Maximizing Chiral Perturbation on Thermally Activated Delayed Fluorescence Emitters and Elaboration of the First Top-Emission Circularly Polarized OLED.
Molecular designs merging circularly polarized luminescence (CPL) and thermally activated delayed fluorescence (CP-TADF) using the concept of chiral perturbation appeared recently as a cornerstone for the development of efficient CP-organic light emitting diodes (CP-OLED). Such devices could strongly increase the energy efficiency and performances of conventional OLED displays, in which 50% of the emitted light is often lost due to the use of antiglare filters. In this context, herein, ten couples of enantiomers derived from novel chiral emitter designs are reported, exhibiting CPL, TADF, and aggregation induced enhancement emission properties (AIEE). Representing the first structure properties relationship investigation for CP-TADF materials, this thorough experimental and theoretical work highlights crucial findings on the key structural and electronic parameters (isomerism, nature of the carbazole substituents) governing the synergy between CPL and TADF properties. To conclude this study, the first top emission CP-OLED is elaborated as a new approach of generating CP light in comparison with classical bottom-emission CP-OLED architecture. Indeed, the top-emission configuration represents the only relevant device architecture for future microdisplay applications. Thereby, in addition to offer molecular guidelines to combine efficiently TADF and CPL properties, this study opens new avenues toward practical applications for CP-OLEDs.


A More Nuanced Discussion Required.
Williams and colleagues make a valuable contribution to the home care policy literature, however, their arguments are not always convincing. Missing is a more nuanced discussion of research showing that even when governments provide more supportive services for older adults, families continue to provide care, and a discussion of alternative forms of caring that may arise in the future such as care from siblings and non-married older adults helping one another. Drawing on research pointing to several countries that offer caregivers a range of services would also have been helpful. Furthermore, it is not clear, as the authors argue, that the reason policy makers have moved toward providing for higher needs patients with fewer and fewer services for lower needs patients is a 'wait and see' attitude. Alternative reasoning is just as plausible. The benefits of providing supports to caregivers of children are well articulated but this does not negate the need among caregivers to older adults where some of the issues differ from caring for sick and disabled minors. Finally, action items for government are not offered but could have been helpful. Examples are provided.


A comprehensive health care directive in a home for the aged.
To examine the use of and compliance with a new comprehensive health care directive by residents of a home for the aged and to determine the effect of the directive on the use of health care services. Descriptive study with a before-after design. A home for the aged providing residential care to women. All 119 residents (ages 71 to 103 years, mean age 87.5 years). Introduction of a comprehensive health care directive and follow-up at 1 year. Residents' treatment choices, compliance with the directive, number of hospital admissions and length of hospital stay, number of deaths and places where deaths occurred. Ninety (76%) of the residents completed the directive. In the event of reversible life-threatening illness 34, 24, 11 and 21 residents requested supportive, limited, maximum and intensive care respectively. For irreversible illness the numbers were 75, 12, 3 and 0 respectively. In case of cardiac arrest 88% requested that cardiopulmonary resuscitation not be done. In the year before the introduction of the directive there were nine deaths, one in the home and eight in hospitals. In the year after there were 17 deaths, 11 in the home and 6 in hospitals. The mean length of hospital stay was significantly lower in that year than in the year before implementation (p less than 0.001). This innovative health care directive seems to be feasible, practical and well supported by residents, their families and health care professionals. Further studies are required to establish the generalizability and reproducibility of the data to other elderly people in institutions, to chronically ill patients and to the community at large.


Colonial histories, racism and health-The experience of Māori and Indigenous peoples.
The health of Māori, the Indigenous peoples of Aotearoa, New Zealand, like that of almost all Indigenous peoples worldwide, is characterised by systematic inequities in health outcomes, differential exposure to the determinants of health, inequitable access to and through health and social systems, disproportionate marginalisation and inadequate representation in the health workforce. As health providers, we are often taught that 'taking a history' is a critical component of a patient consultation to ensure that the underlying conditions are treated rather than the often superficial presenting symptoms. In the same way, attempts to make sense of the health and well-being of Indigenous peoples is inadequate unless health providers engage critically with the history of their respective nations and any subsequent patterns of privilege or disadvantage. Understanding this history, within the framework of western imperialism and other similar colonial projects, allows us to make sense of international patterns of Indigenous health status. While health commentators acknowledge the unequal health outcomes of Indigenous people, and an increasing number also link these inequities to Indigenous marginalisation resulting from historic events, very few go further and expose the deep relationship between racism and coloniality and how these continue to be the basic determinants of Indigenous health today. This work includes honest examination of the role that science and the health disciplines have played historically in colonisation through the subjugation of Indigenous ways of knowing and knowledge production, as well as being complicit in the creation and maintenance of a fabricated hierarchy of humankind. Despite the 'science' of this racial hierarchy being discredited, it retains a false validity in our societies. As long as oppressive systems that continue to re-inscribe racism and white privilege remain in communities, including our academic communities, coloniality continues its discrimination. Indigenous voices on migration, ethnicity, racisma and health will always demand the elimination of inequities in health but to do so will require a parallel commitment to critically interrogating all of our histories and our disciplines, as well as examining how our practice, including research, disrupts or maintains global systems of racism and coloniality.


