illness stigma.
Whereas some research suggests that acknowledgment of the role of biogenetic factors in mental illness could reduce mental illness stigma by diminishing perceived responsibility, other research has cautioned that emphasizing biogenetic aspects of mental illness could produce the impression that mental illness is a stable, intrinsic aspect of a person ("genetic essentialism"), increasing the desire for social distance. We assessed genetic and neurobiological causal attributions about mental illness among 85 people with serious mental illness and 50 members of the public. The perceived responsibility of persons with mental illness for their condition, as well as fear and social distance, was assessed by self-report. Automatic associations between Mental Illness and Guilt and between Self and Guilt were measured by the Brief Implicit Association Test. Among the general public, endorsement of biogenetic models was associated with not only less perceived responsibility, but also greater social distance. Among people with mental illness, endorsement of genetic models had only negative correlates: greater explicit fear and stronger implicit self-guilt associations. Genetic models may have unexpected negative consequences for implicit self-concept and explicit attitudes of people with serious mental illness. An exclusive focus on genetic models may therefore be problematic for clinical practice and anti-stigma initiatives.


The genome sequence of Bacillus anthracis Ames and comparison to closely related bacteria.
Bacillus anthracis is an endospore-forming bacterium that causes inhalational anthrax. Key virulence genes are found on plasmids (extra-chromosomal, circular, double-stranded DNA molecules) pXO1 (ref. 2) and pXO2 (ref. 3). To identify additional genes that might contribute to virulence, we analysed the complete sequence of the chromosome of B. anthracis Ames (about 5.23 megabases). We found several chromosomally encoded proteins that may contribute to pathogenicity--including haemolysins, phospholipases and iron acquisition functions--and identified numerous surface proteins that might be important targets for vaccines and drugs. Almost all these putative chromosomal virulence and surface proteins have homologues in Bacillus cereus, highlighting the similarity of B. anthracis to near-neighbours that are not associated with anthrax. By performing a comparative genome hybridization of 19 B. cereus and Bacillus thuringiensis strains against a B. anthracis DNA microarray, we confirmed the general similarity of chromosomal genes among this group of close relatives. However, we found that the gene sequences of pXO1 and pXO2 were more variable between strains, suggesting plasmid mobility in the group. The complete sequence of B. anthracis is a step towards a better understanding of anthrax pathogenesis.


Cytosolic Fe-S Cluster Protein Maturation and Iron Regulation Are Independent of the Mitochondrial Erv1/Mia40 Import System.
The sulfhydryl oxidase Erv1 partners with the oxidoreductase Mia40 to import cysteine-rich proteins in the mitochondrial intermembrane space. In Saccharomyces cerevisiae, Erv1 has also been implicated in cytosolic Fe-S protein maturation and iron regulation. To investigate the connection between Erv1/Mia40-dependent mitochondrial protein import and cytosolic Fe-S cluster assembly, we measured Mia40 oxidation and Fe-S enzyme activities in several erv1 and mia40 mutants. Although all the erv1 and mia40 mutants exhibited defects in Mia40 oxidation, only one erv1 mutant strain (erv1-1) had significantly decreased activities of cytosolic Fe-S enzymes. Further analysis of erv1-1 revealed that it had strongly decreased glutathione (GSH) levels, caused by an additional mutation in the gene encoding the glutathione biosynthesis enzyme glutamate cysteine ligase (GSH1). To address whether Erv1 or Mia40 plays a role in iron regulation, we measured iron-dependent expression of Aft1/2-regulated genes and mitochondrial iron accumulation in erv1 and mia40 strains. The only strain to exhibit iron misregulation is the GSH-deficient erv1-1 strain, which is rescued with addition of GSH. Together, these results confirm that GSH is critical for cytosolic Fe-S protein biogenesis and iron regulation, whereas ruling out significant roles for Erv1 or Mia40 in these pathways.


An Efficient and Provable Approach for Mixture Proportion Estimation Using Linear Independence Assumption.
In this paper, we study the mixture proportion estimation (MPE) problem in a new setting: given samples from the mixture and the component distributions, we identify the proportions of the components in the mixture distribution. To address this problem, we make use of a linear independence assumption, i.e., the component distributions are independent from each other, which is much weaker than assumptions exploited in the previous MPE methods. Based on this assumption, we propose a method (1) that uniquely identifies the mixture proportions, (2) whose output provably converges to the optimal solution, and (3) that is computationally efficient. We show the superiority of the proposed method over the state-of-the-art methods in two applications including learning with label noise and semi-supervised learning on both synthetic and real-world datasets.


Dichotic Digits Test Performance Across the Ages: Results From Two Large Epidemiologic Cohort Studies.
The Dichotic Digits test (DDT) has been widely used to assess central auditory processing but there is limited information on observed DDT performance in a general population. The purpose of the study was to determine factors related to DDT performance in a large cohort spanning the adult age range. The study was cross-sectional and subjects were participants in the Epidemiology of Hearing Loss Study (EHLS), a population-based investigation of age-related hearing loss, or the Beaver Dam Offspring Study (BOSS), a study of aging in the adult offspring of the EHLS members. Subjects seen during the 4th EHLS (2008 to 2010) or the 2nd BOSS (2010 to 2013) examination were included (N = 3655 participants [1391 EHLS, 2264 BOSS]; mean age = 61.1 years, range = 21 to 100 years). The free and right ear-directed recall DDTs were administered using 25 sets of triple-digit pairs with a 70 dB HL presentation level. Pure-tone audiometric testing was conducted and the pure-tone threshold average (PTA) at 0.5, 1, 2, and 4 kHz was categorized using the worse ear: no loss = PTA ≤ 25 dB HL; mild loss = 25 < PTA ≤ 40 dB HL; moderate or marked loss = PTA > 40 dB HL. Cognitive impairment was defined as a Mini-Mental State Examination score < 24 (maximum = 30) or a self- or proxy-reported history of dementia or Alzheimer's disease. Demographic information was self-reported. General linear models were fit and multiple linear regression was performed. The mean total free recall DDT score was 76.7% (range = 21.3 to 100%). Less than 10% of the participants had a total free recall score below 60% correct. The mean right ear-directed recall score was 98.4% with 69% of the participants scoring 100% and another 15.5% scoring 98.7% (1 incorrect digit). In multivariable modeling of the total free recall scores, the predicted mean free recall score was 1 percentage point lower for every 5-year increase in age, 2.3 percentage points lower in males than females, 8.7 percentage points lower in participants with less than a high school degree than in those with college degrees, 6.8 percentage points lower in participants with a moderate or marked hearing loss compared with no hearing loss, and 8.3 percentage points lower in participants with cognitive impairment compared with those without cognitive impairment. These 5 factors were independently and significantly related to performance and accounted for 22.7% of the total variability in free recall scores. Substantial variation in the total free recall DDT scores but very little variation in the right ear-directed recall DDT scores was observed. Age, sex, education, hearing loss severity, and cognitive impairment were found to be significantly related to DDT scores but explained less than 25% of the total variability in total free recall scores. The right ear-directed recall DDT by itself may not be of benefit in assessing central auditory processing in a general population because of its limited variability but further evaluation of factors potentially related to free recall DDT variability may prove useful.


Photonic-plasmonic-coupled nanoantennas for polarization-controlled multispectral nanofocusing.
We report on the design and experimental demonstration of array-enhanced nanoantennas for polarization-controlled multispectral nanofocusing in the near-IR spectral range. We design plasmonic double bow-tie nanoantennas-coupled to multiple-periodic nanoparticle arrays to harvest radiation of designed wavelengths from a large spatial area and to focus it into a targeted nanoscale region. Near-field calculations were performed on a gold nanoantenna array using three-dimensional finite difference time domain simulations. Cross-shaped optical nanoantennas were fabricated on glass substrates using electron beam lithography. The optical characterization of the fabricated nanoantennas was performed using second harmonic excitation spectroscopy that demonstrates multiwavelength photonic coupling in good agreement with the antenna modeling. The nanoantenna structures introduced in this Letter provide the ability to focus optical energy into deep subwavelength areas and to address multiple spectral regions with polarization control. Such attributes are highly desirable in optical biosensing, enhanced Raman scattering, and for nonlinear plasmonic applications.


