Modelling determinants, impact, and space-time risk of age-specific mortality in rural South Africa: integrating methods to enhance policy relevance.
There is a lack of reliable data in developing countries to inform policy and optimise resource allocation. Health and socio-demographic surveillance sites (HDSS) have the potential to address this gap. Mortality levels and trends have previously been documented in rural South Africa. However, complex space-time clustering of mortality, determinants, and their impact has not been fully examined. To integrate advanced methods enhance the understanding of the dynamics of mortality in space-time, to identify mortality risk factors and population attributable impact, to relate disparities in risk factor distributions to spatial mortality risk, and thus, to improve policy planning and resource allocation. Agincourt HDSS supplied data for the period 1992-2008. Advanced spatial techniques were used to identify significant age-specific mortality 'hotspots' in space-time. Multivariable Bayesian models were used to assess the effects of the most significant covariates on mortality. Disparities in risk factor profiles in identified hotspots were assessed. Increasing HIV-related mortality and a subsequent decrease possibly attributable to antiretroviral therapy introduction are evident in this rural population. Distinct space-time clustering and variation (even in a small geographic area) of mortality were observed. Several known and novel risk factors were identified, and population impact was quantified. Significant differences in the risk factor profiles of the identified 'hotspots' included ethnicity; maternal, partner, and household deaths; household head demographics; migrancy; education; and poverty. A complex interaction of highly attributable multilevel factors continues to demonstrate differential space-time influences on mortality risk (especially for HIV). High-risk households and villages displayed differential risk factor profiles. This integrated approach could prove valuable to decision makers. Tailored interventions for specific child and adult high-risk mortality areas are needed, such as preventing vertical transmission, ensuring maternal survival, and improving water and sanitation infrastructure. This framework can be applied in other settings within the region.


Structure-Property Effects in the Generation of Transient Aqueous Benzoic Acid Anhydrides by Carbodiimide Fuels.
The design of dissipative systems, which operate out-of-equilibrium by consuming chemical fuels, is challenging. As yet, there are a few examples of privileged fuel chemistries that can be broadly applied in abiotic systems in the same way that ATP hydrolysis is exploited throughout biochemistry. The key issue is that designing nonequilibrium systems is inherently about balancing the relative rates of coupled reactions. The use of carbodiimides as fuels to generate transient aqueous carboxylic anhydrides has recently been used in examples of new nonequilibrium materials and supramolecular assemblies. Here, we explore the kinetics of formation and decomposition of a series of benzoic anhydrides generated from the corresponding acids and EDC under typical conditions (EDC = N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride). The reactions can be described by a simple mechanism that merges known behavior for the two processes independently. Structure-property effects in these systems are dominated by differences in the anhydride decomposition rate. The kinetic parameters allow trends in concentration-dependent properties to be simulated, such as reaction lifetimes, peak anhydride concentrations, and yields. For key properties, there are diminishing returns with the addition of increasing amounts of fuel. These results should provide useful guidelines for the design of functional systems making use of this chemistry.


Radioactive source security: the cultural challenges.
Radioactive source security is an essential part of radiation protection. Sources can be abandoned, lost or stolen. If they are stolen, they could be used to cause deliberate harm and the risks are varied and significant. There is a need for a global security protection system and enhanced capability to achieve this. The establishment of radioactive source security requires 'cultural exchanges'. These exchanges include collaboration between: radiation protection specialists and security specialists; the nuclear industry and users of radioactive sources; training providers and regulators/users. This collaboration will facilitate knowledge and experience exchange for the various stakeholder groups, beyond those already provided. This will promote best practice in both physical and information security and heighten security awareness generally. Only if all groups involved are prepared to open their minds to listen to and learn from, each other will a suitable global level of control be achieved.


Phenyl-ring-bearing cationic surfactants: effect of ring location on the micellar structure.
A series of isomeric cationic surfactants (S1-S5) bearing a long alkyl chain that carries a 1,4-phenylene unit and a trimethyl ammonium headgroup was synthesized; the location of the phenyl ring within the alkyl tail was varied in an effort to understand its influence on the amphiphilic properties of the surfactants. The cmc's of the surfactants were estimated using ionic conductivity measurements and isothermal calorimetric titrations (ITC); the values obtained by the two methods were found to be in excellent agreement. The ITC measurements provided additional insight into the various thermodynamic parameters associated with the micellization process. Although all five surfactants have exactly the same molecular formula, their micellar properties were seen to vary dramatically depending on the location of the phenyl ring; the cmc was seen to decrease by almost an order of magnitude when the phenyl ring was moved from the tail end (cmc of S1 is 23 mM) to the headgroup region (cmc of S5 is 3 mM). In all cases, the enthalpy of micellization was negative but the entropy of micellization was positive, suggesting that in all of these systems the formation of micelles is both enthalpically and entropically favored. As expected, the decrease in cmc values upon moving the phenyl ring from the tail end to the headgroup region is accompanied by an increase in the thermodynamic driving force (ΔG) for micellization. To understand further the differences in the micellar structure of these surfactants, small-angle neutron scattering (SANS) measurements were carried out; these measurements reveal that the aggregation number of the micelles increases as the cmc decreases. This increase in the aggregation number is also accompanied by an increase in the asphericity of the micellar aggregate and a decrease in the fractional charge. Geometric packing arguments are presented to account for these changes in aggregation behavior as a function of phenyl ring location.


Evaluation of intravenous immunoglobulin as an agent to lower allosensitization and improve transplantation in highly sensitized adult patients with end-stage renal disease: report of the NIH IG02 trial.
Reported are the reduction of anti-HLA antibody levels and improvement of transplant rates by intravenous immunoglobulin (IVIG) in a randomized, double-blind, placebo-controlled clinical trial. Between 1997 and 2000, a total of 101 adult patients with ESRD who were highly sensitized to HLA antigens (panel reactive antibody [PRA] > or =50% monthly for 3 mo) enrolled onto an NIH-sponsored trial (IG02). Patients received IVIG or placebo. Subjects received IVIG 2 g/kg monthly for 4 mo or an equivalent volume of placebo with additional infusions at 12 and 24 mo after entry if not transplanted. If transplanted, additional infusions were given monthly for 4 mo. Baseline PRA levels were similar in both groups. However, IVIG significantly reduced PRA levels in study subjects compared with placebo. Sixteen IVIG patients (35%) and eight placebo patients (17%) were transplanted. Rejection episodes occurred in 9 of 17 IVIG and 1 of 10 placebo subjects. Seven graft failures occurred (four IVIG, three placebo) among adherent patients with similar 2-yr graft survival rates (80% IVIG, 75% placebo). With a median follow-up of 2 yr after transplant, the viable transplants functioned normally with a mean +/- SEM serum creatinine of 1.68 +/- 0.28 for IVIG versus 1.28 +/- 0.13 mg/dl for placebo. Adverse events rates were similar in both groups. We conclude that IVIG is better than placebo in reducing anti-HLA antibody levels and improving transplantation rates in highly sensitized patients with ESRD. Transplant rates for highly sensitized patients with ESRD awaiting kidney transplants are improved with IVIG therapy.


Comparison of Wits appraisal among different ethnic groups.
The Wits values for various ethnic groups are different and the applicability of the norms described in these analyses to different populations is difficult. The objectives of this study were to establish the normal values of Wits appraisal in a sample from the western region of Saudi Arabia and to evaluate the existence of gender dimorphism. Also, to compare the results with previously published Wits values. A total of 66 lateral cephalometric digital radiographs of Saudi patients from the western region (25 males and 41 females, mean age 19.32±8.16 years and 20.88±8.77 years, respectively). All subjects had angle class-I occlusion, well-balanced faces, all premolars had erupted and in occlusion, and no history of orthodontic treatment. Tracing was performed using the VistadentOC(®) software. Wits mean values were greater in males (-0.73±2.48) than females (1.79±2.06), with significant gender difference (P<0.001). Comparisons with previously published showed that there is a significant differences between ethnic groups, especially in females' data. Wits appraisal appears to be gender-specific and ethnicity-specific for female values.


Scalp psoriasis: European consensus on grading and treatment algorithm.
The scalp is a common site of involvement of psoriasis and, for many patients, is a challenging aspect of their disease. This can be attributed not only to the scaling, itching and cosmetic embarrassment that go with scalp psoriasis, but also to the fact that the scalp skin is relatively inaccessible, making topical therapies difficult to apply. The proximity of sensitive facial skin can also limit the use of potentially irritating topical treatments. Nevertheless, the specific challenges of scalp psoriasis are often neglected by treatment guidelines. This paper summarizes the discussions that took place at an international conference of experts convened in Geneva, Switzerland, in March 2008. The objective of the meeting was to review the available treatments for scalp psoriasis in terms of efficacy, safety, convenience, and the implications for patient compliance with treatment. In addition, definitions of mild, moderate and severe scalp psoriasis were agreed. This paper presents a treatment algorithm that includes recommendations for patients in all three categories. It considers the role of potent topical corticosteroids, vitamin D3 derivatives, salicylic acid preparations, and photo- and radiotherapy, as well as systemic therapies, including newer biological agents, for patients with widespread psoriasis with scalp involvement. Data from clinical trials indicate that a potent topical corticosteroid in a short-contact formulation is the most appropriate treatment for most patients with scalp psoriasis.


Quantum point contact switches.
Switching behavior between electron tunneling and ballistic transport states was induced by repeatedly bringing a sharpened nickel wire into contact with a gold surface. The high-conductivity ballistic state had a quantized conductance of 0.977 +/- 0.015 (2e(2)/h). Switching was accomplished by moving the electrodes with a piezoelectric actuator over a distance of 2 angstroms. The two electrodes and the actuator form a three-terminal device that is demonstrated to be a reliable digital and analog switch; it shows good discrimination between high and low states and possesses the important property of power gain. The conductance channel is most likely only one atom wide and possibly consists of a single atom.