Physiology of Extracorporeal Gas Exchange.
Circulating venous blood outside the body, through an artificial lung (membrane oxygenator), and returning oxygenated blood to the patient is extracorporeal gas exchange. Oxygen and carbon dioxide exchange in a membrane lung is controlled by regulating blood flow, blood composition, and device design. With this control, lung function can be replaced for weeks by artificial organs. © 2020 American Physiological Society. Compr Physiol 10:879-891, 2020.


Removing noise from pyrosequenced amplicons.
In many environmental genomics applications a homologous region of DNA from a diverse sample is first amplified by PCR and then sequenced. The next generation sequencing technology, 454 pyrosequencing, has allowed much larger read numbers from PCR amplicons than ever before. This has revolutionised the study of microbial diversity as it is now possible to sequence a substantial fraction of the 16S rRNA genes in a community. However, there is a growing realisation that because of the large read numbers and the lack of consensus sequences it is vital to distinguish noise from true sequence diversity in this data. Otherwise this leads to inflated estimates of the number of types or operational taxonomic units (OTUs) present. Three sources of error are important: sequencing error, PCR single base substitutions and PCR chimeras. We present AmpliconNoise, a development of the PyroNoise algorithm that is capable of separately removing 454 sequencing errors and PCR single base errors. We also introduce a novel chimera removal program, Perseus, that exploits the sequence abundances associated with pyrosequencing data. We use data sets where samples of known diversity have been amplified and sequenced to quantify the effect of each of the sources of error on OTU inflation and to validate these algorithms. AmpliconNoise outperforms alternative algorithms substantially reducing per base error rates for both the GS FLX and latest Titanium protocol. All three sources of error lead to inflation of diversity estimates. In particular, chimera formation has a hitherto unrealised importance which varies according to amplification protocol. We show that AmpliconNoise allows accurate estimates of OTU number. Just as importantly AmpliconNoise generates the right OTUs even at low sequence differences. We demonstrate that Perseus has very high sensitivity, able to find 99% of chimeras, which is critical when these are present at high frequencies. AmpliconNoise followed by Perseus is a very effective pipeline for the removal of noise. In addition the principles behind the algorithms, the inference of true sequences using Expectation-Maximization (EM), and the treatment of chimera detection as a classification or 'supervised learning' problem, will be equally applicable to new sequencing technologies as they appear.


Biological interpretation of genome-wide association studies using predicted gene functions.
The main challenge for gaining biological insights from genetic associations is identifying which genes and pathways explain the associations. Here we present DEPICT, an integrative tool that employs predicted gene functions to systematically prioritize the most likely causal genes at associated loci, highlight enriched pathways and identify tissues/cell types where genes from associated loci are highly expressed. DEPICT is not limited to genes with established functions and prioritizes relevant gene sets for many phenotypes.


Engineering PQS biosynthesis pathway for enhancement of bioelectricity production in pseudomonas aeruginosa microbial fuel cells.
The biosynthesis of the redox shuttle, phenazines, in Pseudomonas aeruginosa, an ubiquitous microorganism in wastewater microflora, is regulated by the 2-heptyl-3,4-dihydroxyquinoline (PQS) quorum-sensing system. However, PQS inhibits anaerobic growth of P. aeruginosa. We constructed a P. aeruginosa strain that produces higher concentrations of phenazines under anaerobic conditions by over-expressing the PqsE effector in a PQS negative ΔpqsC mutant. The engineered strain exhibited an improved electrical performance in microbial fuel cells (MFCs) and potentiostat-controlled electrochemical cells with an approximate five-fold increase of maximum current density relative to the parent strain. Electrochemical analysis showed that the current increase correlates with an over-synthesis of phenazines. These results therefore demonstrate that targeting microbial cell-to-cell communication by genetic engineering is a suitable technique to improve power output of bioelectrochemical systems.


Watt-level erbium-doped all-fiber laser at 3.44 μm.
We demonstrate a 3.44 μm all-fiber laser emitting a maximum of 1.5 W at room temperature, the highest continuous power ever generated from a mid-IR fiber oscillator clearly beyond 3 μm. The laser operates on the 4F(9/2)→4I(9/2) transition of erbium-doped fluoride glasses and relies on a dual pumping scheme at 974 and 1976 nm. By combining a dichroic mirror deposited on the input fiber tip and a fiber Bragg grating as an output coupler, a stable laser emission is produced with a FWHM bandwidth of less than 0.6 nm. The laser cavity has an efficiency of 19% with respect to the launched pump power at 1976 nm and no saturation is observed provided 974 nm co-pumping is sufficient. The joint effect of the two pumps is also investigated.


Ultraviolet-B radiation induced cross-linking improves physical properties of cold- and warm-water fish gelatin gels and films.
Cold- and warm-water fish gelatin granules were exposed to ultraviolet-B radiation for doses up to 29.7 J/cm(2). Solutions and films were prepared from the granules. Gel electrophoresis and refractive index were used to examine changes in molecular weight of the samples. Also, the gel strength and rheological properties of the solutions as well as the tensile and water vapor barrier properties of the films were characterized. SDS-PAGE and refractive index results indicated cross-linking of gelatin chains after exposure to radiation. Interestingly, UV-B treated samples displayed higher gel strengths, with cold- and warm-water fish gelatin having gel strength increases from 1.39 to 2.11 N and from 7.15 to 8.34 N, respectively. In addition, both gelatin samples exhibited an increase in viscosity for higher UV doses. For gelatin films, the cold-water fish gelatin samples made from irradiated granules showed greater tensile strength. In comparison, the warm-water gelatin films made from irradiated granules had lower tensile strength, but better water vapor barrier properties. This might be due to the UV induced cross-linking in warm-water gelatin that disrupted helical structures.