Indomethacin activates peroxisome proliferator-activated receptor γ to improve insulin resistance in cotton pellet granuloma model.
Inflammation is involved in the development of insulin resistance and diabetes. However, the effectiveness of anti-inflammatory drugs in diabetic therapy remains obscure. In the present study, the possible mechanisms of indomethacin, one of the nonsteroidal anti-inflammatory drugs, in the improvement of insulin resistance were investigated. Indomethacin treatment significantly decreased cotton pellet implantation induced white blood cell count elevation and immune cells infiltration in epididymal white adipose tissue. Also, cotton pellet implantation induced impaired glucose utilization and insulin resistance were improved by indomethacin. The decrement in phosphoinsulin receptor and phospho-Akt levels induced by cotton pellet implantation was improved by indomethacin as well. Moreover, indomethacin decreased cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) expression in epididymal white adipose tissue with a marked reduction of prostaglandin 2 (PGE2) and nitrite/nitrate (NOx) levels in cotton pellet-implanted mice. Furthermore, pretreatment of peroxisome proliferator-activated receptor γ (PPARγ) antagonist, GW9662 not only reversed indomethacin-modified COX-2 and iNOS levels but also reversed indomethacin-improved insulin sensitivity determined by homeostasis model assessment-insulin resistance (HOMA-IR). Taken together, indomethacin might elevate the expression of PPARγ to decrease serum NOx and PGE2 to result in the improvement of insulin resistance.


Mycobacterial biomaterials and resources for researchers.
There are many resources available to mycobacterial researchers, including culture collections around the world that distribute biomaterials to the general scientific community, genomic and clinical databases, and powerful bioinformatics tools. However, many of these resources may be unknown to the research community. This review article aims to summarize and publicize many of these resources, thus strengthening the quality and reproducibility of mycobacterial research by providing the scientific community access to authenticated and quality-controlled biomaterials and a wealth of information, analytical tools and research opportunities.


Heterogeneous and multiphase formation pathways of gypsum in the atmosphere.
Gypsum is a major sulphur-containing component of atmospheric particulate matter. To date, however, its formation pathways in the atmosphere are still not well known. In this study, several potentially important formation pathways of gypsum in atmospheric aerosols are proposed. We found that gypsum was formed in the humidifying-dehumidifying process of mixed sulphate and calcium salts. A deliquescent layer is crucial for the formation of gypsum from Ca(2+) and SO4(2-) ions. In particular, the presence of hygroscopic components, such as (NH4)2SO4 and Ca(NO3)2, is necessary for the conversion of calcium carbonate (CaCO3) upon heterogeneous reaction of either SO2 + O3 or SO2 + NO2 as well as anhydrous calcium sulphate (CaSO4) to form gypsum (CaSO4·2H2O) under ambient conditions. This study provides definitive evidence that synergistic effects in the physical and chemical processing of aerosol particles have a significant effect on their final chemical composition, mixing state and hygroscopic behaviour which dictates the environmental and climate impacts of the resulting aerosol.


Private traits and attributes are predictable from digital records of human behavior.
We show that easily accessible digital records of behavior, Facebook Likes, can be used to automatically and accurately predict a range of highly sensitive personal attributes including: sexual orientation, ethnicity, religious and political views, personality traits, intelligence, happiness, use of addictive substances, parental separation, age, and gender. The analysis presented is based on a dataset of over 58,000 volunteers who provided their Facebook Likes, detailed demographic profiles, and the results of several psychometric tests. The proposed model uses dimensionality reduction for preprocessing the Likes data, which are then entered into logistic/linear regression to predict individual psychodemographic profiles from Likes. The model correctly discriminates between homosexual and heterosexual men in 88% of cases, African Americans and Caucasian Americans in 95% of cases, and between Democrat and Republican in 85% of cases. For the personality trait "Openness," prediction accuracy is close to the test-retest accuracy of a standard personality test. We give examples of associations between attributes and Likes and discuss implications for online personalization and privacy.


Dual-emitting Langmuir-Blodgett film-based organic light-emitting diodes.
Langmuir-Blodgett (LB) films containing alternating layers of the metallosurfactants bis(4,4'-tridecyl-2,2'-bipyridine)-(4,4'-dicarboxy-2,2'-bipyridine) ruthenium(II)-bis(chloride) (1) and bis[2-(2,4-difluorophenyl)pyridine](4,4'-dinonadecyl-2,2'-bipyridine)iridium(III) chloride (2) have been prepared. Langmuir monolayers at the air-water interface of 1 and 2 with different anions in the subphase have been characterized by pi-A compression isotherms and Brewster angle microscopy (BAM). The transferred LB films have been characterized by IR, UV-vis and emission spectroscopy, and atomic force microscopy (AFM). Electroluminescent devices formed by LB films containing alternating layers of these two molecules show dual emission by simple mixing of the two emitters in a single LB film, and by preparing two stacked configurations, in which a LB layer of the ruthenium complexes is deposited on top of a LB layer of the iridium complexes and the inverse situation. The color of the electroluminescence can be tuned by changing the thickness of each LB layer. Due to efficient hole blocking of a layer of the iridium complexes when deposited on top of the layer of ruthenium complexes, in that configuration the green emission of the iridium complexes is suppressed. In the opposite case, excitons are generated in both layers although most likely preferentially in the layer of the iridium complexes.


Comparison of two arylsulfatases for targeted mass spectrometric analysis of microbiota-derived metabolites.
Sulfation of metabolites is the second highest phase II modification in humans, which plays a critical role in the xenobiotics clearance process and gut microbiota-host co-metabolism. Besides the main function to remove xenobiotics from the body, sulfated metabolites have also been linked to inflammation, bacterial pathogenesis and metabolic disorders. A better understanding of how these metabolites impact the human body has turned into an important research area. Analytical methods for selective identification of this metabolite class are scarce. We have recently developed an assay utilizing the arylsulfatase from Helix pomatia due to a high substrate promiscuity combined with state-of-the-art metabolomics bioinformatic analysis for the selective identification of O-sulfated metabolites in human samples. This enzyme requires a multistep purification process as highest purity is needed for the developed mass spectrometric assay. In this study, we have utilized a new and recombinant overexpressed arylsulfatase (ASPC) for the selective identification of organic sulfate esters in human urine samples. We have compared the substrate conversion in urine samples and substrate specificity of this enzyme with purified arylsulfatase from Helix pomatia. Our analysis of urine samples revealed that both enzymes can be utilized for the selective analysis and discovery of sulfated metabolites with high promiscuity as demonstrated by equal hydrolysis of 108 substrates including sulfated conjugates of 27 metabolites of microbial origin. Importantly, we also identified 21 substrates in human urine samples that are exclusively hydrolyzed by ASPC and application of this enzyme increases the discovery of unknown sulfated metabolites with a higher scaffold diversity.


The history of the capillary wall: doctors, discoveries, and debates.
In 1628, William Harvey provided definitive evidence that blood circulates. The notion that blood travels around the body in a circle raised the important question of how nutrients pass between blood and underlying tissue. Perhaps, Harvey posited, arterial blood pours into the flesh as into a sponge, only then to find its way into the veins. Far from solving this problem, Marcello Malpighi's discovery of the capillaries in 1661 only added to the dilemma: surely, some argued, these entities are little more than channels drilled into tissues around them. As we discuss in this review, it would take over 200 years to arrive at a consensus on the basic structure and function of the capillary wall. A consideration of the history of this period provides interesting insights into not only the central importance of the capillary as a focus of investigation, but also the enormous challenges associated with studying these elusive structures.


Innovative health reform models: pay-for-performance initiatives.
Pay-for-performance (P4P) programs have the potential to improve overall quality of care by narrowing gaps between what national care guidelines recommend and those treatments actually delivered in routine community practice. P4P is also viewed as a tool to promote more efficient use of healthcare resources while improving patient outcomes. P4P provides financial incentives for quality of service instead of quantity of service. Despite the promise of healthcare quality, concerns have been raised that P4P may have potential unintended consequences for patients, physicians, and hospitals. The shortcomings of many traditional P4P programs have fueled the emergence of new and innovative models of payment reform. P4P and newer models that link reimbursement with quality and efficiency show promise to improve patient outcomes and lower costs, but multiple approaches are needed to ensure that future initiatives provide value for key stakeholders, including patients, providers, and payers.


Pathogenesis of chronic cardiorenal syndrome: is there a role for oxidative stress?
Cardiorenal syndrome is a frequently encountered clinical condition when the dysfunction of either the heart or kidneys amplifies the failure progression of the other organ. Complex biochemical, hormonal and hemodynamic mechanisms underlie the development of cardiorenal syndrome. Both in vitro and experimental studies have identified several dysregulated pathways in heart failure and in chronic kidney disease that lead to increased oxidative stress. A decrease in mitochondrial oxidative metabolism has been reported in cardiomyocytes during heart failure. This is balanced by a compensatory increase in glucose uptake and glycolysis with consequent decrease in myocardial ATP content. In the kidneys, both NADPH oxidase and mitochondrial metabolism are important sources of TGF-β1-induced cellular ROS. NOX-dependent oxidative activation of transcription factors such as NF-kB and c-jun leads to increased expression of renal target genes (phospholipaseA2, MCP-1 and CSF-1, COX-2), thus contributing to renal interstitial fibrosis and inflammation. In the present article, we postulate that, besides contributing to both cardiac and renal dysfunction, increased oxidative stress may also play a crucial role in cardiorenal syndrome development and progression. In particular, an imbalance between the renin-angiotensin-aldosterone system, the sympathetic nervous system, and inflammation may favour cardiorenal syndrome through an excessive oxidative stress production. This article also discusses novel therapeutic strategies for their potential use in the treatment of patients affected by cardiorenal syndrome.