Recessive inheritance and variable penetrance of slow-channel congenital myasthenic syndromes.
Slow-channel congenital myasthenic syndromes (SCCMS) typically show dominant inheritance. They are caused by missense mutations within the subunits of muscle nicotinic acetylcholine receptors (AChR) that result in prolonged ion channel activations. SCCMS mutations within the AChR subunit are located in various functional domains, whereas fully described mutations in AChR non- subunits have, thus far, been located only in the M2 channel-lining domain. The authors identified and characterized two -subunit mutations, located outside M2, that underlie SCCMS in three kinships. In two of the three kinships, the syndrome showed an atypical inheritance pattern. These methods included clinical diagnosis, mutation detection, haplotype analysis, and functional expression studies using single-channel recordings of mutant AChR transiently transfected into HEK293 cells. The authors identified two SCCMS mutations in the AChR subunit, L78P and L221F. Both mutations prolonged ACh-induced ion channel activations. L78P is present in a consanguineous family and appears to be pathogenic only when present on both alleles, and L221F shows variable penetrance in one of the two families that were identified harboring this mutation. SCCMS mutations may show a recessive inheritance pattern and variable penetrance. A diagnosis of SCCMS should not be ruled out in cases of CMS with an apparent recessive inheritance pattern.


The chemistry of PET imaging with zirconium-89.
This Tutorial Review aims to provide an overview of the use of zirconium-89 complexes in biomedical imaging. Over the past decade there have been many new papers in this field, ranging from chemistry through to preclinical and clinical applications. Here we attempt to summarise the main developments that have occurred in this period. The primary focus is on coordination chemistry but other aspects such as isotope production, isotope properties, handling and radiochemical techniques and characterisation of cold and labelled complexes are included. Selected results from animal and human clinical studies are presented in the context of the stabilities and properties of the labelled bioconjugates.


Remediating doctors' performance to restore patient safety: a realist review protocol.
Underperformance by doctors poses a risk to patient safety. Remediation is an intervention designed to remedy underperformance and return a doctor to safe practice. Remediation is widely used across healthcare systems globally, and has clear implications for both patient safety and doctor retention. Yet, there is a poor evidence base to inform remediation programmes. In particular, there is a lack of understanding as to why and how a remedial intervention may work to change a doctor's practice. The aim of this research is to identify why, how, in what contexts, for whom and to what extent remediation programmes for practising doctors work to support patient safety. Realist review is an approach to evidence synthesis that seeks to develop programme theories about how an intervention works to produce its effects. The initial search strategy will involve: database and grey literature searching, citation searching and contacting authors. The evidence search will be extended as the review progresses and becomes more focused on the development of specific aspects of the programme theory. The development of the programme theory will involve input from a stakeholder group consisting of professional experts in the remediation process and patient representatives. Evidence synthesis will use a realist logic of analysis to interrogate data in order to develop and refine the initial programme theory into a more definitive realist programme theory of how remediation works. The study will follow and be reported according to Realist And Meta-narrative Evidence Syntheses-Evolving Standards (RAMESES). Ethical approval is not required. Our dissemination strategy will include input from our stakeholder group. Customised outputs will be developed using the knowledge-to-action cycle framework, and will be targeted to: policy-makers; education providers and regulators, the National Health Service, doctors and academics. CRD42018088779.


Sex differences in IL-17 contribute to chronicity in male versus female urinary tract infection.
Sex-based differences influence incidence and outcome of infectious disease. Women have a significantly greater incidence of urinary tract infection (UTI) than men, yet, conversely, male UTI is more persistent with greater associated morbidity. Mechanisms underlying these sex-based differences are unknown, in part due to a lack of experimental models. We optimized a model to transurethrally infect male mice and directly compared UTI in both sexes. Although both sexes were initially equally colonized by uropathogenic E. coli, only male and testosterone-treated female mice remained chronically infected for up to 4 weeks. Female mice had more robust innate responses, including higher IL-17 expression, and increased γδ T cells and group 3 innate lymphoid cells in the bladder following infection. Accordingly, neutralizing IL-17 abolished resolution in female mice, identifying a cytokine pathway necessary for bacterial clearance. Our findings support the concept that sex-based responses to UTI contribute to impaired innate immunity in males and provide a rationale for non-antibiotic-based immune targeting to improve the response to UTI.


Comparative secretome analysis of Rhizoctonia solani isolates with different host ranges reveals unique secretomes and cell death inducing effectors.
Rhizoctonia solani is a fungal pathogen causing substantial damage to many of the worlds' largest food crops including wheat, rice, maize and soybean. Despite impacting global food security, little is known about the pathogenicity mechanisms employed by R. solani. To enable prediction of effectors possessing either broad efficacy or host specificity, a combined secretome was constructed from a monocot specific isolate, a dicot specific isolate and broad host range isolate infecting both monocot and dicot hosts. Secretome analysis suggested R. solani employs largely different virulence mechanisms to well-studied pathogens, despite in many instances infecting the same host plants. Furthermore, the secretome of the broad host range AG8 isolate may be shaped by maintaining functions for saprophytic life stages while minimising opportunities for host plant recognition. Analysis of possible co-evolution with host plants and in-planta up-regulation in particular, aided identification of effectors including xylanase and inhibitor I9 domain containing proteins able to induce cell death in-planta. The inhibitor I9 domain was more abundant in the secretomes of a wide range of necrotising fungi relative to biotrophs. These findings provide novel targets for further dissection of the virulence mechanisms and potential avenues to control this under-characterised but important pathogen.


Simultaneous generation of chemical concentration and mechanical shear stress gradients using microfluidic osmotic flow comparable to interstitial flow.
Cells are very sensitive to various microenvironmental cues, including mechanical stress and chemical gradients. Therefore, physiologically relevant models of cells should consider how cells sense and respond to microenvironmental cues. This can be accomplished by using microfluidic systems, in which fluid physics can be realized at a nanoliter scale. Here we describe a simple and versatile method to study the generation of chemical concentration and mechanical shear stress gradients in a single microfluidic chip. Our system uses an osmotic pump that produces very slow (<a few microm/s) and controlled flow, allowing a wide and stable diffusion of specific chemical concentration. We also established a shear stress gradient passively via a circular channel in the interstitial level. For evaluation of the system, we used L929 mouse fibroblast cells and simultaneously exposed them to a mechanical stress gradient and a chemical nutrient gradient. The interstitial shear stress level clearly affected cell alignment, mobility velocity, and attachment. At the same time, cell proliferation reflected nutrient concentration level. Our system, which enables continuous and long-term culture of cells in a combined chemical and mechanical gradient, provides physiologically realistic conditions and will be applicable to studies of cancer metastasis and stem cell differentiation.


Intermonitor variability of GT3X accelerometer.
The main purpose of this study was to assess the inter-monitor reliability of the tri-axial GT3X Actigraph accelerometer over a range of physical activities (PA). This device collects motion data on each of the vertical (Y), horizontal right-left (X), and horizontal front-back (Z) axes and also calculates the vector summed value √X(2)+Y(2)+Z(2) known as 'vector magnitude' (VM). 8 GT3X accelerometers were worn at the same time by the same participant. Accelerometers were placed back-to-front, all facing forward and in sets of 4 securely taped together, attached to a belt and allocating each block above either left or right hip at waist level. Inter-monitor reliability was assessed during 6 conditions: rest, walking (4 and 6 km·h(-1)), running (8 and 10 km·h(-1)) and repeated sit-to-stand (40 times·min(-1)). The intra-class correlation coefficients were high for X, Y and Z axes (i.e., all ≥ 0.925) and for VM (≥ 0.946). In conclusion, we found good inter-instrument reliability of the GT3X accelerometer across all planes, yet our results also suggest that the X and Z axes do not provide further benefits over the 'traditional' Y-axis to assess the movement in typical PA.


Abietane-Type Diterpenoids Inhibit Protein Tyrosine Phosphatases by Stabilizing an Inactive Enzyme Conformation.
Protein tyrosine phosphatases (PTPs) contribute to a striking variety of human diseases, yet they remain vexingly difficult to inhibit with uncharged, cell-permeable molecules; no inhibitors of PTPs have been approved for clinical use. This study uses a broad set of biophysical analyses to evaluate the use of abietane-type diterpenoids, a biologically active class of phytometabolites with largely nonpolar structures, for the development of pharmaceutically relevant PTP inhibitors. Results of nuclear magnetic resonance analyses, mutational studies, and molecular dynamics simulations indicate that abietic acid can inhibit protein tyrosine phosphatase 1B, a negative regulator of insulin signaling and an elusive drug target, by binding to its active site in a non-substrate-like manner that stabilizes the catalytically essential WPD loop in an inactive conformation; detailed kinetic studies, in turn, show that minor changes in the structures of abietane-type diterpenoids (e.g., the addition of hydrogens) can improve potency (i.e., lower IC50) by 7-fold. These findings elucidate a previously uncharacterized mechanism of diterpenoid-mediated inhibition and suggest, more broadly, that abietane-type diterpenoids are a promising source of structurally diverse-and, intriguingly, microbially synthesizable-molecules on which to base the design of new PTP-inhibiting therapeutics.


Multiplex RT-PCR and Automated Microarray for Detection of Eight Bovine Viruses.
Microarrays can be a useful tool for pathogen detection as it allow for simultaneous interrogation of the presence of a large number of genetic sequences in a sample. However, conventional microarrays require extensive manual handling and multiple pieces of equipment for printing probes, hybridization, washing and signal detection. In this study, a reverse transcription (RT)-PCR with an accompanying novel automated microarray for simultaneous detection of eight viruses that affect cattle [vesicular stomatitis virus (VSV), bovine viral diarrhoea virus type 1 and type 2, bovine herpesvirus 1, bluetongue virus, malignant catarrhal fever virus, rinderpest virus (RPV) and parapox viruses] is described. The assay accurately identified a panel of 37 strains of the target viruses and identified a mixed infection. No non-specific reactions were observed with a panel of 23 non-target viruses associated with livestock. Vesicular stomatitis virus was detected as early as 2 days post-inoculation in oral swabs from experimentally infected animals. The limit of detection of the microarray assay was as low as 1 TCID50 /ml for RPV. The novel microarray platform automates the entire post-PCR steps of the assay and integrates electrophoretic-driven capture probe printing in a single user-friendly instrument that allows array layout and assay configuration to be user-customized on-site.