Measurement of the Earth's rotation: 720 BC to AD 2015.
New compilations of records of ancient and medieval eclipses in the period 720 BC to AD 1600, and of lunar occultations of stars in AD 1600-2015, are analysed to investigate variations in the Earth's rate of rotation. It is found that the rate of rotation departs from uniformity, such that the change in the length of the mean solar day (lod) increases at an average rate of +1.8 ms per century. This is significantly less than the rate predicted on the basis of tidal friction, which is +2.3 ms per century. Besides this linear change in the lod, there are fluctuations about this trend on time scales of decades to centuries. A power spectral density analysis of fluctuations in the range 2-30 years follows a power law with exponent -1.3, and there is evidence of increased power at a period of 6 years. There is some indication of an oscillation in the lod with a period of roughly 1500 years. Our measurements of the Earth's rotation for the period 720 BC to AD 2015 set firm boundaries for future work on post-glacial rebound and core-mantle coupling which are invoked to explain the departures from tidal friction.


Dental pulp stem cells, niches, and notch signaling in tooth injury.
Stem cells guarantee tissue repair and regeneration throughout life. The decision between cell self-renewal and differentiation is influenced by a specialized microenvironment called the 'stem cell niche'. In the tooth, stem cell niches are formed at specific anatomic locations of the dental pulp. The microenvironment of these niches regulates how dental pulp stem cell populations participate in tissue maintenance, repair, and regeneration. Signaling molecules such as Notch proteins are important regulators of stem cell function, with various capacities to induce proliferation or differentiation. Dental injuries often lead to odontoblast apoptosis, which triggers activation of dental pulp stem cells followed by their proliferation, migration, and differentiation into odontoblast-like cells, which elaborate a reparative dentin. Better knowledge of the regulation of dental pulp stem cells within their niches in pathological conditions will aid in the development of novel treatments for dental tissue repair and regeneration.


Bristles before down: a new perspective on the functional origin of feathers.
Over the course of the last two decades, the understanding of the early evolution of feathers in nonavian dinosaurs has been revolutionized. It is now recognized that early feathers had a simple form comparable in general structure to the hairs of mammals. Insight into the prevalence of simple feathers throughout the dinosaur family tree has gradually arisen in tandem with the growing evidence for endothermic dinosaur metabolisms. This has led to the generally accepted opinion that the early feather coats of dinosaurs functioned as thermo insulation. However, thermo insulation is often erroneously stated to be a likely functional explanation for the origin of feathers. The problem with this explanation is that, like mammalian hair, simple feathers could serve as insulation only when present in sufficiently high concentrations. The theory therefore necessitates the origination of feathers en masse. We advocate for a novel origin theory of feathers as bristles. Bristles are facial feathers common among modern birds that function like mammalian tactile whiskers, and are frequently simple and hair-like in form. Bristles serve their role in low concentrations, and therefore offer a feasible first stage in feather evolution.


Preparation and evaluation of novel mixed micelles as nanocarriers for intravenous delivery of propofol.
Novel mixed polymeric micelles formed from biocompatible polymers, poly(ethylene glycol)-poly(lactide) (mPEG-PLA) and polyoxyethylene-660-12-hydroxy stearate (Solutol HS15), were fabricated and used as a nanocarrier for solubilizing poorly soluble anesthetic drug propofol. The solubilization of propofol by the mixed micelles was more efficient than those made of mPEG-PLA alone. Micelles with the optimized composition of mPEG-PLA/Solutol HS15/propofol = 10/1/5 by weight had particle size of about 101 nm with narrow distribution (polydispersity index of about 0.12). Stability analysis of the mixed micelles in bovine serum albumin (BSA) solution indicated that the diblock copolymer mPEG efficiently protected the BSA adsorption on the mixed micelles because the hydrophobic groups of the copolymer were efficiently screened by mPEG, and propofol-loaded mixed micelles were stable upon storage for at least 6 months. The content of free propofol in the aqueous phase for mixed micelles was lower by 74% than that for the commercial lipid emulsion. No significant differences in times to unconsciousness and recovery of righting reflex were observed between mixed micelles and commercial lipid formulation. The pharmacological effect may serve as pharmaceutical nanocarriers with improved solubilization capacity for poorly soluble drugs.