Adenovirus receptors: implications for targeting of viral vectors.
Cancer, cardiovascular disease, and infectious diseases are all global health threats. To combat these diseases with gene therapies, adenovirus-based vectors have been developed. Although certain clinical trials appear successful, there is an obvious need to improve the efficacy of most adenovirus-based vectors. For the most commonly used vector (based on type 5; Ad5), a main problem is its accumulation in the liver, which can be attributed to interactions with specific host factors. The diverse tropism for types other than Ad5 implies that vectors based on alternative types could have advantages. The numerous interactions of different adenoviruses with host molecules - such as the recently identified desmoglein-2 receptor - may cause novel and unexpected obstacles, but also may provide possibilities for vectors based on alternative types. This review provides an update of new and previously known molecules that mediate cellular attachment of human adenoviruses and discusses how these may influence the targeting of adenovirus-based vectors.


Narrow-line, cw orange light generation in a diode-pumped Nd:YVO4 laser using volume Bragg gratings.
We report on the demonstration of a narrow-line, cw orange 593-nm laser achieved via intracavity sum-frequency generation (SFG) of a diode-pumped dual-wavelength (1064 and 1342 nm) Nd:YVO(4) laser using two volume Bragg grating (VBG) reflectors. At diode pump power of up to 3.6 W, the 593-nm intracavity SFG laser radiates at the single longitudinal mode of spectral linewidth as narrow as approximately 15 MHz. More than 23-mW single-longitudinal-mode or 40-mW, <8.5-GHz (10-pm) linewidth (at 4.2-W diode pump power) 593-nm orange lights can be obtained from this compact laser system. Spectral tuning of the orange light was performed via the temperature tuning of the two VBGs in this system, achieving an effective tuning rate of ~5 pm/degrees C.


Musculoskeletal impairment of traumatic etiology in Rwanda: prevalence, causes, and service implications.
The present study examines demographics, causes, and diagnoses of traumatic musculoskeletal impairment (MSI) in Rwanda and identifies treatment barriers in order to describe the injury burden and inform service planning. In all, 105 clusters were chosen by multistage stratified cluster random sampling with probability proportional to size. Eighty people from each cluster were identified for screening by a modified compact segment sampling method. A screening questionnaire was applied and suspected cases and 10% of suspected non-cases underwent standardized examination. A structured interview obtained a detailed history, and an algorithmic classification system allocated diagnosis. Of 8,368 enumerated subjects, 6,756 were screened. Of these, 111 were traumatic MSI cases, with 121 diagnoses, giving a prevalence of 1.64% (95% CI 1.35-1.98). Extrapolation to the Rwandan population estimates 68,716 traumatic MSI cases, mostly in people of working age. Most affected were hand/finger joints (23%), elbow (16%), shoulder region (9%), and knee joint (9%). Some 11% of impairments were severe, 47.7% were moderate, and 41.3% were mild. Most common diagnoses were fracture malunion (21.5%) and post-traumatic joint stiffness (20.7%). The number of treatments needed was 199, including physiotherapy (87.2%) and surgery (53.7%), but 43% (95% CI 34-53) received less treatment than required. Of those who were undertreated, 63% cited cost. In Rwanda the prevalence of traumatic MSI of 1.64%, mostly in people of working age, makes usual activities difficult or impossible and is therefore a significant national burden. The results of the present study identify the need for immediate surgical intervention and physiotherapy, with cost as a treatment barrier. This study may direct aid providers toward subsidizing access to orthopedic care and thus reduce the impact of traumatic MSI.


Elovl4 5-bp deletion does not accelerate cone photoreceptor degeneration in an all-cone mouse.
Mutations in the elongation of very long chain fatty acid 4 (ELOVL4) gene cause Stargardt macular dystrophy 3 (STGD3), a rare, juvenile-onset, autosomal dominant form of macular degeneration. Although several mouse models have already been generated to investigate the link between the three identified disease-causing mutations in the ELOVL4 gene, none of these models recapitulates the early-onset cone photoreceptor cell death observed in the macula of STGD3 patients. To address this specifically, we investigated the effect of mutant ELOVL4 in a mouse model with an all-cone retina. Hence, we bred mice carrying the heterozygously mutated Elovl4 gene on the R91W;Nrl-/- all-cone background and analyzed the retinal lipid composition, morphology, and function over the course of 1 year. We observed a reduction of total phosphatidylcholine-containing very long chain-polyunsaturated fatty acids (PC-VLC-PUFAs) by 39% in the R91W;Nrl-/-;Elovl4 mice already at 6 weeks of age with a pronounced decline of the longest forms of PC-VLC-PUFAs. Total levels of shorter-chain fatty acids (< C26) remained unaffected. However, this reduction in PC-VLC-PUFA content in the all-cone retina had no impact on morphology or function and did not accelerate retinal degeneration in the R91W;Nrl-/-;Elovl4 mice. Taken together, mutations in the ELOVL4 gene lead to cone degeneration in humans, whereas mouse models expressing the mutant Elovl4 show predominant rod degeneration. The lack of a phenotype in the all-cone retina expressing the mutant form of the protein supports the view that aberrant function of ELOVL4 is especially detrimental for rods in mice and suggests a more subtle role of VLC-PUFAs for cone maintenance and survival.


Event-specific cannabis use and use-related impairment: the relationship to campus traditions.
Despite high rates of college cannabis use, little work has identified high-risk cannabis use events. For instance, Mardi Gras (MG) and St. Patrick's Day (SPD) are characterized by more college drinking, yet it is unknown whether they are also related to greater cannabis use. Further, some campuses may have traditions that emphasize substance use during these events, whereas other campuses may not. Such campus differences may affect whether students use cannabis during specific events. The present study tested whether MG and SPD were related to more cannabis use at two campuses with different traditions regarding MG and SPD. Further, given that Campus A has specific traditions regarding MG whereas Campus B has specific traditions regarding SPD, cross-campus differences in event-specific use were examined. Current cannabis-using undergraduates (N = 154) at two campuses completed an online survey of event-specific cannabis use and event-specific cannabis-related problems. Participants used more cannabis during MG and SPD than during a typical weekday, typical day on which the holiday fell, and a holiday unrelated to cannabis use (Presidents' Day). Among those who engaged in event-specific use, MG and SPD cannabis use was greater than typical weekend use. Campus differences were observed. For example, Campus A reported more cannabis-related problems during MG than SPD, whereas Campus B reported more problems during SPD than MG. Specific holidays were associated with more cannabis use and use-related problems. Observed between-campus differences indicate that campus traditions may affect event-specific cannabis use and use-related problems.


B2-kinin receptor plays a key role in B1-, angiotensin converting enzyme inhibitor-, and vascular endothelial growth factor-stimulated in vitro angiogenesis in the hypoxic mouse heart.
Angiotensin converting enzyme (ACE) inhibition reduces heart disease and vascular stiffness in hypertension and leads to kinin accumulation. In this study, we analysed the role and importance of two kinin receptor subtypes in angiogenesis during ACE inhibition in an in vitro model of angiogenesis of the mouse heart. First, we analysed the angiogenic properties of bradykinin and enalapril on wild-type C57Bl/6 and B2 receptor(-/-) mouse heart under normoxia (21% O(2)) and hypoxia (1% O(2)) in vitro and the contribution of B1 and B2 kinin receptors to this effect. Bradykinin induced dose-dependent endothelial sprout formation in vitro in adult mouse heart only under hypoxia (1.7 fold, n = 6, P < 0.05). The B2 receptor mediated sprouting that was induced by bradykinin and vascular endothelial growth factor (VEGF(164); n = 6, P < 0.05), but did not mediate sprouting that was induced by growth factors bFGF or PDGF-BB. Enalapril induced sprouting through both the B1 and B2 kinin receptors, but it required the presence of the B2 receptor in both scenarios and was dependent on BK synthesis. B1-receptor agonists induced sprout formation via the B1 receptor (2.5 fold, n = 6, P < 0.05), but it required the presence of the B2 receptor for them to do so. Both B2-receptor and B1-receptor agonist-induced angiogenesis required nitric oxide biosynthesis. The kinin B2 receptor plays a crucial role in angiogenesis that is induced by different vasoactive molecules, namely bradykinin, ACE inhibitors, B1-stimulating kinin metabolites, and VEGF164 in an in vitro model of angiogenesis of mouse heart under hypoxia. Therapeutic treatment of hypertensive patients by using ACE inhibitors may potentially benefit the ischaemic heart through inducing B2-dependent heart neovascularization.