Reversibly tuning hydrogel stiffness through photocontrolled dynamic covalent crosslinks.
Controlling the physical properties of soft materials with external stimuli enables researchers to mimic and study dynamic systems. Of particular interest are hydrogels, polymer networks swollen by water with broad applicability to biomedicine. To control hydrogel mechanics with light, researchers have relied on a limited number of photochemical reactions. Here we introduce an approach to reversibly tune hydrogel mechanics with light by manipulating the stability of dynamic covalent crosslinks at the molecular level. The equilibrium between a boronic acid and diol to form a boronic ester can be altered by the configuration of an adjacent azobenzene photoswitch. By irradiating branched polymers bearing azobenzene-boronic acid and diol end groups with two different wavelengths of light, we can stiffen or soften the resulting hydrogel. Alternating irradiation induces reversible mechanical changes. Rheological characterization reveals that the hydrogels are viscoelastic, exhibiting stress relaxation on the order of seconds, and the stiffness is tuned independently of the crossover frequency. We have also demonstrated that this approach can be extended to use visible light for both softening and stiffening. These photocontrolled dynamic covalent crosslinks provide a versatile platform for tunable dynamic materials.


An immunohistochemical analysis of tissue thrombin expression in the human atria.
Thrombin, the final coagulation product of the coagulation cascade, has been demonstrated to have many physiological effects, including pro-fibrotic actions via protease-activated receptor (PAR)-1. Recent investigations have demonstrated that activation of the cardiac local coagulation system was associated with atrial fibrillation. However, the distribution of thrombin in the heart, especially difference between the atria and the ventricle, remains to be clarified. We herein investigated the expression of thrombin and other related proteins, as well as tissue fibrosis, in the human left atria and left ventricle. We examined the expression of thrombin and other related molecules in the autopsied hearts of patients with and without atrial fibrillation. An immunohistochemical analysis was performed in the left atria and the left ventricle. The thrombin was immunohistologically detected in both the left atria and the left ventricles. Other than in the myocardium, the expression of thrombin was observed in the endocardium and the subendocardium of the left atrium. Thrombin was more highly expressed in the left atrium compared to the left ventricle, which was concomitant with more tissue fibrosis and inflammation, as detected by CD68 expression, in the left atrium. We also confirmed the expression of prothrombin in the left atrium. The expression of PAR-1 was observed in the endocardium, subendocardium and myocardium in the left atrium. In patients with atrial fibrillation, strong thrombin expression was observed in the left atrium. The strong expression levels of thrombin, prothrombin and PAR-1 were demonstrated in the atrial tissues of human autopsied hearts.


Dengue and Chikungunya Virus Infections among Young Febrile Adults Evaluated for Acute HIV-1 Infection in Coastal Kenya.
Fever is common among patients seeking care in sub-Saharan Africa (sSA), but causes other than malaria are rarely diagnosed. We assessed dengue and chikungunya virus infections among young febrile adults evaluated for acute HIV infection (AHI) and malaria in coastal Kenya. We tested plasma samples obtained in a cross-sectional study from febrile adult patients aged 18-35 years evaluated for AHI and malaria at urgent care seeking at seven health facilities in coastal Kenya in 2014-2015. Dengue virus (DENV) and chikungunya virus (CHIKV) were amplified using quantitative real-time reverse-transcription polymerase chain reaction. We conducted logistic regression analyses to determine independent predictors of dengue virus infection. 489 samples that were negative for both AHI and malaria were tested, of which 43 (8.8%, 95% confidence interval [CI]: 6.4-11.7) were positive for DENV infection. No participant was positive for CHIKV infection. DENV infections were associated with clinic visits in the rainy season (adjusted odds ratio (AOR) = 3.0, 95% CI: 1.3-6.5) and evaluation at a private health facility (AOR 5.2, 95% CI: 2.0-13.1) or research health facility (AOR = 25.6, 95% CI: 8.9-73.2) instead of a public health facility. A high prevalence of DENV infections was found in febrile young adult patients evaluated for AHI. Our data suggests that DENV, along with AHI and malaria, should be considered in the differential diagnosis of the adult patient seeking care for fever in coastal Kenya.


Guidelines for the number of embryos to transfer following in vitro fertilization.
To review the effect of the number of embryos transferred on the outcome of in vitro fertilization (IVF), to provide guidelines on the number of embryos to transfer in IVF-embryo transfer (ET) in order to optimize healthy live births and minimize multiple pregnancies. Rates of live birth, clinical pregnancy, and multiple pregnancy or birth by number of embryos transferred are compared. Clinical pregnancy, multiple pregnancy, and live birth rates. The Cochrane Library and MEDLINE were searched for English language articles from 1990 to April 2006. Search terms included embryo transfer (ET), assisted reproduction, in vitro fertilization (IVF), ntracytoplasmic sperm injection (ICSI), multiple pregnancy, and multiple gestation. Additional references were identified through hand searches of bibliographies of identified articles. Available evidence was reviewed by the Reproductive Endocrinology and Infertility Committee and the Maternal-Fetal Medicine Committee of the Society of Obstetricians and Gynaecologists of Canada and the Board of the Canadian Fertility and Andrology Society, and was qualified using the Evaluation of Evidence Guidelines developed by the Canadian Task Force on the Periodic Health Exam. This guideline is intended to minimize the occurrence of multifetal gestation, particularly high-order multiples (HOM), while maintaining acceptable overall pregnancy and live birth rates following IVF-ET.


Immune responses induced by oligogalacturonides are differentially affected by AvrPto and loss of BAK1/BKK1 and PEPR1/PEPR2.
Plants possess an innate immune system capable of restricting invasion by most potential pathogens. At the cell surface, the recognition of microbe-associated molecular patterns (MAMPs) and/or damage-associated molecular patterns (DAMPs) by pattern recognition receptors (PRRs) represents the first event for the prompt mounting of an effective immune response. Pathogens have evolved effectors that block MAMP-triggered immunity. The Pseudomonas syringae effector AvrPto abolishes immunity triggered by the peptide MAMPs flg22 and elf18, derived from the bacterial flagellin and elongation factor Tu, respectively, by inhibiting the kinase function of the corresponding receptors FLS2 and EFR, as well as their co-receptors BAK1 and BKK1. Oligogalacturonides (OGs), a well-known class of DAMPs, are oligomers of α-1,4-linked galacturonosyl residues, released on partial degradation of the plant cell wall homogalacturonan. We show here that AvrPto affects only a subset of the OG-triggered immune responses and that, among these responses, only a subset is affected by the concomitant loss of BAK1 and BKK1. However, the antagonistic effect on auxin-related responses is not affected by either AvrPto or the loss of BAK1/BKK1. These observations reveal an unprecedented complexity among the MAMP/DAMP response cascades. We also show that the signalling system mediated by Peps, another class of DAMPs, and their receptors PEPRs, contributes to OG-activated immunity. We hypothesize that OGs are sensed through multiple and partially redundant perception/transduction complexes, some targeted by AvrPto, but not necessarily comprising BAK1 and BKK1.


Polarization-sensitive reflectance imaging in skeletal muscle.
We acquired polarization-sensitive reflectance images in freshly excised skeletal muscle samples. The obtained raw images varied depending on the incident and detection polarization states. The Stokes vectors were measured for incident light of four different polarization states, and the whole Mueller matrix images were also calculated. We found that the images obtained in skeletal muscles exhibited different features from those obtained in a typical polystyrene sphere solution. The back-reflected light in muscle maintained a higher degree of polarization along the axis perpendicular to muscle fiber orientation. Our analysis indicates that the unique muscle sarcomere structure plays an important role in modulating the propagation of polarized light in whole muscle.


Gray matter volumes in symptomatic and asymptomatic offspring of parents diagnosed with bipolar disorder.
Children of parents diagnosed with bipolar disorder (BD), termed high-risk offspring (HRO), are at greater risk of developing psychiatric disorders compared to healthy children of healthy parents (HCO). Gray matter volume (GMV) abnormalities have been observed in HRO, however, these reports are inconsistent. We posit that this variability may be attributed to differences in methodology among offspring studies; in particular, the presence of psychiatric symptoms in HRO. Here, we directly compared GMVs between symptomatic and asymptomatic HRO, and HCO. High-resolution T1-weighted MR images were collected from 31 HRO (18 symptomatic and 13 asymptomatic) and 20 age- and sex-matched HCO. HRO had at least one parent diagnosed with BD. Symptomatic HRO were defined as having a psychiatric diagnosis other than BD, while asymptomatic HRO were required to be free of any psychiatric diagnosis. Scans were processed using voxel-based morphometry methods and between group analyses were performed in SPM. Compared to HCO, the HRO group showed decreased GMV in the right inferior orbitofrontal, right middle frontal, and bilateral superior and middle temporal regions. Both symptomatic and asymptomatic HRO groups showed decreased GMV in these regions separately when compared to HCO. When comparing symptomatic and asymptomatic HRO, GMVs were comparable in all regions except the lateral occipital cortex. Our study compared symptomatic and asymptomatic HRO directly. In doing so, we provided further support for the presence of discrete GMV deficits in HRO, and confirmed that these deficits are present irrespective of the presence of symptoms in HRO.


Invasive Candida Infections in the ICU: Diagnosis and Therapy.
Invasive fungal infections have become a serious problem in the critically ill. One of the main reasons is the development of an immunocompromised condition. The most frequently found pathogens are Candida species. In order to provide adequate treatment, understanding this potentially life-threatening infection is mandatory. The aim of this summary is to view Candida infections from a different perspective and to give an overview on epidemiology, the range of pathophysiology from colonization to the invasive infections, and its impact on mortality. New therapeutic options will also be discussed and how these relate to current guidelines. Finally, the key issue of the choice of anti-fungal agents will be evaluated.