Cell cycle events associated with the termination of proliferation by cytotoxic and differentiation-inducing actions of 6-thioguanine on HL-60 cells.
Delayed growth arrest was observed in HL-60 acute promyelocytic leukemia cells after exposure to 6-thioguanine (TG). This growth arrest occurred in both wild-type HL-60 cells exposed to 2 microM TG and an HL-60 clone lacking hypoxanthine-guanine phosphoribosyltransferase (HGPRT) activity at a 500-fold higher concentration of drug. Both cell lines continued replication during an initial 4-day period of exposure to TG; however, upon removal of the purine antimetabolite and reincubation in fresh medium in the absence of drug, no further increase in cell number was observed over the next 4 days. Extensive differentiation, as measured by the reduction of nitroblue tetrazolium, occurred in TG-treated, HL-60 HGPRT-negative cells, whereas no significant increase in the number of nitroblue tetrazolium-positive cells was observed in wild-type HL-60 cells exposed to the purinethiol. Thus, termination of proliferation in wild-type cells appeared to be an expression of cytotoxicity, while in the HGPRT-negative clone, cell replication was apparently terminated by conversion of cells to end-stage forms with a mature phenotype. In support of this conclusion, differences occurred in the stage of the cell cycle arrest, determined on Day 6 after exposure to TG. Approximately 85% of parental HL-60 cells treated with TG were present in the S and G2 + M phases of the cell cycle, with the greatest proportional change from untreated controls being in the G2-M phase (i.e., a 63% increase over untreated controls). In contrast, HL-60 HGPRT-negative cells treated with TG accumulated in G1, with 68% of the population located in this phase (i.e., an 80% increase compared to controls), as might be expected for a differentiated population. Dimethyl sulfoxide, which produced differentiation in both parental HL-60 and HL-60 HGPRT-negative cells, was used as a positive control. Both cell lines responded identically to dimethyl sulfoxide, with growth arrest being due at least in part to differentiation, which corresponded to an increase in G1 cells.


Environmental factors influencing heat stress in feedlot cattle.
Data from 3 summer feedlot studies were utilized to determine the environmental factors that influence heat stress in cattle and also to determine wind speed (WSPD; m.s(-1)) and solar radiation (RAD; W.m(-2)) adjustments to the temperature-humidity index (THI). Visual assessments of heat stress, based on panting scores (0 = no panting to 4 = severe panting), were collected from 1400 to 1700. Mean daily WSPD, black globe temperature at 1500, and minimums for nighttime WSPD, nighttime black globe THI, and daily relative humidity were found to have the greatest influence on panting score from 1400 to 1700 (R2 = 0.61). From hourly values for THI, WSPD, and RAD, panting score was determined to equal -7.563 + (0.121 x THI) - (0.241 x WSPD) + (0.00082 x RAD) (R2 = 0.49). Using the ratio of WSPD to THI and RAD to THI (- 1.992 and 0.0068 for WSPD and RAD, respectively), adjustments to the THI were derived for WSPD and RAD. On the basis of these ratios and the average hourly data for 1400 to 1700, the THI, adjusted for WSPD and RAD, equals [4.51 + THI - (1.992 x WSPD) + (0.0068 x RAD)]. Four separate cattle studies, comparable in size, type of cattle, and number of observations to the 3 original studies, were utilized to evaluate the accuracy of the THI equation adjusted for WSPD and RAD, and the relationship between the adjusted THI and panting score. Mean panting score derived from individual observations of black-hided cattle in these 4 studies were 1.22, 0.94, 1.32, and 2.00 vs. the predicted panting scores of 1.15, 1.17, 1.30, and 1.96, respectively. Correlations between THI and panting score in these studies ranged from r = 0.47 to 0.87. Correlations between the adjusted THI and mean panting score ranged from r = 0.64 to 0.80. These adjustments would be most appropriate to use, within a day, to predict THI during the afternoon hours using hourly data or current conditions. In addition to afternoon conditions, nighttime conditions, including minimum WSPD, minimum black globe THI, and minimum THI, were also found to influence heat stress experienced by cattle. Although knowledge of THI alone is beneficial in determining the potential for heat stress, WSPD and RAD adjustments to the THI more accurately assess animal discomfort.


Comparative Analysis of Two Gene-Targeting Approaches Challenges the Tumor-Suppressive Role of the Protein Kinase MK5/PRAK.
MK5 (MAPK-activated protein kinase 5) or PRAK (p38-regulated and -activated kinase) are alternative names for a serine/threonine protein kinase downstream to ERK3/4 and p38 MAPK. A previous gene targeting approach for MK5/PRAK (termed here MK5/PRAK-Δex8) revealed a seemingly tumor-suppressive role of MK5/PRAK in DMBA-induced one step skin carcinogenesis and Ras-induced transformation. Here we demonstrate that an alternative targeting strategy of MK5/PRAK (termed MK5/PRAK-Δex6) increased neither tumor incidence in the one step skin carcinogenesis model, nor Ras-induced transformation in primary cells. Interestingly, due to the targeting strategies and exon skipping both knockouts do not completely abolish the generation of MK5/PRAK protein, but express MK5/PRAK deletion mutants with different biochemical properties depending on the exon targeted: Targeting of exon 6 leads to expression of an unstable cytoplasmic catalytically inactive MK5/PRAK-Δex6 mutant while targeting of exon 8 results in a more stable nuclear MK5/PRAK-Δex8 mutant with residual catalytic activity. The different properties of the MK5/PRAK deletion mutants could be responsible for the observed discrepancy between the knockout strains and challenge the role of MK5/PRAK in p53-dependent tumor suppression. Further MK5/PRAK knockout and knock-in mouse strains will be necessary to assign a physiological function to MK5/PRAK in this model organism.