Geographic population structure of the African malaria vector Anopheles gambiae suggests a role for the forest-savannah biome transition as a barrier to gene flow.
The primary Afrotropical malaria mosquito vector Anopheles gambiae sensu stricto has a complex population structure. In west Africa, this species is split into two molecular forms and displays local and regional variation in chromosomal arrangements and behaviors. To investigate patterns of macrogeographic population substructure, 25 An. gambiae samples from 12 African countries were genotyped at 13 microsatellite loci. This analysis detected the presence of additional population structuring, with the M-form being subdivided into distinct west, central, and southern African genetic clusters. These clusters are coincident with the central African rainforest belt and northern and southern savannah biomes, which suggests restrictions to gene flow associated with the transition between these biomes. By contrast, geographically patterned population substructure appears much weaker within the S-form.


Reflections on the ethics of recruiting foreign-trained human resources for health.
Developed countries' gains in health human resources (HHR) from developing countries with significantly lower ratios of health workers have raised questions about the ethics or fairness of recruitment from such countries. By attracting and/or facilitating migration for foreign-trained HHR, notably those from poorer, less well-resourced nations, recruitment practices and policies may be compromising the ability of developing countries to meet the health care needs of their own populations. Little is known, however, about actual recruitment practices. In this study we focus on Canada (a country with a long reliance on internationally trained HHR) and recruiters working for Canadian health authorities. We conducted interviews with health human resources recruiters employed by Canadian health authorities to describe their recruitment practices and perspectives and to determine whether and how they reflect ethical considerations. We describe the methods that recruiters used to recruit foreign-trained health professionals and the systemic challenges and policies that form the working context for recruiters and recruits. HHR recruiters' reflections on the global flow of health workers from poorer to richer countries mirror much of the content of global-level discourse with regard to HHR recruitment. A predominant market discourse related to shortages of HHR outweighed discussions of human rights and ethical approaches to recruitment policy and action that consider global health impacts. We suggest that the concept of corporate social responsibility may provide a useful approach at the local organizational level for developing policies on ethical recruitment. Such local policies and subsequent practices may inform public debate on the health equity implications of the HHR flows from poorer to richer countries inherent in the global health worker labour market, which in turn could influence political choices at all government and health system levels.


Nucleotides regulate the mechanical hierarchy between subdomains of the nucleotide binding domain of the Hsp70 chaperone DnaK.
The regulation of protein function through ligand-induced conformational changes is crucial for many signal transduction processes. The binding of a ligand alters the delicate energy balance within the protein structure, eventually leading to such conformational changes. In this study, we elucidate the energetic and mechanical changes within the subdomains of the nucleotide binding domain (NBD) of the heat shock protein of 70 kDa (Hsp70) chaperone DnaK upon nucleotide binding. In an integrated approach using single molecule optical tweezer experiments, loop insertions, and steered coarse-grained molecular simulations, we find that the C-terminal helix of the NBD is the major determinant of mechanical stability, acting as a glue between the two lobes. After helix unraveling, the relative stability of the two separated lobes is regulated by ATP/ADP binding. We find that the nucleotide stays strongly bound to lobe II, thus reversing the mechanical hierarchy between the two lobes. Our results offer general insights into the nucleotide-induced signal transduction within members of the actin/sugar kinase superfamily.


A Volunteer Program to Connect Primary Care and the Home to Support the Health of Older Adults: A Community Case Study.
Primary care providers are critical in providing and optimizing health care to an aging population. This paper describes the volunteer component of a program (Health TAPESTRY) which aims to encourage the delivery of effective primary health care in novel and proactive ways. As part of the program, volunteers visited older adults in their homes and entered information regarding health risks, needs, and goals into an electronic application on a tablet computer. A total of 657 home visits were conducted by 98 volunteers, with 22.45% of volunteers completing at least 20 home visits over the course of the program. Information was summarized in a report and electronically sent to the health care team via clients' electronic medical records. The report was reviewed by the interprofessional team who then plan ongoing care. Volunteer recruitment, screening, training, retention, and roles are described. This paper highlights the potential role of a volunteer in a unique connection between primary care providers and older adult patients in their homes.


Experiences of faith group members using new reproductive and genetic technologies: A qualitative interview study.
This paper explores the experiences of members of faith groups deciding whether or not to use new reproductive or genetic technologies (NRGTs). It is based on 16 in-depth, semi-structured interviews with people with direct experience of NRGTs. Participants identified as members of Christian or Muslim faith traditions and had been faced with deciding whether or not to make use of novel forms of fertility treatment or genetic testing. The findings show that members of faith groups may experience specific barriers of access, and distinctive ethical difficulties, when considering the use of different forms of NRGTs. Both Christian and Muslim interviewees reported difficulties in obtaining information on the official faith teaching, or found that their faith group had not yet crafted an official position. Participants' needs for information, and the opportunity to discuss the faith implications of their clinical choices, were not being met in either the clinic or the faith setting. This paper concludes that clinics should indicate more clearly their acknowledgement of patients' faith concerns. Appropriate training is needed for both healthcare professionals and chaplains, while faith groups should be encouraged to engage with healthcare providers to ensure that guidance is available to their members.


A socio-technical model to explore urban water systems scenarios.
This article reports on the ongoing work and research involved in the development of a socio-technical model of urban water systems. Socio-technical means the model is not so much concerned with the technical or biophysical aspects of urban water systems, but rather with the social and institutional implications of the urban water infrastructure and vice versa. A socio-technical model, in the view purported in this article, produces scenarios of different urban water servicing solutions gaining or losing influence in meeting water-related societal needs, like potable water, drainage, environmental health and amenity. The urban water system is parameterised with vectors of the relative influence of each servicing solution. The model is a software implementation of the Multi-Pattern Approach, a theory on societal systems, like urban water systems, and how these develop and go through transitions under various internal and external conditions. Acknowledging that social dynamics comes with severe and non-reducible uncertainties, the model is set up to be exploratory, meaning that for any initial condition several possible future scenarios are produced. This article gives a concise overview of the necessary theoretical background, the model architecture and some initial test results using a drainage example.


In vacuo interfacial tetrapyrrole metallation.
The metallation of tetrapyrroles at well-defined surfaces under ultra-high vacuum conditions represents an unconventional synthesis approach to achieve tetrapyrrole-based metal-organic complexes and architectures. Different protocols, pioneered over the last decade, and now widely applied in several fields, provide an elegant route to metallo-tetrapyrrole systems often elusive to conventional procedures and give access and exquisite insight into on-surface tetrapyrrole chemistry. As highlighted by the functionality of metallo-porphyrins in biological or other environments and by the eminent role of metallo-phthalocyanines in synthetic materials, the control on the metal centres incorporated into the macrocycle is of utmost importance to achieve tailored properties in tetrapyrrole-based nanosystems. In the on-surface scenario, precise metallation pathways were developed, including reactions of tetrapyrroles with metals supplied by physical vapour deposition, chemical vapour deposition or the tip of a scanning tunnelling microscope, and self-metallation by atoms of an underlying support. Herein, we provide a comprehensive overview of in vacuo tetrapyrrole metallation, addressing two-dimensional as well as three-dimensional systems. Furthermore, we comparatively assess the available library of on-surface metallation protocols and elaborate on the state-of-the-art methodology.


"Some like it hot": spectators who score high on the personality trait openness enjoy the excitement of hearing dancers breathing without music.
Music is an integral part of dance. Over the last 10 years, however, dance stimuli (without music) have been repeatedly used to study action observation processes, increasing our understanding of the influence of observer's physical abilities on action perception. Moreover, beyond trained skills and empathy traits, very little has been investigated on how other observer or spectators' properties modulate action observation and action preference. Since strong correlations have been shown between music and personality traits, here we aim to investigate how personality traits shape the appreciation of dance when this is presented with three different music/sounds. Therefore, we investigated the relationship between personality traits and the subjective esthetic experience of 52 spectators watching a 24 min lasting contemporary dance performance projected on a big screen containing three movement phrases performed to three different sound scores: classical music (i.e., Bach), an electronic sound-score, and a section without music but where the breathing of the performers was audible. We found that first, spectators rated the experience of watching dance without music significantly different from with music. Second, we found that the higher spectators scored on the Big Five personality factor openness, the more they liked the no-music section. Third, spectators' physical experience with dance was not linked to their appreciation but was significantly related to high average extravert scores. For the first time, we showed that spectators' reported entrainment to watching dance movements without music is strongly related to their personality and thus may need to be considered when using dance as a means to investigate action observation processes and esthetic preferences.