Association of metabolic syndrome with knee and hand osteoarthritis: A community-based study of women.
It is unclear whether the association between osteoarthritis (OA) and metabolic syndrome (MetS) varies with the site of the affected joint and the presence of pain. Our aim was to describe the association between MetS and radiographic OA (ROA) affecting the knee or the hand in the presence or absence of concurrent joint pain. Cross-sectional data of 952 women, aged 45-65years from the Chingford study, a population-based longitudinal cohort of middle-aged women initiated in 1988-1989 in London (UK), was analysed. MetS was defined using the National Cholesterol Education Program Treatment Panel III criteria. Data was collected on components of MetS: waist circumference, triglycerides, high-density lipoprotein (HDL), blood pressure and blood glucose. The outcome was four knee and hand OA groups: painful ROA, ROA only, pain only and neither ROA nor pain (reference category). Multinomial logistic regression models adjusted for age and body mass index (BMI) were used to evaluate the effect of presence of MetS and its individual components on OA subgroups for knee and hand separately. 952 eligible women, aged 45-65years was analysed. A significant association was observed between the presence and the number of MetS with painful knee ROA when adjusted for age; however, this association disappeared when BMI was included in the model. In contrast, the presence and the number of MetS were associated with painful interphalangeal (IPJ) OA after adjusting for both age and BMI. Four out of the five MetS components, including triglycerides, HDL-c, hypertension and glucose, were associated with painful IPJ OA. MetS is associated with painful IPJ OA but not with knee OA once BMI is taking into consideration. Further attention to MetS and OA at different sites is needed to understand the metabolic phenotype in OA.


Outbreak of amebiasis in Tbilisi, Republic of Georgia, 1998.
In 1998, we investigated a suspected outbreak of amebic liver abscesses caused by Entamoeba histolytica in the Republic of Georgia, using a case-control study. A questionnaire was administered and blood samples were obtained from cases and controls for serologic diagnosis. Medical records showed that E. histolytica infections were rarely diagnosed before 1998. However, from July through September 1998, 177 cases of suspected amebiasis were identified. Of 52 persons who had diagnosed liver abscesses, 37 (71%) were confirmed serologically to have antibodies against E. histolytica, compared with 11 of 53 persons (20.8%) diagnosed with intestinal amebiasis. In addition, 9-14% of asymptomatic controls were seropositive. Logistic regression identified the fact that interruptions in the water supply, decreases in water pressure, and increased water consumption were significantly associated with infection. The data support the hypothesis that drinking water was the source of infection, either because of inadequate municipal water treatment or contamination of municipal water in the distribution system.


Complex compulsive behaviour in the temporal variant of frontotemporal dementia.
As metabolic and structural changes in frontotemporal-subcortical pathways have been reported in patients with obsessive-compulsive disorders, we investigated the correlation between complex compulsive behaviour (CCB) and the distribution of atrophy in a group of 90 patients with frontotemporal dementia (FTD). CCB was defined as complex, intentional, and time consuming repetitive behaviour, which was distinguished from simple compulsive behaviour (SCB), such as verbal and motor repetitions and utilisation behaviour. Cortical atrophy on CT and/or MRI was semi-quantitatively assessed in frontal, temporal, parietal and occipital regions, and the pattern of atrophy was compared between patients with and without CCB or SCB. Linear measures were used to establish the presence of caudate atrophy (bicaudate ratio) and ventricular enlargement (bifrontal ratio). CCB was reported in 18 (21%) and SCB in 53 (61%) FTD patients. Frontotemporal atrophy was present in 64 patients (74%), and predominant temporal atrophy in 23 (26%). The pattern of atrophy was asymmetric in 25 patients (29%). Logistic regression analysis showed that temporal lobe atrophy (p < 0.005), as well as asymmetry of atrophy (p < 0.05) were independently associated with CCB, after adjusting for age at onset, gender, duration of symptoms at the time of imaging, severity of atrophy, and bicaudate and bifrontal ratio. No relationship was found between the presence of SCB and the distribution of atrophy, although patients with SCB tended to have more caudate atrophy (p < 0.1). Temporal lobe atrophy appears to mediate CCB in patients with FTD, especially if asymmetry of atrophy is present. Future studies with quantitative and volumetric measurements of the cortical and subcortical structures may further clarify the aetiology of CCB in FTD.


Hyperlipoproteinaemia in primary gout: hyperlipoproteinaemic phenotype and influence of alcohol intake and obesity in Japan.
Serum lipoprotein profiles were investigated in 108 male patients with primary gout before treatment to elucidate the prevalence of each individual phenotype of coexisting hyperlipoproteinaemia and pathogenic factors responsible for it. The mean serum triglyceride (TG) and total cholesterol (TC) levels in the patients with gout were 2.10 +/- 0.14 mmol/l and 5.26 +/- 0.10 mmol/l (mean +/- SEM) respectively, which were significantly higher (p less than 0.01 and p less than 0.05 respectively) than the levels in age matched controls without gout (1.30 +/- 0.07 mmol/l and 4.77 +/- 0.08 mmol/l respectively). Serum high density lipoprotein cholesterol (HDL-C) values were slightly decreased in patients with gout compared with controls (1.24 +/- 0.08 mmol/l v 1.40 +/- 0.03 mmol/l, p less than 0.05). Hyperlipoproteinaemia was seen in 61 patients (56%), of whom patients with type IIa, IIb, and IV hyperlipoproteinaemia formed 13, 15, and 69% respectively. Thus the prevalence of type IV hyperlipoproteinaemia was high in primary gout as compared with primary hyperlipoproteinaemia with primary hyperlipoproteinaemia (69% v 43%, p less than 0.01). The independent and relative influences of clinical data of the patients upon the concentrations of serum lipids were assessed by stepwise multiple regression analysis. Two major predictors of serum TG level were alcohol intake (p less than 0.01) and serum uric acid level (p less than 0.05). The most significant predictive variable was alcohol intake, but its influence was judged to be small (r2 = 0.067). None of the other variables, including obesity index, had any significant influence. The relationships between any of these variables and serum TC or HDL-C levels were not significant. In addition, serum lipid levels were investigated in patients with neither obesity (defined as 120% or more of ideal body weight) nor a history of alcohol intake. Their serum TG and TC concentrations were also significantly higher than the respective control levels. Thus hyperlipoproteinaemia in primary gout its unlikely to be secondary to excess alcohol intake or obesity, or both. Instead, it may result from genetic factors such as a combined hyperlipidaemic trait.


Tamoxifen (estrogen antagonist) inhibits voltage-gated calcium current and contractility in vascular smooth muscle from rats.
Tamoxifen (Tx) has been used in breast cancer treatment and prophylaxis because of its antiestrogenic activity; however, Tx may also have beneficial cardiovascular effects and other actions mediated by mechanisms other than estrogen receptors. Previous studies showing interactions of Tx with Ca+(+)-channel blockers suggested that Tx may affect Ca++ channels, an hypothesis that was investigated using whole cell patch clamp techniques in vascular smooth muscle cells (cell line A7r5 and freshly dissociated cells) and by determining effects on contractions of isolated blood vessels. Tx reduced current through L-type Ca+2 channels, with an ID50 of 2 x 10(-6) M when applied by cumulative addition to A7r5 cells. With acute application, 10(-6) M Tx significantly reduced L-type current in A7r5 cells within 2 min to 88% of control (vehicle, 0.1% ethanol) in A7r5 cells, 67% of control in aortic vascular smooth muscle cells, and 60% of control in tail artery vascular smooth muscle cells. Tx also decreased the rate of inactivation of L-type current. Inhibition of T-type current by Tx was less than for L-type current but was significant at 10(-5) M Tx. Treatment of tail artery rings with Tx (10(-5) M, 15 min; 10(-6) M, 4 hr) reduced K+-elicited contractions. Since therapeutic concentrations of Tx during treatment may exceed 10(-6) M, these effects of Tx on vascular smooth muscle Ca++ channels and vessel contractions may have a role in the efficacy and side-effects of Tx treatment.


Increased superoxide and endothelial NO synthase uncoupling in blood vessels of Bmal1-knockout mice.
Disruption of the circadian clock in mice produces vascular dysfunction as evidenced by impairments in endothelium-dependent signaling, vasomotion, and blood vessel remodeling. Although the altered function of endothelial NO synthase and the overproduction of reactive oxygen species are central to dysfunction of the endothelium, to date, the impact of the circadian clock on endothelial NO synthase coupling and vascular reactive oxygen species production is not known. The goals of the present study were to determine whether deletion of a critical component of the circadian clock, Bmal1, can influence endothelial NO synthase coupling and reactive oxygen species levels in arteries from Bmal1-knockout (KO) mice. Endothelial function was reduced in aortae from Bmal1-KO mice and improved by scavenging reactive oxygen species with polyethylene glycol-superoxide dismutase and nonselectively inhibiting cyclooxygenase isoforms with indomethacin. Aortae from Bmal1-KO mice exhibited enhanced superoxide levels as determined by electron paramagnetic resonance spectroscopy and dihydroethidium fluorescence, an elevation that was abrogated by administration of nitro-l-arginine methyl ester. High-performance liquid chromatography analysis revealed a reduction in tetrahydrobiopterin and an increase in dihydrobiopterin levels in the lung and aorta of Bmal1-KO mice, whereas supplementation with tetrahydrobiopterin improved endothelial function in the circadian clock KO mice. Furthermore, levels of tetrahydrobiopterin, dihydrobiopterin, and the key enzymes that regulate biopterin bioavailability, GTP cyclohydrolase and dihydrofolate reductase exhibited a circadian expression pattern. Having an established influence in the metabolic control of glucose and lipids, herein, we describe a novel role for the circadian clock in metabolism of biopterins, with a significant impact in the vasculature, to regulate coupling of endothelial NO synthase, production of superoxide, and maintenance of endothelial function.


Tailoring the permselectivity of water desalination membranes via nanoparticle assembly.
Thin film composite membranes can selectively separate mono- and divalent ions from water via solution-diffusion of each species through a dense but ultrathin, highly cross-linked polymer "skin" layer; water is transported across the membrane faster than associated salts. Changing the selectivity of the "skin" layer typically requires adjusting the monomer chemistries that make up the polymer "skin" layer, but doing so also impacts a host of other membrane properties. Here, we employ electrostatic layer-by-layer deposition of inorganic nanoparticles to enhance the permselectivity of an existing commercial nanofiltration membrane. We chose this approach because it is simple and robust and does not require any change to the underlying chemistry of the thin film composite (TFC) membrane. We found that a single layer of nanoparticles was sufficient to increase the permselectivity of the membrane by nearly 50%, compared to the virgin TFC membrane. In order to understand the mechanism for permselectivity enhancement, we developed a modified solution-diffusion model to account for the additional hydraulic resistance of the nanoparticle layer, which can faithfully capture the effect of nanoparticle layer thickness on the observed water and salt flux of the modified TFC membrane.