The PREMIER intervention helps participants follow the Dietary Approaches to Stop Hypertension dietary pattern and the current Dietary Reference Intakes recommendations.
To examine the influence of the PREMIER study lifestyle interventions on dietary intakes and adherence to the Dietary Approaches to Stop Hypertension (DASH) dietary pattern and the Dietary Reference Intakes (DRI). An 18-month multicenter, randomized controlled trial comparing two multicomponent lifestyle intervention programs to an advice only control group. A total of 810 participants were recruited from local communities and randomized into the study. Individuals were eligible if they were aged 25 years or older, had body mass index between 18.5 and 45.0, not taking antihypertensive medication, and had prehypertension or stage 1 hypertension (systolic blood pressure 120 to 159 mm Hg and diastolic blood pressure 80 to 95 mm Hg). The two active intervention programs were a behavioral lifestyle intervention that implements established recommendations, and an established intervention plus the DASH dietary pattern. Both interventions consisted of intensive group and individual counseling sessions. The control group received a brief advice session after randomization and again after 6 months of data collection. Dietary intakes were collected by two random 24-hour recalls at baseline, 6 months, and 18 months. The primary outcome of the PREMIER study was change in systolic blood pressure at 6 months. The main outcomes examined here include dietary variables collected by 24-hour recall at each time point. Nutrient intakes were calculated and compared among the time points and the three intervention groups using mixed models with repeated measures at 6 and 18 months. Proportion of participants who met or achieved the original DASH nutrient intake levels and the DRIs were calculated and compared among the three intervention groups. P<0.01 was considered statistically significant. Participants in both the established intervention and established intervention plus DASH dietary pattern groups substantially reduced energy, total fat, saturated fat, and sodium intake and these reductions persisted throughout the study. Established intervention plus DASH dietary pattern group participants increased intakes of fruits, vegetables, dairy, and many vitamins and minerals; these increases were significantly greater than that of the control and established intervention groups. A majority of established intervention plus DASH dietary pattern group participants achieved at least two thirds of the DRI recommendations for most nutrients at 6 months, despite their reduction in total energy intake. Some but relatively small recidivism occurred at 18 months. Both the established intervention and established intervention plus DASH dietary pattern group intervention were effective in helping participants follow established recommendations to control blood pressure. The advice-only control group also made some behavior changes, mainly decreasing energy and sodium intake. Only the established intervention plus DASH dietary pattern group significantly increased intakes of DASH-specific food groups, including fruits, vegetables, and dairy products, and nutrients, including protein, fiber, calcium, potassium, and magnesium. Most of the increases did not reach the levels consumed in the original DASH feeding studies. Whereas the established intervention plus DASH dietary pattern group intervention provides a useful platform to achieve the DASH dietary pattern and current DRI recommendations, intervention enhancements, including a greater emphasis on nutrient-dense foods, would likely improve this intervention.


Nebulized but not parenteral IFN-gamma decreases IgE production and normalizes airways function in a murine model of allergen sensitization.
An animal model of local allergen (airways) sensitization was employed to study the effects of rIFN-gamma administered by ultrasonic nebulization through the airways on IgE production and airways responsiveness. BALB/c mice exposed to aerosolized OVA daily for 10 days developed a predominant anti-OVA IgE response, immediate cutaneous reactivity to OVA, and increased airways responsiveness (AR). Mice were treated with rIFN-gamma, either systemically or locally via the airways, following different protocols; i.p. rIFN-gamma failed to modulate the course of OVA sensitization, although total IgE levels in the serum were decreased by 50%. Anti-OVA IgE levels remained elevated, immediate skin test responses to OVA persisted, and AR was increased. However, local treatment of the airways with nebulized rIFN-gamma caused a 66% decrease in serum anti-OVA IgE and a twofold rise in IgG2a levels. Cutaneous reactivity to OVA was reduced and AR was also normalized after nebulized rIFN-gamma. In contrast to the i.p. route, treatment with nebulized rIFN-gamma resulted in a reduction in the in vitro IgE production by lymphocytes in response to OVA and IL-4. The timing of treatment with nebulized rIFN-gamma was important in determining the immunomodulatory response. Treatment after day 7 of OVA exposure failed to modulate sensitization. Treatment regimens with nebulized rIFN-gamma that began before day 7 of OVA exposure were able to decrease anti-OVA IgE. Only treatment regimens that included 3 days of nebulized IFN-gamma before OVA sensitization caused a decrease in cutaneous reactivity and normalization of AR. The data demonstrate that both the route and timing of rIFN-gamma administration are critical factors in the immunomodulation of the immediate allergic response to allergen sensitization via the airways.