Intercostal vessel screening prior to pleural interventions by the respiratory physician: a prospective study of real world practice.
The rising incidence of pleural disease is seeing an international growth of pleural services, with physicians performing an ever-increasing volume of pleural interventions. These are frequently conducted at sites without immediate access to thoracic surgery or interventional radiology and serious complications such as pleural bleeding are likely to be under-reported. To assess whether intercostal vessel screening can be performed by respiratory physicians at the time of pleural intervention, as an additional step that could potentially enhance safe practice. This was a prospective, observational study of 596 ultrasound-guided pleural procedures conducted by respiratory physicians and trainees in a tertiary centre. Operators did not have additional formal radiology training. Intercostal vessel screening was performed using a low frequency probe and the colour Doppler feature. The intercostal vessels were screened in 95% of procedures and the intercostal artery (ICA) was successfully identified in 53% of cases. Screening resulted in an overall site alteration rate of 16% in all procedures, which increased to 30% when the ICA was successfully identified. This resulted in procedure abandonment in 2% of cases due to absence of a suitable entry site. Intercostal vessel screening was shown to be of particular value in the context of image-guided pleural biopsy. Intercostal vessel screening is a simple and potentially important additional step that can be performed by respiratory physicians at the time of pleural intervention without advanced ultrasound expertise. Whether the widespread use of this technique can improve safety requires further evaluation in a multi-centre setting with a robust prospective study.


Ex vivo expansion of bovine corneal endothelial cells in xeno-free medium supplemented with platelet releasate.
Clinical-grade ex vivo expansion of corneal endothelial cells can increase the availability of corneal tissues for transplantation and treatment of corneal blindness. However, these cells have very limited proliferative capacity. Successful propagation has required so far to use very complex growth media supplemented with fetal bovine serum and other xenocomponents. We hypothesized that human platelet releasates rich in multiple growth factors, and in particular neurotrophins, could potentially be a useful supplement for ex vivo expansion of corneal endothelium cells due to their neural crest origin. Platelet releasates were prepared by calcium salt activation of apheresis platelet concentrates, subjected or not to complement inactivation by heat treatment at 56°C for 30 minutes. Platelet releasates were characterized for their content in proteins and were found to contain high amount of growth factors including platelet-derived growth factor-AB (30.56 to 39.08 ng/ml) and brain-derived neurotrophic factor (30.57 to 37.11 ng/ml) neurotrophins. We compared the growth and viability of corneal endothelium cells in DMEM-F12 medium supplemented with different combinations of components, including 2.5%∼10% of the platelet releasates. Corneal endothelium cells expanded in platelet releasates exhibited good adhesion and a typical hexagonal morphology. Their growth and viability were enhanced when using the complement-inactivated platelet releasate at a concentration of 10%. Immunostaining and Western blots showed that CECs maintained the expressions of four important membrane markers: Na-K ATPase α1, zona occludens-1, phospho-connexin 43 and N-cadherin. In conclusion, our study provides the first proof-of-concept that human platelet releasates can be used for ex vivo expansion of corneal endothelium cells. These findings open a new paradigm for ex vivo propagation protocols of corneal endothelium cells in compliance with good tissue culture practices and regulatory recommendations to limit the use of xenogenic materials.


Malignant pleural mesothelioma.
The incidence of malignant pleural mesothelioma (MPM) has risen for some decades and is expected to peak between 2010 and 2020. Up to now, no single treatment has been proven to be effective and death usually occurs within about 12-17 months after diagnosis. Perhaps because of this poor prognosis, early screening has incited little interest. However, certain forms may have a better prognosis when diagnosed early and treated by multimodal therapy or intrapleural immunotherapy. Diagnosis depends foremost on histological analysis of samples obtained by thoracoscopy. This procedure allows the best staging of the pleural cavity with an attempt to detect visceral pleural involvement, which is one of the most important prognostic factors. Although radiotherapy seems necessary and is efficient in preventing the malignant seeding after diagnostic procedures in patients, there has been no randomized phase III study showing the superiority of any treatment compared with another. However, for the early-stage disease (stage I) a logical therapeutic approach seems to be neoadjuvant intrapleural treatment using cytokines. For more advanced disease (stages II and III) resectability should be discussed with the thoracic surgeons and a multimodal treatment combining surgery, radiotherapy and chemotherapy should be proposed for a randomized controlled study. Palliative treatment is indicated for stage IV. In any case, each patient should be enrolled in a clinical trial.


Halos in cirrus clouds: why are classic displays so rare?
Upper tropospheric cirrus clouds consist of hexagonal ice crystals, which geometrical ray-tracing-theory predicts should regularly produce a variety of optical phenomena such as vivid 22 degrees and 46 degrees halos. Yet, cirrus inconsistently generate such optical displays, while a class of more exotic displays are reported, albeit rarely. I review current knowledge of the cirrus cloud microphysical factors that control ice crystal shape, and hence halo/arc formation, but also appeal to halo enthusiasts to help investigate the causes of unusually complex, brilliant, or rare optical displays. Currently, a wealth of meteorological information can be tapped from the Internet to help advance our knowledge of the basic meteorological factors leading to these rare events.


Risk factors and consequences of decreased kidney function in nursing home residents: A longitudinal study.
The aim of the present study was to study the renal function and the relationship of deterioration in renal function with major outcomes in elderly nursing home residents. A second aim was to compare the internationally recommended formulae for estimated glomerular filtration rate (eGFR) consisting of both creatinine and cystatin C in a nursing home population. A total of 429 patients from 11 nursing homes were included during 2008-2011. GFR was estimated, from formulae based on both creatinine and cystatin C, at baseline and after 1 and 2 years. The patients were divided into groups based on chronic kidney disease level, and comparisons were made for mortality, morbidity, the use of medications and between the different formulae for eGFR. Survival was lower in the groups with lower renal function. Over 60% of the residents had impaired renal function. Those with impaired renal function were older, had a higher number of medications and a higher prevalence of heart failure. Higher number of medications was associated with a greater risk of rapid decline in renal function with an odds ratio of 1.2 (95% confidence interval 1.06-1.36, P = 0.003). The compared eGFR formulae based on both cystatin C and creatinine were in excellent concordance with each other. Decreased renal function was associated with increased mortality. A majority of nursing home residents had declining renal function, which should be considered when prescribing medications. The more medications, the higher the risk for rapidly declining renal function. Geriatr Gerontol Int 2017; 17: 791-797.


Fibroblast growth factor receptor signaling activates the human interstitial collagenase promoter via the bipartite Ets-AP1 element.
Interstitial collagenases participate in the remodeling of skeletal matrix and are regulated by fibroblast growth factor (FGF). A 0.2-kb fragment of the proximal human interstitial collagenase [matrix metalloproteinase (MMP1)] promoter conveys 4- to 8-fold induction of a luciferase reporter in response to FGF2 in MC3T3-E1 osteoblasts. By 5'-deletion, this response maps to nucleotides -100 to -50 relative to the transcription initiation site. The 63- bp MMP1 promoter fragment -123 to -61 confers this FGF2 response on the rous sarcoma virus minimal promoter. Intact Ets and AP1 cognates in this element are both required for responsiveness. The AP1 site supports basal and FGF-inducible promoter activity. The intact Ets cognate represses basal transcriptional activity in both heterologous and native promoter contexts and is also required for FGF activation. FGF2 up-regulates a DNA-binding activity that recognizes the MMP1 AP1 cognate and contains immunoreactive Fra1 and c-Jun. Both constitutive and FGF-inducible DNA-binding activities are present in MC3T3-E1 cells that recognize the MMP1 Ets cognate; prototypic Ets transcriptional activators are not present in these complexes. Inhibitors of protein kinase C, phosphatidyl inositol 3-OH kinase, and calmodulin-dependent protein kinase do not attenuate MMP1 promoter activation. FGF2 activates ERK1/ERK2 signaling in osteoblasts; however, 25 microM MAPK-ERK kinase (MEK) inhibitor PD98059 (inhibits by > 85% the phosphorylation of ERK1/ERK2) has no effect on MMP1 promoter activation by FGF2. Ligand-activated and constitutively active FGF receptors initiate MMP1 induction. Dominant negative Ras abrogates MMP1 induction by constitutively active FGFR2-ROS, but dominant negative Rho and Rac do not inhibit induction. The mitogen-activated protein kinase (MAPK) phosphatase MKP2 [inactivates extracellular regulated kinase (ERK) = Jun N-terminal kinase (JNK) > p38 MAPK] completely abrogates MMP1 activation, whereas PAC1 (inactivates ERK = p38 > JNK) attenuates but does not completely prevent induction. Thus, a Ras- and MKP2-regulated MAPK pathway, independent of ERK1/ERK2 MAPK activity, mediates FGF2 transcriptional activation of MMP1 in MC3T3-E1 osteoblasts, converging upon the bipartite Ets-AP1 element. The DNA-protein interactions and signal cascades mediating FGF induction of the MMP1 promoter are distinct from two other recently described FGF response elements: the MMP1 promoter (-123 to -61) represents a third FGF-activated transcriptional unit.