Oral Coenzyme Q10 supplementation does not prevent cardiac alterations during a high altitude trek to everest base cAMP.
Exposure to high altitude is associated with sustained, but reversible, changes in cardiac mass, diastolic function, and high-energy phosphate metabolism. Whilst the underlying mechanisms remain elusive, tissue hypoxia increases generation of reactive oxygen species (ROS), which can stabilize hypoxia-inducible factor (HIF) transcription factors, bringing about transcriptional changes that suppress oxidative phosphorylation and activate autophagy. We therefore investigated whether oral supplementation with an antioxidant, Coenzyme Q10, prevented the cardiac perturbations associated with altitude exposure. Twenty-three volunteers (10 male, 13 female, 46±3 years) were recruited from the 2009 Caudwell Xtreme Everest Research Treks and studied before, and within 48 h of return from, a 17-day trek to Everest Base Camp, with subjects receiving either no intervention (controls) or 300 mg Coenzyme Q10 per day throughout altitude exposure. Cardiac magnetic resonance imaging and echocardiography were used to assess cardiac morphology and function. Following altitude exposure, body mass fell by 3 kg in all subjects (p<0.001), associated with a loss of body fat and a fall in BMI. Post-trek, left ventricular mass had decreased by 11% in controls (p<0.05) and by 16% in Coenzyme Q10-treated subjects (p<0.001), whereas mitral inflow E/A had decreased by 18% in controls (p<0.05) and by 21% in Coenzyme Q10-treated subjects (p<0.05). Coenzyme Q10 supplementation did not, therefore, prevent the loss of left ventricular mass or change in diastolic function that occurred following a trek to Everest Base Camp.


Dysferlin interacts with annexins A1 and A2 and mediates sarcolemmal wound-healing.
Mutations in the dysferlin gene cause limb girdle muscular dystrophy type 2B and Miyoshi myopathy. We report here the results of expression profile analyses and in vitro investigations that point to an interaction between dysferlin and the Ca2+ and lipid-binding proteins, annexins A1 and A2, and define a role for dysferlin in Ca2+-dependent repair of sarcolemmal injury through a process of vesicle fusion. Expression profiling identified a network of genes that are co-regulated in dysferlinopathic mice. Co-immunofluorescence, co-immunoprecipitation, and fluorescence lifetime imaging microscopy revealed that dysferlin normally associates with both annexins A1 and A2 in a Ca2+ and membrane injury-dependent manner. The distribution of the annexins and the efficiency of sarcolemmal wound-healing are significantly disrupted in dysferlin-deficient muscle. We propose a model of muscle membrane healing mediated by dysferlin that is relevant to both normal and dystrophic muscle and defines the annexins as potential muscular dystrophy genes.


"An indelible mark" the response to participation in euthanasia and physician-assisted suicide among doctors: A review of research findings.
The debate regarding euthanasia and physician-assisted suicide (E/PAS) raises key issues about the role of the doctor, and the professional, ethical, and clinical dimensions of the doctor-patient relationship. This review aimed to examine the published evidence regarding the response of doctors who have participated in E/PAS. Original research papers were identified reporting either qualitative or qualitative data published in peer-reviewed literature between 1980 and March 2018, with a specific focus on the impact on, or response from, physicians to their participation in E/PAS. PRISMA and CASP guidelines were followed. Nine relevant papers met selection criteria. Given the limited published data, a descriptive synthesis of quantitative and qualitative findings was performed. Quantitative surveys were limited in scope but identified a mixed set of responses. Where studies measured psychological impact, 30-50% of doctors described emotional burden or discomfort about participation, while findings also identified a comfort or satisfaction in believing the request of the patient was met. Significant, ongoing adverse personal impact was reported between 15% to 20%. A minority of doctors sought personal support, generally from family or friends, rather than colleagues. The themes identified from the qualitative studies were summarized as: 1) coping with a request; 2) understanding the patient; 3) the doctor's role and agency in the death of a patient; 4) the personal impact on the doctor; and 5) professional guidance and support. Participation in E/PAS can have a significant emotional impact on participating clinicians. For some doctors, participation can contrast with perception of professional roles, responsibilities, and personal expectations. Despite the importance of this issue to medical practice, this is a largely neglected area of empirical research. The limited studies to date highlight the need to address the responses and impact on clinicians, and the support for clinicians as they navigate this challenging area.


A novel hybridization approach for detection of citrus viroids.
Citrus plants are natural hosts of several viroid species all belonging to the family Pospiviroidae. Previous attempts to detect viroids from field-grown species and cultivars yielded erratic results unless analyses were performed using Etrog citron a secondary bio-amplification host. To overcome the use of Etrog citron a number of RT-PCR approaches have been proposed with different degrees of success. Here we report the suitability of an easy to handle northern hybridization protocol for viroid detection of samples collected from field-grown citrus species and cultivars. The protocol involves: (i) Nucleic acid preparations from bark tissue samples collected from field-grown trees regardless of the growing season and storage conditions; (ii) Separation in 5% PAGE or 1% agarose, blotting to membrane and fixing; (iii) Hybridization with viroid-specific DIG-labelled probes and detection with anti-DIG-alkaline phosphatase conjugate and autoradiography with the CSPD substrate. The method has been tested with viroid-infected trees of sweet orange, lemon, mandarin, grapefruit, sour orange, Swingle citrumello, Tahiti lime and Mexican lime. This novel hybridization approach is extremely sensitive, easy to handle and shortens the time needed for reliable viroid indexing tests. The suitability of PCR generated DIG-labelled probes and the sensitivity achieved when the samples are separated and blotted from non-denaturing gels are discussed.


Max-margin based learning for discriminative Bayesian network from neuroimaging data.
Recently, neuroimaging data have been increasingly used to study the causal relationship among brain regions for the understanding and diagnosis of brain diseases. Recent work on sparse Gaussian Bayesian network (SGBN) has shown it as an efficient tool to learn large scale directional brain networks from neuroimaging data. In this paper, we propose a learning approach to constructing SGBNs that are both representative and discriminative for groups in comparison. A max-margin criterion built directly upon the SGBN models is proposed to effectively optimize the classification performance of the SGBNs. The proposed method shows significant improvements over the state-of-the-art works in the discriminative power of SGBNs.


A Designed Experiments Approach to Optimizing MALDI-TOF MS Spectrum Processing Parameters Enhances Detection of Antibiotic Resistance in Campylobacter jejuni.
MALDI-TOF MS has been utilized as a reliable and rapid tool for microbial fingerprinting at the genus and species levels. Recently, there has been keen interest in using MALDI-TOF MS beyond the genus and species levels to rapidly identify antibiotic resistant strains of bacteria. The purpose of this study was to enhance strain level resolution for Campylobacter jejuni through the optimization of spectrum processing parameters using a series of designed experiments. A collection of 172 strains of C. jejuni were collected from Luxembourg, New Zealand, North America, and South Africa, consisting of four groups of antibiotic resistant isolates. The groups included: (1) 65 strains resistant to cefoperazone (2) 26 resistant to cefoperazone and beta-lactams (3) 5 strains resistant to cefoperazone, beta-lactams, and tetracycline, and (4) 76 strains resistant to cefoperazone, teicoplanin, amphotericin, B and cephalothin. Initially, a model set of 16 strains (three biological replicates and three technical replicates per isolate, yielding a total of 144 spectra) of C. jejuni was subjected to each designed experiment to enhance detection of antibiotic resistance. The most optimal parameters were applied to the larger collection of 172 isolates (two biological replicates and three technical replicates per isolate, yielding a total of 1,031 spectra). We observed an increase in antibiotic resistance detection whenever either a curve based similarity coefficient (Pearson or ranked Pearson) was applied rather than a peak based (Dice) and/or the optimized preprocessing parameters were applied. Increases in antimicrobial resistance detection were scored using the jackknife maximum similarity technique following cluster analysis. From the first four groups of antibiotic resistant isolates, the optimized preprocessing parameters increased detection respective to the aforementioned groups by: (1) 5% (2) 9% (3) 10%, and (4) 2%. An additional second categorization was created from the collection consisting of 31 strains resistant to beta-lactams and 141 strains sensitive to beta-lactams. Applying optimal preprocessing parameters, beta-lactam resistance detection was increased by 34%. These results suggest that spectrum processing parameters, which are rarely optimized or adjusted, affect the performance of MALDI-TOF MS-based detection of antibiotic resistance and can be fine-tuned to enhance screening performance.


Identification of high resource utilizing patients on internal medicine hospital services.
In order to provide high quality, cost-efficient care, it is critical to understand drivers of the cost of care. Therefore, we sought to identify clinical variables associated with high utilization (cost) in patients admitted to medical services and to develop a robust model to identify high utilization patients. In this case-control analysis, cases were identified as the 200 most costly patients admitted to internal medicine/internal medicine subspecialty services using our institution's computerized clinical data warehouse over a 7-month time period (November 1, 2012-May 31, 2013). 400 patients admitted in the same time period were randomly selected to serve as controls. The mean cost for the highest utilization patients was $126,343, while that for randomly matched patients was $15,575. In a multivariable regression model, the following variables were associated with high utilization of resources: African American race, age 35-44, admission through the emergency department, primary service of hematology-oncology, a history of heart failure or paralysis, a diagnosis of HIV, cancer, collagen vascular diseases and/or coagulopathy, a reduced albumin, and/or an elevated creatinine. The in hospital mortality rate for high utilization patients was 19%, compared to 8% for controls (p=0.0002). A predictive model using 14 different readily available clinical variables predicted high utilization with an area under the curve of 0.85. The data suggest that high utilization patients share similar demographic and clinical features. We speculate that a predictive model using commonly known patient characteristics should be able to predict high utilization patients.