Generalization of a prototype intelligent hybrid system for hard gelatin capsule formulation development.
The aim of this project was to expand a previously developed prototype expert network for use in the analysis of multiple biopharmaceutics classification system (BCS) class II drugs. The model drugs used were carbamazepine, chlorpropamide, diazepam, ibuprofen, ketoprofen, naproxen, and piroxicam. Recommended formulations were manufactured and tested for dissolution performance. A comprehensive training data set for the model drugs was developed and used to retrain the artificial neural network. The training and the system were validated based on the comparison of predicted and observed performance of the recommended formulations. The initial test of the system resulted in high error values, indicating poor prediction capabilities for drugs other than piroxicam. A new data set, containing 182 batches, was used for retraining. Ten percent of the test batches were used for cross-validation, resulting in models with R2 > or = 70%. The comparison of observed performance to the predicted performance found that the system predicted successfully. The hybrid network was generally able to predict the amount of drug dissolved within 5% for the model drugs. Through validation, the system was proven to be capable of designing formulations that met specific drug performance criteria. By including parameters to address wettability and the intrinsic dissolution characteristics of the drugs, the hybrid system was shown to be suitable for analysis of multiple BCS class II drugs.


Transposable elements in a clade of three tetraploids and a diploid relative, focusing on Gypsy amplification.
Polyploidization can activate specific transposable elements, leading to their accumulation. At the same time, the preferential loss of repetitive elements in polyploids may be central to diploidization. The paucity of studies of transposable element (TE) dynamics in closely related diploid and polyploid species, however, prevents generalizations about these patterns. Here, we use low-coverage Illumina sequencing data for a clade of three tetraploid Orobanche species and a diploid relative to quantify the abundance and relative frequencies of different types of TEs. We confirmed tetraploidy in the sequenced individuals using standard cytogenetic methods and inferred the time of origin of the tetraploid clade with a rate-calibrated molecular clock. The sequenced individuals of Orobanche austrohispanica, Orobanche densiflora, and Orobanche gracilis have 2n = 76 chromosomes, are tetraploid, and shared a most recent common ancestor some 6.7 Ma ago. Comparison of TE classifications from the Illumina data with classification from 454 data for one of the species revealed strong effects of sequencing technology on the detection of certain types of repetitive DNA. The three tetraploids show repeat enrichment especially of Gypsy TE families compared to eight previously analyzed Orobanchaceae. However, the diploid Orobanche rapum-genistae genome also has a very high proportion (30%) of Gypsy elements. We had earlier suggested that tetraploidization might have contributed to an amplification of Gypsy elements, particularly of the Tekay clade, and that O. gracilis underwent genome downsizing following polyploidization. The new data reveal that Gypsy amplification in Orobanchaceae does not consistently relate to tetraploidy and that more species sampling is required to generalize about Tekay accumulation patterns.


Pre-ovulation control of hatchling sex ratio in the Seychelles warbler.
Females of some bird species have a high degree of control over the sex ratio of their offspring at laying. Although several mechanisms have been put forward to explain how females might control the sex of their eggs, virtually nothing is known. As females are the heterogametic sex in birds, adjustment of the clutch sex ratio could arise either by pre- or post-ovulation control mechanisms. The Seychelles warbler (Acrocephalus sechellensis) exhibits extreme adaptive egg sex ratio bias. Typically, warblers produce only single-egg clutches, but by translocating pairs to vacant habitat of very high quality, most females were induced to produce two-egg clutches. Overall, females skewed clutch sex ratios strongly towards daughters (86.6%). This bias was evident in the first egg, but critically, also in the second eggs laid a day apart, even when all absent, unhatched, or unsexed second eggs were assumed to be male. Although a bias in the first egg may arise through either pre- or post-ovulation mechanisms, the skew observed in second eggs could only arise through pre-ovulation control. Post-ovulation adjustment may also contribute to skewed hatchling sex ratios, but as sex-biased release of gametes is likely to be a more efficient process of control, pre-ovulation mechanisms may be the sole means of adjustment in this species. High fitness differentials between sons and daughters, as apparent in the Seychelles warblers, may be necessary for primary sex ratio adjustment to evolve.


Some studies of the spectra of thermal and stimulated molecular scattering of light.
This paper gives the results of a study of the spectraof thermal and stimulated molecular light scattering in various media. The velocity and absorption of hypersound in liquids were measured. The indicatrix of the spectrum of thermal scattering in the wing of the Rayleigh line was studied in a number of liquids. A new phenomenon is described-the fine structure in the spectrum in the thermal wing of the Rayleigh line in liquids. A theory is developed of the induced scattering of light in the wing of the Rayleigh line; the results of the observation of this phenomenon in a number of liquids as well as the results of the investigation of its temperature dependence are presented. Results of the study of stimulated Mandelstam-Brillouin scattering in compressed gases, liquids, glasses, and in a quartz crystal, are presented. A Mandelstam-Brillouin phonon generator has been obtained under conditions where the quartz single crystal could not be damaged under the influence of a giant laser pulse. The experimental and theoretical studies in the area of molecular scattering of light in many countries are so extensive that the authors were forced to confine themselves to a presentation of only a part of their work.