Pathology of pulmonary aspergillomas.
Aspergilloma refers to a fungal ball formed by saprophytic overgrowth of Aspergillus species and is seen secondary to cavitatory/cystic respiratory diseases. Paucity of clinical and pathological data of aspergilloma in India prompted us to analyze cases of aspergilloma over 15 years. The clinical features were recorded in all and correlated with detailed pathological examination. Aspergillomas were identified in 41 surgical excisions or at autopsy. There was male predominance; half the patients were in their fourth decade. Episodic hemoptysis was the commonest mode of presentation (85.4%). Forty aspergillomas were complex, occurring in cavitatory lesions (82.9%) or in bronchiectasis (14.6%). Simple aspergilloma was seen as an incidental finding in only one. Tuberculosis was the etiological factor in 31 patients, producing cavitatory or bronchiectatic lesions; other causes were chronic lung abscess and bronchiectasis (unrelated to tuberculosis). Surgical resections are endorsed in view of high risk of unpredictable, life-threatening hemoptysis.


A placebo-controlled pilot study of intensification of antiretroviral therapy with mycophenolate mofetil.
We studied the safety, tolerability, virologic, and immunologic effects of mycophenolate mofetil (MMF) added to a stable antiretroviral therapy (ART) in the setting of low-level viremia. MMF 500 mg BID or placebo was given to patients thought to be adherent on stable ART with plasma viremia between 200 and 4000 copies/mL. At week 4 unblinding was performed and patients on placebo were offered open-label MMF. Six patients were enrolled. At entry mean plasma HIV-1 RNA (VL) was 2.98 log10 copies/mL; mean CD4 count was 523. All subjects randomized to placebo elected to cross over to open label MMF. No significant adverse events were observed during MMF therapy. Three patients on MMF achieved VL < 50 copies/mL by week 4; a fourth had VL decline of > 0.5 log. Two patients on placebo had declines of VL. One of these had further decline on open label MMF. Cell surface markers of apoptosis, activation, and proliferation on CD4+ and CD8+ cells declined modestly or remained low. CD4 counts were stable at week 24. All but one subject had rebound of viremia by week 24, universally associated with missed doses of medication by pill count. MMF appears to be safe, and its administration lead to decreased T cell activation. During periods of adherence to therapy, the use of MMF was correlated with declines in viremia, but this small pilot study could not prove this association. Further study of MMF in patients with viremia should be considered for whom additional or alternative antiretrovirals are impractical.


[Retinal manifestations of infectious diseases].
The retina and the choroids are richly vascularised structures and can therefore be colonised by germs via the haematogenous route in the course of a systemic infectious disease. The germs responsible for this type of infection can be fungi, viruses, bacteria and parasites. Ocular candidiasis is outstanding amongst these colonisations because of its frequency; it can manifest itself as an endophthalmitis with a slow and hidden course. The so-called ocular histoplasmosis syndrome, although it is infrequent in our setting, is an important cause of choroidal neovascularisation. The viruses that most frequently affect the retina are of the herpes type and can produce devastating symptoms in immunoincompetent patients, named acute retinal necrosis syndrome. Retinitis due to cytomegalovirus is more frequent in immunodepressed patients, as in the case of AIDS, but it must also be contemplated in patients with lymphoma and immunomodulatory treatment. The most frequent bacterial diseases that affect the retina are syphilis and tuberculosis. Disease due to cat scratches, caused by a borrelia, can produce a neuroretinitis. Toxoplasmosis is the most common of the infectious diseases caused by a parasite and gives rise to chorioretinitis. Toxocariasis, also caused by a parasite, is second in importance, giving rise to choroidal granulomas and retinal tractions.


Violent obsessions are associated with suicidality in an OCD analog sample of college students.
The picture of suicide in obsessive-compulsive disorder (OCD) is unclear because previous research did not uniformly control for depressive symptoms when examining the relationship between OCD and suicidality. Specific links between OC symptom dimensions and suicidality were also not adequately studied. As such, we investigated specific associations between OC symptom dimensions and suicidality, beyond the contribution of depressive symptoms, in an OCD analog sample of college students, a group traditionally at risk for suicide. One hundred and forty-six college students (103 females; 43 males) who exceeded the clinical cut-off for OC symptoms on the Obsessive-Compulsive Inventory, Revised (OCI-R) were recruited. Participants completed an online questionnaire containing measures that assessed suicidality and OC and depressive symptom severity. Total OC symptom severity, unacceptable thoughts, and especially violent obsessions exhibited significant positive zero-order correlations with suicidality. However, analyses of part correlations indicated that only violent obsessions had a significant unique association with suicidality after controlling for depressive symptoms. Our findings support the hypothesis that violent obsessions have a specific role in suicidality beyond the influence of depressive symptoms in an OCD analog sample of college students. A strong clinical focus on suicide risk assessment and safety planning in college students reporting violent obsessions is therefore warranted. Future related research should employ longitudinal or prospective designs and control for other possible comorbid symptoms in larger and more representative samples of participants formally diagnosed with OCD in order to verify the generalizability of our findings to these groups.


RapidCaP, a novel GEM model for metastatic prostate cancer analysis and therapy, reveals myc as a driver of Pten-mutant metastasis.
Genetically engineered mouse (GEM) models are a pillar of functional cancer research. Here, we developed RapidCaP, a GEM modeling system that uses surgical injection for viral gene delivery to the prostate. We show that in Pten deficiency, loss of p53 suffices to trigger metastasis to distant sites at greater than 50% penetrance by four months, consistent with results from human prostate cancer genome analysis. Live bioluminescence tracking showed that endogenous primary and metastatic disease responds to castration before developing lethal castration resistance. To our surprise, the resulting lesions showed no activation of Akt but activation of the Myc oncogene. Using RapidCaP, we find that Myc drives local prostate metastasis and is critical for maintenance of metastasis, as shown by using the Brd4 inhibitor JQ1. Taken together, our data suggest that a "MYC-switch" away from AKT forms a critical and druggable event in PTEN-mutant prostate cancer metastasis and castration resistance.


Prospective analysis of a rapid trauma ultrasound examination performed by emergency physicians.
The objective of this prospective study was to determine the sensitivity, specificity, and accuracy of the rapid trauma ultrasound examination, performed by emergency physicians, for detecting free peritoneal and thoracic fluid in patients presenting to a level I trauma center with major blunt or penetrating torso trauma. Emergency medicine residents and faculty were trained to perform an ultrasound examination of the torso evaluating for free intraperitoneal, retroperitoneal, pleural, and pericardial fluid. In the 245 study patients, emergency physicians examined 975 intracavitary spaces and demonstrated 64 positive findings for free fluid as documented by computed tomography scan, diagnostic peritoneal lavage, exploratory laparotomy, chest radiography, tube thoracostomy, or formal two-dimensional echocardiography. The rapid trauma ultrasound examination was 90% sensitive, 99% specific, and 99% accurate. Ultrasonography can serve as an accurate diagnostic adjunct in detecting free peritoneal and thoracic fluid in trauma patients. Appropriately trained emergency physicians can accurately perform and interpret these trauma ultrasound examinations.


The Effect of Hearing-Protection Devices on Auditory Situational Awareness and Listening Effort.
Hearing-protection devices (HPDs) are made available, and often are required, for industrial use as well as military training exercises and operational duties. However, these devices often are disliked, and consequently not worn, in part because they compromise situational awareness through reduced sound detection and localization performance as well as degraded speech intelligibility. In this study, we carried out a series of tests, involving normal-hearing subjects and multiple background-noise conditions, designed to evaluate the performance of four HPDs in terms of their modifications of auditory-detection thresholds, sound-localization accuracy, and speech intelligibility. In addition, we assessed their impact on listening effort to understand how the additional effort required to perceive and process auditory signals while wearing an HPD reduces available cognitive resources for other tasks. Thirteen normal-hearing subjects participated in a protocol, which included auditory tasks designed to measure detection and localization performance, speech intelligibility, and cognitive load. Each participant repeated the battery of tests with unoccluded ears and four hearing protectors, two active (electronic) and two passive. The tasks were performed both in quiet and in background noise. Our findings indicate that, in variable degrees, all of the tested HPDs induce performance degradation on most of the conducted tasks as compared to the open ear. Of particular note in this study is the finding of increased cognitive load or listening effort, as measured by visual reaction time, for some hearing protectors during a dual-task, which added working-memory demands to the speech-intelligibility task. These results indicate that situational awareness can vary greatly across the spectrum of HPDs, and that listening effort is another aspect of performance that should be considered in future studies. The increased listening effort induced by hearing protectors may lead to earlier cognitive fatigue in noisy environments. Further study is required to characterize how auditory performance is limited by the combination of hearing impairment and the use of HPDs, and how the effects of such limitations can be linked to safe and effective use of hearing protection to maximize job performance.