Circulating Tumor Cells in Diagnosing Lung Cancer: Clinical and Morphologic Analysis.
The purpose of this study was to evaluate the value of circulating non-hematologic cells to differentiate benign from malignant lung lesions and their comparison with clinico-histologic features of corresponding primary lesions. Circulating cells were isolated by size method from peripheral blood of 77 patients with malignant (n = 60) and benign (n = 17) lung lesions. They were morphologically classified as cells with malignant feature; cells with uncertain malignant feature; and cells with benign feature; then statistically correlated with clinico-cytopathologic characteristics of corresponding lung lesion. Malignant circulating cells were detected in 54 of 60 (90%) malignant patients, and in 1 of 17 (5%) benign patients; benign circulating cells in 1 of 60 (1%) malignant patients and in 15 of 17 (88%) benign patients; and circulating cells with uncertain malignant aspect in 5 of 60 (8%) malignant patients and 1 of 17 (5%) benign patients. For a malignant circulating cells count greater than 25, sensitivity and specificity were 89% and 100%, respectively. The count was significantly correlated with stage, size, and standard uptake value of primary tumor. In 39 of 54 (72%) cases, the malignant circulating cells allowed a specific histologic diagnosis of the corresponding primary tumor after immunohistochemical analysis. Malignant circulating cells may be a valid marker in the diagnostic workup of lung lesions. However, our resuts should be corroborated by larger future studies especially for patients having small nodules.


G protein-coupled receptor Gpr115 (Adgrf4) is required for enamel mineralization mediated by ameloblasts.
Dental enamel, the hardest tissue in the human body, is derived from dental epithelial cell ameloblast-secreted enamel matrices. Enamel mineralization occurs in a strictly synchronized manner along with ameloblast maturation in association with ion transport and pH balance, and any disruption of these processes results in enamel hypomineralization. G protein-coupled receptors (GPCRs) function as transducers of external signals by activating associated G proteins and regulate cellular physiology. Tissue-specific GPCRs play important roles in organ development, although their activities in tooth development remain poorly understood. The present results show that the adhesion GPCR Gpr115 (Adgrf4) is highly and preferentially expressed in mature ameloblasts and plays a crucial role during enamel mineralization. To investigate the in vivo function of Gpr115, knockout (Gpr115-KO) mice were created and found to develop hypomineralized enamel, with a larger acidic area because of the dysregulation of ion composition. Transcriptomic analysis also revealed that deletion of Gpr115 disrupted pH homeostasis and ion transport processes in enamel formation. In addition, in vitro analyses using the dental epithelial cell line cervical loop-derived dental epithelial (CLDE) cell demonstrated that Gpr115 is indispensable for the expression of carbonic anhydrase 6 (Car6), which has a critical role in enamel mineralization. Furthermore, an acidic condition induced Car6 expression under the regulation of Gpr115 in CLDE cells. Thus, we concluded that Gpr115 plays an important role in enamel mineralization via regulation of Car6 expression in ameloblasts. The present findings indicate a novel function of Gpr115 in ectodermal organ development and clarify the molecular mechanism of enamel formation.


A descriptive cross-sectional study of annoyance from low frequency noise installations in an urban environment.
In order to improve the living conditions for respondents highly exposed to traffic noise, it has been recommended that one side of the building should face a "quiet side". Quiet may, however, be spoilt by noise from installations such as ventilation and air-conditioning systems. The noises generated by installations of this kind often have a dominant portion of low frequencies (20-200 Hz) and may be a source of great annoyance and sleep disturbance. This paper describes the cross-sectional part of an intended intervention study among residents exposed to traffic noise on one side of the building and to low frequency noise from installations on the other side of the building. A questionnaire masked as a general living environment study was delivered to a randomly selected person in each household. In total 41 respondents answered the questionnaire (71% response rate). Noise from installations was measured indoors in a bedroom facing the courtyard in a selection of apartments and outdoors in the yard. 24h traffic noise outdoor and indoor levels were calculated. The noise levels from installations were slightly above or at the Swedish recommendations for low frequency noise indoors with the window closed and exceeded the recommendations by about 10 dB SPL when the window was slightly opened. The proportion of persons who reported that they were very or extremely annoyed indoors from noise from installations was more than twice as high as for traffic noise. Installation noise also affected respondents' willingness to have their windows open and to sleep with an open window. The high disturbance of installation noises found in this study indicates the importance of also regulating the noise exposure on the "quiet side" of buildings. Further studies will give a better base for the extent of annoyance and acceptable levels of installation noises.


Intracranial pressure monitoring among children with severe traumatic brain injury.
OBJECT Well-designed studies linking intracranial pressure (ICP) monitoring with improved outcomes among children with severe traumatic brain injury (TBI) are lacking. The main objective of this study was to examine the relationship between ICP monitoring in children and in-hospital mortality following severe TBI. METHODS An observational study was conducted using data derived from 153 adult or mixed (adult and pediatric) trauma centers participating in the American College of Surgeons (ACS) Trauma Quality Improvement Program (TQIP) and 29 pediatric trauma centers participating in the pediatric pilot TQIP between 2010 and 2012. Random-intercept multilevel modeling was used to examine the association between ICP monitoring and in-hospital mortality among children with severe TBI ≤16 years of age after adjusting for important confounders. This association was evaluated at the patient level and at the hospital level. In a sensitivity analysis, this association was reexamined in a propensity-matched cohort. RESULTS A total of 1705 children with severe TBI were included in the study cohort. The overall in-hospital mortality was 14.3% of patients (n = 243), whereas the mortality of the 273 patients (16%) who underwent invasive ICP monitoring was 11% (n = 30). After adjusting for patient- and hospital-level characteristics, ICP monitoring was associated with lower in-hospital mortality (adjusted OR 0.50; 95% CI 0.30-0.85; p = 0.01). It is possible that patients who were managed with ICP monitoring were selected because of an anticipated favorable or unfavorable outcome. To further address this potential selection bias, the analysis was repeated with the hospital-specific rate of ICP monitoring use as the exposure. The adjusted OR for death of children treated at high ICP-use hospitals was 0.49 compared with those treated at low ICP-use hospitals (95% CI 0.31-0.78; p = 0.003). Variations in ICP monitoring use accounted for 15.9% of the interhospital variation in mortality among children with severe TBI. Similar results were obtained after analyzing the data using propensity score-matching methods. CONCLUSIONS In this observational study, ICP monitoring use was associated with lower hospital mortality at both the patient and hospital levels. However, the contribution of variable ICP monitoring rates to interhospital variation in pediatric TBI mortality was modest.


Determination of regional bone blood flow by means of fluorescent microspheres using an automated sample-processing procedure.
The determination of regional blood flow utilizing fluorescent microspheres (FMs) is an established method for numerous organs. Recent progress, in particular the automation of sample processing, has further improved this method. However, the FM method (reference sample technique), which allows repetitive measurement of regional organ blood flow, has so far not been used for the determination of blood flow in bone. The aim of the present study was to establish FM for the quantification of regional bone blood flow (RBBF). Female, anesthetized New Zealand rabbits (n = 6) received left ventricular injections of different amounts of FM at six subsequent time points. In order to examine the precision of RBBF determination, two different FM species were injected simultaneously at the sixth injection. At the end of the experiments the femoral and tibial condyles of each hind limb were removed and the fluorescence intensity in the tissue samples was measured by an automated procedure. In an in vitro study we have shown that acid digestion of the crystalline matrix has no effect on the fluorescence characteristics of FM. The determination of the number of spheres per tissue sample revealed that depending on the tissue sample size up to 3 x 10(6) spheres/injection were necessary to obtain about 400 microspheres in the individual bone samples. RBBF values of the tibial and femoral condyles did not differ at various injection intervals. The tibial blood flow values varied between 6.6 +/- 1.1 and 8.5 +/- 1.4 ml/min/100 g and were significantly higher than those of the femur (4.3 +/- 1.1 to 6.0 +/- 1.8 ml/min/100 g). The bone blood flow values obtained by simultaneous injection of two FM species correlated significantly (r = 0.96, slope = 1.06, intercept = 0.05), the mean difference was 0.39 +/- 1.11 ml/min/100 g. Our data demonstrate that the measurement of RBBF by means of FM allows a valid determination of RBBF.


Interactive ontology debugging: Two query strategies for efficient fault localization.
Effective debugging of ontologies is an important prerequisite for their broad application, especially in areas that rely on everyday users to create and maintain knowledge bases, such as the Semantic Web. In such systems ontologies capture formalized vocabularies of terms shared by its users. However in many cases users have different local views of the domain, i.e. of the context in which a given term is used. Inappropriate usage of terms together with natural complications when formulating and understanding logical descriptions may result in faulty ontologies. Recent ontology debugging approaches use diagnosis methods to identify causes of the faults. In most debugging scenarios these methods return many alternative diagnoses, thus placing the burden of fault localization on the user. This paper demonstrates how the target diagnosis can be identified by performing a sequence of observations, that is, by querying an oracle about entailments of the target ontology. To identify the best query we propose two query selection strategies: a simple "split-in-half" strategy and an entropy-based strategy. The latter allows knowledge about typical user errors to be exploited to minimize the number of queries. Our evaluation showed that the entropy-based method significantly reduces the number of required queries compared to the "split-in-half" approach. We experimented with different probability distributions of user errors and different qualities of the a priori probabilities. Our measurements demonstrated the superiority of entropy-based query selection even in cases where all fault probabilities are equal, i.e. where no information about typical user errors is available.


Processing deficits for familiar and novel faces in patients with left posterior fusiform lesions.
Pure alexia (PA) arises from damage to the left posterior fusiform gyrus (pFG) and the striking reading disorder that defines this condition has meant that such patients are often cited as evidence for the specialisation of this region to processing of written words. There is, however, an alternative view that suggests this region is devoted to processing of high acuity foveal input, which is particularly salient for complex visual stimuli like letter strings. Previous reports have highlighted disrupted processing of non-linguistic visual stimuli after damage to the left pFG, both for familiar and unfamiliar objects and also for novel faces. This study explored the nature of face processing deficits in patients with left pFG damage. Identification of famous faces was found to be compromised in both expressive and receptive tasks. Discrimination of novel faces was also impaired, particularly for those that varied in terms of second-order spacing information, and this deficit was most apparent for the patients with the more severe reading deficits. Interestingly, discrimination of faces that varied in terms of feature identity was considerably better in these patients and it was performance in this condition that was related to the size of the length effects shown in reading. This finding complements functional imaging studies showing left pFG activation for faces varying only in spacing and frontal activation for faces varying only on features. These results suggest that the sequential part-based processing strategy that promotes the length effect in the reading of these patients also allows them to discriminate between faces on the basis of feature identity, but processing of second-order configural information is most compromised due to their left pFG lesion. This study supports a view in which the left pFG is specialised for processing of high acuity foveal visual information that supports processing of both words and faces.