Qualitative and quantitative aspects of the ligase chain reaction assay for Chlamydia trachomatis in genital tract samples and urines.
The performance of the ligase chain reaction (LCR) assay for Chlamydia trachomatis was evaluated in a genitourinary medicine (GUM) clinic population. Its sensitivity was 100%, 91% and 95%, respectively, for cervical, vaginal and urine samples from 417 women, when compared with direct fluorescent antibody (DFA) staining of cervical samples, and 100% and 91%, respectively, for urethral and urine samples from 317 men, when compared with DFA staining of urethral smears. An enzyme immunoassay (EIA) was only 65% sensitive for cervical samples. Urethral swabs from a number of treated men remained LCR-positive when antigen was no longer detectable by DFA staining. An association between quantitative data from the LCR assay (i.e. the optical density of samples, measured in relation to internal controls and calibrators) and the antigen load of the samples, measured by DFA staining, indicated a lack of significant inhibition in the LCR assay in this study. This was probably due to freezing of the samples before testing. Diluting 20 LCR-positive urines with a range of antigen loads resulted in loss of positivity in 3, and a reduction in the signal in 13. The implications of the antigen load on the performance of detection assays for chlamydia-positive patients are discussed.


The reference frame of visual motion priming depends on underlying motion mechanisms.
Several different types of motion mechanisms function in the human visual system. The purpose of this study was to clarify the type of reference frame, such as retinotopic and spatiotopic frames of reference, at which those different motion mechanisms function. To achieve this, we used a phenomenon called visual motion priming, in which the perceived direction of a directionally ambiguous test stimulus is influenced by the moving direction of a preceding stimulus. Previous studies have indicated that negative motion priming is induced by a low-level motion mechanism, such as a first-order motion sensor, whereas positive motion priming is induced by a high-level motion mechanism, such as a feature-tracking system. In the experiments, subjects made a saccade after the termination of a smoothly drifting priming stimulus and judged the perceived direction of a 180° phase-shifted sine-wave grating presented subsequently in retinotopic or screen-based spatiotopic coordinates. By manipulating the stimulus parameters, such as primer duration, velocity, and contrast, both positive and negative priming were observed. We found that positive priming was observed in spatiotopic coordinates, whereas negative priming was observed in retinotopic coordinates. Prominent positive priming in spatiotopic coordinates was observed only when the interval between the priming and test stimuli was longer than around 600 ms. This delayed priming effect was not caused by saccadic eye movements. These results suggest that a low-level motion mechanism functions in retinotopic coordinates, whereas a high-level motion mechanism functions in spatiotopic coordinates, in which the representation builds up slowly.


Cell therapy for age-related disorders: myocardial infarction and stroke--a mini-review.
The leading causes of death and disability in the elderly are from cardiovascular and cerebrovascular diseases. The biological role of stem cells in the hematopoietic system has been well characterized and has led to the development of hematopoietic stem and progenitor cell (HSPC) transplantation for the treatment of numerous malignant and nonmalignant diseases. More recently, stem cells have been found in many other tissues of the body including the heart and brain. As the field of stem cell biology has progressed, cell therapies for the treatment of myocardial infarction and stroke have been tested in early stage clinical trials using a variety of cellular agents. To review the clinical evidence supporting the role of cell therapies for myocardial infarction and stroke. A systematic review of the literature was conducted to identify clinical trials using cell therapies for myocardial infarction and stroke. Clinical trials of granulocyte colony-stimulating factor to mobilize HSPC after percutaneous coronary intervention for acute myocardial infarction have not shown clinical benefit. Direct delivery of HSPC to coronary arteries supplying the infarcted region using percutaneous coronary intervention does improve hemodynamic endpoints such as left ventricular ejection fraction in many studies. One randomized trial demonstrated improvement in clinically meaningful endpoints such as death, recurrence of myocardial infarction and re-hospitalization for heart failure. Several small trials of cell therapy for stroke have been reported, including cytokine-mobilized HSPC, mesenchymal stromal cells and cell lines transplanted stereotactically into the region affected by stroke. In some prospective randomized trials, cell therapy for myocardial infarction leads to improvement in hemodynamic parameters. Cell therapy for stroke is a relatively new area of translational and clinical research with preliminary studies showing safety and some measurable benefit in small numbers of subjects.


Consequences of retinal image clarity versus occlusion (absent) versus diffusion.
A series of clinical questions and stated hypotheses suggested in the pre-1960s regarding the differences between stimuli of occlusion and diffusion are presented (Part I) and are answered and confirmed by a series of experiments and data in animals and humans. A diffusion stimulus is extremely destructive to development of the acuity system in an eye per se (as well as producing myopia), and a unilateral diffusion stimulus is also destructive to development of the binocular system. Real occlusion is a no-stimulus condition that can be used to preserve normal acuity and binocular development, and as a delay tactic to successfully counteract the detrimental effect of diffusion. Binocular input differences (especially if one is a diffusion stimulus) are a major cause of strabismus in both the immature and mature binocular systems. The hypothesis was proposed that preoperative full-time alternate occlusion in infantile esotropia enhanced the binocularity outcome (for which supportive experimental data in animals and humans from our laboratories are discussed in Part III). Animal experiments during the 1960s and 1970s are reviewed relative to the confusion and conflict generated (Part II), since many of these experiments were based on the false assumptions that the unilateral eyelid closure model was a no-stimulus condition (because of the small amount of light transmitted). In fact, it was a worst-case severe stimulus with both monocular and binocular detrimental consequences. And the unilateral eyelid closure model usually produced either undetected or ignored strabismus in the animal experiments, with such strabismus severely compounding the detrimental effects of the eyelid closure model. Further confusion was added by the amblyopia therapeutic model in animals of "reverse eyelid occlusion" (which was really reverse diffusion) and which the author maintains was a gross distortion of the clinician's real occlusive patch over the better eye in the therapy of amblyopia of the poorer eye. These confusions and conflicts were at variance with long-standing clinical percepts. Part III provides data from the series of animal and human experiments from our laboratories at Smith-Kettlewell Eye Research Institute, which clarify the confusion and conflicts of some of the animal experiments described. Our data support the original hypotheses (Part I) enabling the clinician to use occlusion measures in selected patients to expand the therapeutic timing options and to improve visual outcomes. Binocular system outcomes are shown to be improved by our recent data in animal and human experiments, thus supporting the beneficial sensory effects of preoperative full-time alternate occlusion regimes in infantile esotropia.