Antiepileptic drugs and suicide: a systematic review of adverse effects.
Since the FDA (Food and Drug Administration) report on antiepileptic drugs (AEDs) and suicide risk was released (2008), several studies have been published on this controversial relationship. This systematic review (SR) gives an updated approach to this health issue. We searched 6 databases. We ultimately included 11 publications: 4 cohort studies, 1 case-crossover study, 2 community case-control studies, and 4 SRs. Overall, 1 SR described studies already included; 3 studies reported a 2- to 4-fold overall increase in risk; 1 study reported an increased risk of suicide among epilepsy patients on AEDs with high risk of depression; 1study showed a protective effect among epilepsy patients; 2 studies were conducted with patients with bipolar disorder (1 showed a protective effect, whereas the other showed a 3-fold increase in risk of suicide), and the other 3 studies reported results for single AEDs. Several biases affected the published results. There is no clear evidence of an association between the use of AEDs and an increased risk of suicide because of the heterogeneity in the studies at the clinical and methodological level. A future study should cover all indications for use, retrieve information from a healthcare database, and include a defined set of covariates to avoid bias.


Optimization of de novo transcriptome assembly from high-throughput short read sequencing data improves functional annotation for non-model organisms.
The k-mer hash length is a key factor affecting the output of de novo transcriptome assembly packages using de Bruijn graph algorithms. Assemblies constructed with varying single k-mer choices might result in the loss of unique contiguous sequences (contigs) and relevant biological information. A common solution to this problem is the clustering of single k-mer assemblies. Even though annotation is one of the primary goals of a transcriptome assembly, the success of assembly strategies does not consider the impact of k-mer selection on the annotation output. This study provides an in-depth k-mer selection analysis that is focused on the degree of functional annotation achieved for a non-model organism where no reference genome information is available. Individual k-mers and clustered assemblies (CA) were considered using three representative software packages. Pair-wise comparison analyses (between individual k-mers and CAs) were produced to reveal missing Kyoto Encyclopedia of Genes and Genomes (KEGG) ortholog identifiers (KOIs), and to determine a strategy that maximizes the recovery of biological information in a de novo transcriptome assembly. Analyses of single k-mer assemblies resulted in the generation of various quantities of contigs and functional annotations within the selection window of k-mers (k-19 to k-63). For each k-mer in this window, generated assemblies contained certain unique contigs and KOIs that were not present in the other k-mer assemblies. Producing a non-redundant CA of k-mers 19 to 63 resulted in a more complete functional annotation than any single k-mer assembly. However, a fraction of unique annotations remained (~0.19 to 0.27% of total KOIs) in the assemblies of individual k-mers (k-19 to k-63) that were not present in the non-redundant CA. A workflow to recover these unique annotations is presented. This study demonstrated that different k-mer choices result in various quantities of unique contigs per single k-mer assembly which affects biological information that is retrievable from the transcriptome. This undesirable effect can be minimized, but not eliminated, with clustering of multi-k assemblies with redundancy removal. The complete extraction of biological information in de novo transcriptomics studies requires both the production of a CA and efforts to identify unique contigs that are present in individual k-mer assemblies but not in the CA.


Impact of Environmental Stress-Tolerant Transgenic Potato on Genotypic Diversity of Microbial Communities and Soil Enzyme Activities under Stress Conditions.
Transgenic crops able to tolerate environmental stress are being developed throughout the world. However, little data is available on the impact of environmental stress-tolerant transgenic crops on soil microorganisms and biochemistry. Recently developed transgenic potato plants carrying an environmental stress-related gene, DREB1A, with a stress-inducible promoter, are being evaluated for growth performance in greenhouses. In this study, we investigated microbial diversity and soil function to assess potential environmental risks of these transgenic potato lines. Genotypic diversity of the 16S-23S rRNA intergenic spacer region and activity levels of four enzymes were used as indicators of microbial genetic diversity and soil function, respectively. Salinity had a major effect on both bacterial (88-93%) and fungal (54-55%) diversity, while the transgene had a relatively small effect on genotypic structure (0-5%) based on the analysis of variance. However, a few genotypes appeared only in soils planted with the transgenic lines. Some enzyme activities were found to differ significantly between the transgenic and non-transgenic lines, although the results were not repeatable in the second trial. These results suggest that abiotic growth environments had a stronger impact on soil microorganisms and biochemistry than did plant genotypes.


Structure determination of functional membrane proteins using small-angle neutron scattering (sans) with small, mixed-lipid liposomes: native beef heart mitochondrial cytochrome c oxidase forms dimers.
The low-resolution three-dimensional structure of purified native beef heart mitochondrial cytochrome c oxidase (COX) in asolectin unilamellar liposomes has been measured by small-angle neutron scattering under the conditions where the protein remains fully functional. From a neutron scattering perspective, the use of mixed-lipid liposomes provided for a more homogeneous matrix than can be achieved using a single lipid. As a result, the measurements were able to be performed under conditions where the liposome scattering was essentially eliminated (contrast-matched conditions). The protein structure in the membrane was modeled as a simple parallelepiped with side lengths of (59 × 70 × 120) Å with uncertainties, respectively, (11, 12, 20 Å). The molecular mass calculated for a typical protein with this volume is estimated to be (410 ± 124) kDa, which indicates the mass of a COX dimer. The longest dimension has some uncertainty due to intermolecular scattering contributing to the data. Nevertheless, that length was estimated using an average protein density and the known dimer molecular mass. Using the same cross sectional dimensions for the structure, the length is estimated to be 120 Å. However, the measured scattering curve of the dimer in the liposome differs significantly from that calculated from the X-ray structure of the dimer in a crystal of mixed micelles (PDB 3AG1). The calculated SANS scattering from the crystal structure was fit with a parallelepiped, measuring (59 × 101 × 129) Å with fitting uncertainties, respectively, (2, 3, 3 Å). Our results suggest that COX is a functional dimer when reconstituted into mixed-lipid liposomes.


HIV-1 subtype distribution in the Gambia and the significant presence of CRF49_cpx, a novel circulating recombinant form.
Detailed local HIV-1 sequence data are essential for monitoring the HIV epidemic, for maintaining sensitive sequence-based diagnostics, and to aid in designing vaccines. Reported here are full envelope sequences derived from 38 randomly selected HIV-1 infections identified at a Gambian clinic between 1991 and 2009. Special care was taken to generate sequences from circulating viral RNA as uncloned products, either by limiting dilution or single genome amplification polymerase chain reaction (PCR). Within these 38 isolates, eight were subtyped as A and 18 as CRF02_AG. A small number of subtype B, C, D viruses were identified. Surprising, however, was the identification of six isolates with subtype J-like envelopes, a subtype found normally in Central Africa and the Democratic Republic of the Congo (DRC), with gag p24 regions that clustered with subtype A sequences. Near full-length sequence from three of these isolates confirmed that these represent a novel circulating recombinant form of HIV-1, now named CRF49_cpx. This study expands the HIV-1 sequence database from the Gambia and will provide important data for HIV diagnostics, patient care, and vaccine development.