Prevalence and Causes of Visual Loss Among the Indigenous Peoples of the World: A Systematic Review.
Studies have documented a higher disease burden in indigenous compared with nonindigenous populations, but no global data on the epidemiology of visual loss in indigenous peoples are available. A systematic review of literature on visual loss in the world's indigenous populations could identify major gaps and inform interventions to reduce their burden of visual loss. To conduct a systematic review on the prevalence and causes of visual loss among the world's indigenous populations. A search of databases and alternative sources identified literature on the prevalence and causes of visual loss (visual impairment and blindness) and eye diseases in indigenous populations. Studies from January 1, 1990, through August 1, 2017, that included clinical eye examinations of indigenous participants and, where possible, compared findings with those of nonindigenous populations were included. Methodologic quality of studies was evaluated to reveal gaps in the literature. Limited data were available worldwide. A total of 85 articles described 64 unique studies from 24 countries that examined 79 598 unique indigenous participants. Nineteen studies reported comparator data on 42 085 nonindigenous individuals. The prevalence of visual loss was reported in 13 countries, with visual impairment ranging from 0.6% in indigenous Australian children to 48.5% in native Tibetans 50 years or older. Uncorrected refractive error was the main cause of visual impairment (21.0%-65.1%) in 5 of 6 studies that measured presenting visual acuity. Cataract was the main cause of visual impairment in all 6 studies measuring best-corrected acuity (25.4%-72.2%). Cataract was the leading cause of blindness in 13 studies (32.0%-79.2%), followed by uncorrected refractive error in 2 studies (33.0% and 35.8%). Most countries with indigenous peoples do not have data on the burden of visual loss in these populations. Although existing studies vary in methodologic quality and reliability, they suggest that most visual loss in indigenous populations is avoidable. Improvements in quality and frequency of research into the eye health of indigenous communities appear to be required, and coordinated eye care programs should be implemented to specifically target the indigenous peoples of the world.


(-)-Epigallocatechin-3-gallate ameliorates memory impairment and rescues the abnormal synaptic protein levels in the frontal cortex and hippocampus in a mouse model of Alzheimer's disease.
(-)-Epigallocatechin-3-gallate (EGCG) is the most abundant polyphenolic extract in green tea and it has attracted increasing attention for its multiple bioactive effects. However, the mechanisms by which EGCG exerts its neuroprotective actions in Alzheimer's disease (AD) are presently lacking. In the present study, a sporadic AD transgenic mouse model known as senescence-accelerated mouse prone 8 (SAMP8) was used to investigate whether oral administration of EGCG could improve recognition and memory function through reduction of amyloid β (Aβ) and tau hyperphosphorylation. We also investigated the effects of chronic EGCG treatment on the synaptic dysfunction in the frontal cortex (FC) and the hippocampus (Hip) of AD mice. The results showed that long-term oral consumption of EGCG at a relatively high dose (15 mg/kg) improved memory function in SAMP8 mice in the Y-maze and Morris water maze. The levels of Aβ1-42 and BACE-1 in FC and Hip were significantly reduced by EGCG treatment. EGCG treatment also prevented the hyperphosphorylation of tau and reversed the decreased synaptic protein marker synaptophysin and postsynaptic density protein 95 in FC and Hip of SAMP8 mice. The present study suggests that long-term oral consumption of EGCG ameliorates impairments in spatial learning and memory and rescues the reduction in synaptic proteins observed in an AD mouse model. Thus, EGCG may represent a novel candidate agent for the treatment of neurodegenerative diseases.


Complications of mandibular fracture: study of the treatment methods in calabar, Nigeria.
The plethora of techniques available for the treatment of mandibular fractures suggests that there is controversy regarding their definitive outcome. The purpose of this study was to clinically study the complications associated with the different treatment methods of mandibular fractures at the University of Calabar Teaching Hospital (UCTH), Nigeria. This was a three-year prospective study carried out at the Dental and Maxillofacial Clinic of the hospital. Patients who met the inclusion criteria had their data recorded in a proforma questionnaire. Out of the 256 patients studied, 17.2% developed complications. Complications were commoner (70.5%) between ages 21 and 50 years. Thirty-five (79.5%) were males while nine (20.5%) were females with a male:female ratio of 4.9:1. Following treatment by closed reduction, conservative and open reduction, 16.6%, 17.2% and 20.7% had complications, respectively. Whereas occlusal derangement was the most common complication, numbness of the cheek and lower lip was recorded following all treatment methods. Although the complications recorded in this patient population were managed during postoperative follow-up period, the methods of treatment available give good results, are cost-effective and patient compliance is good. This suggests that the older methods of treatment of mandibular fractures can still be used with reliability in contemporary dental practice.


Population Growth Potential of the Bed Bug, Cimex lectularius L.: A Life Table Analysis.
Experimental life tables were constructed and analyzed for three strains of the common bed bug: a pyrethroid-susceptible laboratory strain (HS), a highly resistant field strain (RR), and a field strain with a declining level of resistance (KR). Egg to adult survival in the RR strain was 94% compared with 79% and 69% in the HS and KR strains, respectively. The RR strain also developed significantly faster from egg to adult (~35 days) than the other two strains (~40 days). Analysis of a survivorship and fecundity life table for the RR strain produced the following results. The average life expectancy for a newly laid egg was ~143 days, and that of a newly molted adult was ~127 days. Females produced an average of 0.64 daughter eggs/day with the highest weekly production during the fifth week of adult life. Analysis of daily reproductive parity showed that females produced 1-3 and 4-6 eggs on 79 and 21% of the days, respectively, when egg laying occurred. The net reproductive rate (R₀) of the RR strain was ~35, which represents a 35-fold increase in the population per generation (~92 days). The intrinsic rate of increase, r, was 0.054 indicating that the population multiplies 1.1 times/female/day (λ) and doubles in size every 13 days. The stable age distribution (cx) was dominated by nymphs (54%), followed by eggs (34%) and adults (12%). Reproductive values (vx) for the strain increased from egg to the adult stage.


Comparison of tensile strength of fibrin glue and suture in microflap closure.
Suture closure and fibrin glue placement have been advocated as alternatives to healing by secondary intention. The aim of this study was to examine the tensile strength of these microflap closure techniques. Basic research. Three pairs of excised bovine true vocal folds underwent microflap creation and closure by either single 6-0 polyglactin suture or fibrin glue. Vocal folds were distracted to failure on a universal testing system. Excised porcine true vocal folds underwent microflap creation and were closed with either single 6-0 polyglactin suture or fibrin glue, or were left without closure. Tensile strength testing was performed with a universal testing system measuring load at 1 mm, 5 mm, and 10 mm of distraction. The bovine vocal fold model failed after an average extension of 22.6 mm (range, 21.4-23.9 mm) corresponding to 11.61 N (range, 8.04-13.47 N), with no failure of the suture prior to model failure. Fibrin glue did not demonstrate any measureable resistance to tension application. In the porcine vocal fold model, there was a significant difference between the median tensile load of suture closure (2.91 N) and no closure (1.16 N) at 10 mm of distraction (P = .01). There was no significant difference in median load of vocal folds undergoing fibrin glue closure or no closure. There is no significant difference in tensile strength of a microflap closed with fibrin glue or not closed. Suture closure of a microflap provides a significantly stronger mechanical closure than no closure. This suggests that use of fibrin glue is of little benefit on the vocal folds.


Long-Term Follow-Up of Retinal Degenerations Associated With LRAT Mutations and Their Comparability to Phenotypes Associated With RPE65 Mutations.
To investigate the natural history in patients with LRAT-associated retinal degenerations (RDs), in the advent of clinical trials testing treatment options. A retrospective cohort of 13 patients with LRAT-RDs. Twelve patients from a genetic isolate carried a homozygous c.12del mutation. One unrelated patient carried a homozygous c.326G>T mutation. The mean follow-up time was 25.3 years (SD 15.2; range 4.8-53.5). The first symptom was nyctalopia (n = 11), central vision loss (n = 1), or light-gazing (n = 1), and was noticed in the first decade of life. Seven patients (54%) reached low vision (visual acuity < 20/67), four of whom reaching blindness (visual acuity < 20/400), respectively, at mean ages of 49.9 (SE 5.4) and 59.9 (SE 3.1) years. The fundus appearance was variable. Retinal white dots were seen in six patients (46%). Full-field electroretinograms (n = 11) were nondetectable (n = 2; ages 31-60), reduced in a nonspecified pattern (n = 2; ages 11-54), or showed rod-cone (n = 6; ages 38-48) or cone-rod (n = 1; age 29) dysfunction. Optical coherence tomography (n = 4) showed retinal thinning but relative preservation of the (para-)foveal outer retinal layers in the second (n = 1) and sixth decade of life (n = 2), and profound chorioretinal degeneration from the eighth decade of life (n = 1). LRAT-associated phenotypes in this cohort were variable and unusual, but generally milder than those seen in RPE65-associated disease, and may be particularly amenable to treatment. The window of therapeutic opportunity can be extended in patients with a mild phenotype. Knowledge of the natural history of LRAT-RDs is essential in determining the window of opportunity in ongoing and future clinical trials for novel therapeutic options.


Staphylococcus saprophyticus bacteremia after ESWL in an immunocompetent woman.
Staphylococcus saprophyticus is a well-known cause of uncomplicated urinary tract infections, especially in young and sexually active women. Presence in blood cultures is rare and often attributed to contamination. When bacteremia is significant, it occurs mostly in patients with hematologic malignancies and is predominantly catheter-related. However, we describe a case of significant bacteremia with S. saprophyticus associated with urinary tract infection after extracorporeal shock wave lithotripsy of an ureterolithiasis in an otherwise healthy patient.


Toussaintines A-E: antimicrobial indolidinoids, a cinnamoylhydrobenzofuranoid and a cinnamoylcyclohexenoid from Toussaintia orientalis leaves.
Toussaintine A (N-cinnamoyl-5,6-dehydro-4-hydroxyindolidin-2,7-dione), toussaintine B (N-cinnamoyl-5,6-dehydro-4,7-dihydroxyindolidin-2-one), toussaintine C (N-cinnamoyl-5,6-dehydro-4-hydroxyindolidin-7-one), toussaintine D (N-cinnamoyl-2-amino-4-hydroxy-7-oxo-2,3,8,9-tetrahydrobenzofuran) and toussaintine E (N-cinnamoyl-1-acetoxymethyl-2-amino-1-hydroxycyclox-5-en-4-one) were isolated as antibacterial and antifungal constituents of the leaves of Toussaintia orientalis Verdc. (Annonaceae) and their structures established from analysis of spectroscopic data. The compounds belong to a series of variously cyclized aminocinnamoyl tetraketide derivatives, showing the importance of rarely occurring Annonaceae species as sources of structurally diverse natural products.


Impact of OATP transporters on pharmacokinetics.
Membrane transporters are now recognized as important determinants of the transmembrane passage of drugs. Organic anion transporting polypeptides (OATP) form a family of influx transporters expressed in various tissues important for pharmacokinetics. Of the 11 human OATP transporters, OATP1B1, OATP1B3 and OATP2B1 are expressed on the sinusoidal membrane of hepatocytes and can facilitate the liver uptake of their substrate drugs. OATP1A2 is expressed on the luminal membrane of small intestinal enterocytes and at the blood-brain barrier, potentially mediating drug transport at these sites. Several clinically used drugs have been identified as substrates of OATP transporters (e.g. many statins are substrates of OATP1B1). Some drugs may inhibit OATP transporters (e.g. cyclosporine) causing pharmacokinetic drug-drug interactions. Moreover, genetic variability in genes encoding OATP transporters can result in marked inter-individual differences in pharmacokinetics. For example, a single nucleotide polymorphism (c.521T > C, p.Val174Ala) in the SLCO1B1 gene encoding OATP1B1 decreases the ability of OATP1B1 to transport active simvastatin acid from portal circulation into the liver, resulting in markedly increased plasma concentrations of simvastatin acid and an enhanced risk of simvastatin-induced myopathy. SLCO1B1 polymorphism also affects the pharmacokinetics of many other, but not all (fluvastatin), statins and that of the antidiabetic drug repaglinide, the antihistamine fexofenadine and the endothelin A receptor antagonist atrasentan. This review compiles the current knowledge about the expression and function of human OATP transporters, their substrate and inhibitor specificities, as well as pharmacogenetics.


Submicroscopic Plasmodium prevalence in relation to malaria incidence in 20 villages in western Cambodia.
Cambodia has seen a marked reduction in the incidence of Plasmodium falciparum over the past decade without a corresponding decline in Plasmodium vivax incidence. It is unknown to what extent local transmission is sustained by a chain of clinical and sub-clinical infections or by continued re-introduction via migration. Using an ultrasensitive molecular technique, 20 villages in western Cambodia were surveyed to detect the low season prevalence of P. falciparum and P. vivax and local treatment records were reviewed. During March to May 2015 cross-sectional surveys were conducted in 20 villages in Battambang, western Cambodia. Demographic and epidemiological data and venous blood samples were collected from 50 randomly selected adult volunteers in each village. Blood was tested for Plasmodium infections by rapid diagnostic test (RDT), microscopy and high volume (0.5 ml packed red blood cell) quantitative polymerase chain reaction (uPCR). Positive samples were analysed by nested PCR to determine the Plasmodium species. Malaria case records were collected from the Provincial Health Department and village malaria workers to determine incidence and migration status. Among the 1000 participants, 91 (9.1%) were positive for any Plasmodium infection by uPCR, seven (0.7%) by microscopy, and two (0.2%) by RDT. uPCR P. vivax prevalence was 6.6%, P. falciparum 0.7%, and undetermined Plasmodium species 1.8%. Being male (adjusted OR 2.0; 95% CI 1.2-3.4); being a young adult <30 years (aOR 2.1; 95% CI 1.3-3.4); recent forest travel (aOR 2.8; 95% CI 1.6-4.8); and, a history of malaria (aOR 5.2; 95% CI 2.5-10.7) were independent risk factors for parasitaemia. Of the clinical malaria cases diagnosed by village malaria workers, 43.9% (297/634) and 38.4% (201/523) were among migrants in 2013 and in 2014, respectively. Plasmodium vivax prevalence determined by uPCR significantly correlated with vivax malaria incidences in both 2014 and 2015 (p = 0.001 and 0.002, respectively), whereas no relationship was observed in falciparum malaria (p = 0.36 and p = 0.59, respectively). There was heterogeneity in the malaria parasite reservoir between villages, and Plasmodium prevalence correlated with subsequent malaria incidence. The association was attributable chiefly to P. vivax infections, which were nine-fold more prevalent than P. falciparum infections. In the absence of a radical cure with 8-aminoquinolines, P. vivax transmission will continue even as P. falciparum prevalence declines. Migration was associated with over a third of incident cases of clinical malaria. Trial registration clinicaltrials.gov (NCT01872702). Registered 4 June 2013.


Positive and negative affect and health functioning indicators among older adults with chronic illnesses.
Emotional states have been linked with physical and mental health outcomes. In this study the role of positive and negative affect was investigated as determinants of health functioning for a community-dwelling sample of 153 older adults (age 60 or older) with chronic illnesses. High positive affect and low negative affect were found to be associated with lower levels of symptom distress, fewer depressive symptoms, higher daily activity scores, and higher perceived physical and mental health-related quality of life. These results have important clinical implications for the use of positive and negative affect as an indicator of life functioning among older adults. The relationship of positive and negative affect to reported health functioning found in this study suggests that measuring affect can provide a valuable means for understanding how individuals view their mental health as well as their symptoms of illness.


Nurses on the move: a global overview.
To look at nurse migration flows in the light of national nursing workforce imbalances, examine factors that encourage or inhibit nurse mobility, and explore the potential benefits of circular migration. The number of international migrants has doubled since 1970 and nurses are increasingly part of the migratory stream. Critical nursing shortages in industrialized countries are generating a demand that is fueling energetic international recruitment campaigns. Structural adjustments in the developing countries have created severe workforce imbalances and shortfalls often coexist with large numbers of unemployed health professionals. A nurse's motivation to migrate is multifactorial, not limited to financial incentives, and barriers exist that discourage or slow the migration process. The migration flows vary in direction and magnitude over time, responding to socioeconomic factors present in source and destination countries. The dearth of data on which to develop international health human resource policy remains. There is growing recognition, however, that migration will continue and that temporary migration will be a focus of attention in the years to come. Today's search for labor is a highly organized global hunt for talent that includes nurses. International migration is a symptom of the larger systemic problems that make nurses leave their jobs. Nurse mobility becomes a major issue only in a context of migrant exploitation or nursing shortage. Injecting migrant nurses into dysfunctional health systems-ones that are not capable of attracting and retaining staff domestically-will not solve the nursing shortage.


Improving experience of medical abortion at home in a changing therapeutic, technological and regulatory landscape: a realist review.
To inform UK service development to support medical abortion at home, appropriate for person and context. Realist review SETTING/PARTICIPANTS: Peer-reviewed literature from 1 January 2000 to 9 December 2021, describing interventions or models of home abortion care. Participants included people seeking or having had an abortion. Interventions and new models of abortion care relevant to the UK. Causal explanations, in the form of context-mechanism-outcome configurations, to test and develop our realist programme theory. We identified 12 401 abstracts, selecting 944 for full text assessment. Our final review included 50 papers. Medical abortion at home is safe, effective and acceptable to most, but clinical pathways and user experience are variable and a minority would not choose this method again. Having a choice of abortion location remains essential, as some people are unable to have a medical abortion at home. Choice of place of abortion (home or clinical setting) was influenced by service factors (appointment number, timing and wait-times), personal responsibilities (caring/work commitments), geography (travel time/distance), relationships (need for secrecy) and desire for awareness/involvement in the process. We found experiences could be improved by offering: an option for self-referral through a telemedicine consultation, realistic information on a range of experiences, opportunities to personalise the process, improved pain relief, and choice of when and how to discuss contraception. Acknowledging the work done by patients when moving medical abortion care from clinic to home is important. Patients may benefit from support to: prepare a space, manage privacy and work/caring obligations, decide when/how to take medications, understand what is normal, assess experience and decide when and how to ask for help. The transition of this complex intervention when delivered outside healthcare environments could be supported by strategies that reduce surprise or anxiety, enabling preparation and a sense of control.


Pulmonary resection in patients aged 80 years or over with clinical stage I non-small cell lung cancer: prognostic factors for overall survival and risk factors for postoperative complications.
This retrospective study was designed to identify the predictors of long-term survival and the risk factors for complications after surgery in patients aged 80 years or older with clinical (c)-stage I non-small cell lung cancer. The Japanese Joint Committee of Lung Cancer Registry collated the clinicopathological profiles and outcomes of 13,344 patients who underwent pulmonary resection for primary lung cancer in 1999. The data of 367 patients aged 80 years or older with c-stage I non-small cell lung cancer were analyzed for prognostic factors and risk factors for postoperative complications. The median age was 82 years (range, 80-90 years). Of the total patient number, 102 (27.8%) had some form of comorbidity diagnosed preoperatively. Thirty-one (8.4%) patients presented with postoperative complications, and the operative mortality was 1.4%. The 5-year survival rates were 55.7% for c-stage I patients, 62.0% for c-stage IA, and 47.2% for c-stage IB. Advanced pathologic stage and comorbidity were significant independent predictors of shortened survival (p < 0.0001 and p = 0.032, respectively). Comorbidity and mediastinal lymph node dissection were identified as factors that increased the risk of postoperative complications (p < 0.0001 and p = 0.036, respectively). Survival rates were independent of the extent of pulmonary resection (lobectomy or limited resection). Octogenarian patients with c-stage I lung cancer in this study had a satisfactory long-term outcome and low-mortality rate. Comorbidity is a factor associated with both prognosis and operative risks. A selection of the patients who would be curable without mediastinal lymph node dissection after an accurate preoperative staging is beneficial to decrease the postoperative complications because this procedure is a risk factor.