Consequences of N,C,N'- and C,N,N'-coordination modes on electronic and photophysical properties of cyclometalated aryl ruthenium(II) complexes.
The effects of isoelectronic replacement of a neutral nitrogen donor atom by an anionic carbon atom in terpyridine ruthenium(II) complexes on the electronic and photophysical properties of the resulting N,C,N'- and C,N,N'-cyclometalated aryl ruthenium(II) complexes were investigated. To this end, a series of complexes was prepared either with ligands containing exclusively nitrogen donor atoms, that is, [Ru(R(1)-tpy)(R(2)-tpy)](2+) (R(1), R(2) = H, CO(2)Et), or bearing either one N,C,N'- or C,N,N'-cyclometalated ligand and one tpy ligand, that is, [Ru(R(1)-N(/\)C(/\)N)(R(2)-tpy)](+) and [Ru(R(1)-C(/\)N(/\)N)(R(2)-tpy)](+), respectively. Single-crystal X-ray structure determinations showed that cyclometalation does not significantly alter the overall geometry of the complexes but does change the bond lengths around the ruthenium(II) center, especially the nitrogen-to-ruthenium bond length trans to the carbanion. Substitution of either of the ligands with electron-withdrawing ester functionalities fine-tuned the electronic properties and resulted in the presence of an IR probe. Using trends obtained from redox potentials, emission energies, IR spectroelectrochemical responses, and the character of the lowest unoccupied molecular orbitals from DFT studies, it is shown that the first reduction process and luminescence are associated with the ester-substituted C,N,N'-cyclometalated ligand in [Ru(EtO(2)C-C(/\)N(/\)N)(tpy)](+). Cyclometalation in an N,C,N'-bonding motif changed the energetic order of the ruthenium d(zx), d(yz), and d(xy) orbitals. The red-shifted absorption in the N,C,N'-cyclometalated complexes is assigned to MLCT transitions to the tpy ligand. The red shift observed upon introduction of the ester moiety is associated with an increase in intensity of low-energy transitions, rather than a red shift of the main transition. Cyclometalation in the C,N,N'-binding motif also red-shifts the absorption, but the corresponding transition is associated with both ligand types. Luminescence of the cyclometalated complexes is relatively independent of the mode of cyclometalation, obeying the energy gap law within each individual series.


Influence of Power Clean Ability and Training Age on Adaptations to Weightlifting-Style Training.
James, LP, Comfort, P, Suchomel, TJ, Kelly, VG, Beckman, EM, and Haff, GG. Influence of power clean ability and training age on adaptations to weightlifting-style training. J Strength Cond Res 33(11): 2936-2944, 2019-The purpose of this investigation was to determine whether weightlifting actions are a viable method for improving athletic performance among weaker, inexperienced lifters when compared with individuals with a greater power clean (PC) result, and hence weightlifting ability and experience. Two groups of males with distinctly different PC performances (higher performance [HP]: N = 8; body mass [BM] = 78.1 ± 4.0 kg; 1 repetition maximum [1RM] PC = 1.08 ± 0.09 kg·BM; lower performance [LP]: N = 8; BM = 82.6 ± 14.0 kg; 1RM PC = 0.78 ± 0.1 kg·BM) and resistance training age (HP: resistance training experience = 3.5 ± 1.2 years; LP: resistance training experience = 1.44 ± 1.50 years) undertook 10 weeks of training involving weightlifting derivatives, in addition to supplemental ballistic and plyometric exercises. Testing of athletic performance (represented by measures derived from the countermovement jump) occurred at baseline, after 5 weeks of training, and after 10 weeks of training. Both groups significantly improved across the majority of outcome variables after training (Hedges' g = 0.98-2.55, p ≤ 0.01-0.05). Only the HP participants experienced significant changes at midtest (g = 0.99-1.27, p ≤ 0.01-0.05), whereas no significant changes were revealed between midtest and posttest in this group. In contrast to this, the LP participants displayed a significant improvement in relative impulse (g = 1.39, p < 0.01) and rate of force development (g = 1.91, p < 0.01) during this final period (p < 0.01). As weaker, inexperienced lifters underwent a significant and meaningful enhancement in maximal neuromuscular measures after weightlifting derivative-focused training, practitioners should consider early implementation of such exercises. However, it is important for coaches to note that a delayed training effect might be present in weaker, less experienced lifters.


Comparative economic evaluation of Haemophilus influenzae type b vaccination in Belarus and Uzbekistan.
Hib vaccine has gradually been introduced into more and more countries during the past two decades, partly due to GAVI Alliance support to low-income countries. However, since Hib disease burden is difficult to establish in settings with limited diagnostic capacities and since the vaccine continues to be relatively expensive, some Governments remain doubtful about its value leading to concerns about financial sustainability. Similarly, several middle-income countries have not introduced the vaccine. The aim of this study is to estimate and compare the cost-effectiveness of Hib vaccination in a country relying on self-financing (Belarus) and a country eligible for GAVI Alliance support (Uzbekistan). A decision analytic model was used to estimate morbidity and mortality from Hib meningitis, Hib pneumonia and other types of Hib disease with and without the vaccine. Treatment costs were attached to each disease event. Data on disease incidence, case fatality ratios and costs were primarily determined from national sources. For the Belarus 2009 birth cohort, Hib vaccine is estimated to prevent 467 invasive disease cases, 4 cases of meningitis sequelae, and 3 deaths, while in Uzbekistan 3,069 invasive cases, 34 sequelae cases and 341 deaths are prevented. Estimated costs per discounted DALY averted are US$ 9,323 in Belarus and US$ 267 in Uzbekistan. The primary reason why the cost-effectiveness values are more favourable in Uzbekistan than in Belarus is that relatively more deaths are averted in Uzbekistan due to higher baseline mortality burden. Two other explanations are that the vaccine price is lower in Uzbekistan and that Uzbekistan uses a three dose schedule compared to four doses in Belarus. However, when seen in the context of the relative ability to pay for public health, the vaccine can be considered cost-effective in both countries.


Phase II study of Dovitinib in recurrent glioblastoma.
Dovitinib is an oral, potent inhibitor of FGFR and VEGFR, and can be a promising strategy in patients with recurrent or progressive glioblastoma (GBM). This was an open label phase II study of two arms: Arm 1 included anti-angiogenic naïve patients with recurrent GBM and Arm 2 included patients with recurrent GBM that had progressed on prior anti-angiogenic therapy. Nineteen subjects were enrolled in Arm 1 and 14 subjects in Arm 2. The primary endpoint was 6-month progression-free survival (PFS-6) in Arm 1 and time to progression (TTP) in Arm 2. The secondary endpoints were toxicity, objective response rate (ORR) and overall survival. Patients in Arm 2 (compared to Arm 1) tended to have longer intervals from diagnosis to study entry (median 26.9 vs. 8.9 months, p = 0.002), experienced more recurrences (64%, had 3-4 prior recurrences compared to 0, p < 0.0001) and tended to be heavily pretreated (71% vs. 26-32% p = 0.04 or 0.02). 6-month PFS was 12% ± 6% for the Arm 1 and 0% for Arm 2. TTP was similar in both treatment arms (median 1.8 months Arm 1 and 0.7-1.8 months Arm 2, p = 0.36). Five patients (15%) had grade 4 toxicities and 22 patients (67%) had grade 3 toxicities. There were no significant differences between the two arms with respect to the amount of change in the levels of biomarkers from baseline. Dovitinib was not efficacious in prolonging the PFS in patients with recurrent GBM irrespective of prior treatment with anti-angiogenic therapy (including bevacizumab).


Design of the oxygen and substrate pathways. II. Defining the upper limits of carbohydrate and fat oxidation.
This paper quantifies maximal flows of carbohydrates and lipids through the pathways supplying the mitochondria. Maximal flow rates are the main functional parameter used in testing the principle of symmorphosis, which states that structural capacities are quantitatively matched to functional demand. Only under rate-limiting conditions will all of the structural capacity be used. Dogs and goats were compared to obtain large differences in absolute rates. We exercised the animals for long enough to reach steady-state O2 and CO2 exchange rates at intensities eliciting 40%, 60% and 85% of the maximal rate of oxygen consumption (MO2max). We then calculated rates of fat and carbohydrate oxidation from the ratio of CO2 produced to O2 consumed (the respiratory exchange ratio). The dog's Mo2max was more than twice that of the goat (6517 versus 3026 mumol O2 kg-1 min-1). We found the same pattern of fuel selection as a function of exercise intensity in both species, and it appears to be general to mammals. Maximal rates of fat oxidation were reached at 40% exercise intensity, where 77% of the energy was supplied by fat. As exercise intensity increased, all additional energy was supplied by carbohydrates. We conclude that the partitioning of fuel supply to the fat and carbohydrate pathways follows the same pattern in both dogs and goats.


Seeing Beyond Salience and Guidance: The Role of Bias and Decision in Visual Search.
Visual search is a popular tool for studying a range of questions about perception and attention, thanks to the ease with which the basic paradigm can be controlled and manipulated. While often thought of as a sub-field of vision science, search tasks are significantly more complex than most other perceptual tasks, with strategy and decision playing an essential, but neglected, role. In this review, we briefly describe some of the important theoretical advances about perception and attention that have been gained from studying visual search within the signal detection and guided search frameworks. Under most circumstances, search also involves executing a series of eye movements. We argue that understanding the contribution of biases, routines and strategies to visual search performance over multiple fixations will lead to new insights about these decision-related processes and how they interact with perception and attention. We also highlight the neglected potential for variability, both within and between searchers, to contribute to our understanding of visual search. The exciting challenge will be to account for variations in search performance caused by these numerous factors and their interactions. We conclude the review with some recommendations for ways future research can tackle these challenges to move the field forward.