Use of in vivo complementation in Mycobacterium tuberculosis to identify a genomic fragment associated with virulence.
Novel molecular tools and genetic methods were developed to isolate genomic fragments of Mycobacterium tuberculosis that may be associated with virulence. We sought to restore virulence, a characteristic of M. tuberculosis that is correlated with growth rate in mouse spleen and lung tissue, to the avirulent strain H37Ra by complementation. A representative library of the virulent M. tuberculosis strain H37Rv was constructed and transformed into H37Ra. Enrichment for individual faster-growing recombinants was achieved by passage of pools of H37Ra transformants harboring the H37Rv library through mice. A molecular strategy was devised to isolate and clone the H37Rv genomic DNA fragment ivg, which conferred a more rapid in vivo growth rate to H37Ra.


Long-term benefit from immune modulation and anti-inflammatory treatment in metastatic mesothelioma.
A 64 year old male heating engineer was investigated for a persistent cough and found to have epithelioid mesothelioma with pleural effusion, lung nodules and increased thoracic lymph nodes. He declined standard of care treatment following his own research and he was enrolled in a named patient programme of IMM-101. He was advised to correct his low vitamin D3 level and to start using anti-inflammatories such as aspirin, bromelain and low dose Naltrexone. At review one year later a CT scan showed no change and he continued on the regimen. Four years after the diagnosis a CT scan showed that there was a modest but definite progression of the left malignant pleural thickening, and a new right-sided effusion, enlargement of several intrathoracic nodes which had been noted on the early scans. The chest wall lump eventually broke down and required local radiotherapy. He then developed abdominal pain and found to have peritoneal disease. Last year he obtained the cannabinoids CBD and THC which slowed down the disease and a CT scan after he had been on this for six months, showed that his disease was fairly stable with marginal progression.


Adnaviria: a New Realm for Archaeal Filamentous Viruses with Linear A-Form Double-Stranded DNA Genomes.
The International Committee on Taxonomy of Viruses (ICTV) has recently adopted a comprehensive, hierarchical system of virus taxa. The highest ranks in this hierarchy are realms, each of which is considered monophyletic but apparently originated independently of other realms. Here, we announce the creation of a new realm, Adnaviria, which unifies archaeal filamentous viruses with linear A-form double-stranded DNA genomes and characteristic major capsid proteins unrelated to those encoded by other known viruses.


Plasticity and Aggregation of Juvenile Porcine Islets in Modified Culture: Preliminary Observations.
Diabetes is a major health problem worldwide, and there is substantial interest in developing xenogeneic islet transplantation as a potential treatment. The potential to relieve the demand on an inadequate supply of human pancreata is dependent upon the efficiency of techniques for isolating and culturing islets from the source pancreata. Porcine islets are favored for xenotransplantation, but mature pigs (>2 years) present logistic and economic challenges, and young pigs (3-6 months) have not yet proven to be an adequate source. In this study, islets were isolated from 20 juvenile porcine pancreata (~3 months; 25 kg Yorkshire pigs) immediately following procurement or after 24 h of hypothermic machine perfusion (HMP) preservation. The resulting islet preparations were characterized using a battery of tests during culture in silicone rubber membrane flasks. Islet biology assessment included oxygen consumption, insulin secretion, histopathology, and in vivo function. Islet yields were highest from HMP-preserved pancreata (2,242 ± 449 IEQ/g). All preparations comprised a high proportion (>90%) of small islets (<100 μm), and purity was on average 63 ± 6%. Morphologically, islets appeared as clusters on day 0, loosely disaggregated structures at day 1, and transitioned to aggregated structures comprising both exocrine and endocrine cells by day 6. Histopathology confirmed both insulin and glucagon staining in cultures and grafts excised after transplantation in mice. Nuclear staining (Ki-67) confirmed mitotic activity consistent with the observed plasticity of these structures. Metabolic integrity was demonstrated by oxygen consumption rates = 175 ± 16 nmol/min/mg DNA, and physiological function was intact by glucose stimulation after 6-8 days in culture. In vivo function was confirmed with blood glucose control achieved in nearly 50% (8/17) of transplants. Preparation and culture of juvenile porcine islets as a source for islet transplantation require specialized conditions. These immature islets undergo plasticity in culture and form fully functional multicellular structures. Further development of this method for culturing immature porcine islets is expected to generate small pancreatic tissue-derived organoids termed "pancreatites," as a therapeutic product from juvenile pigs for xenotransplantation and diabetes research.


Whole-genome chromatin profiling from limited numbers of cells using nano-ChIP-seq.
Chromatin immunoprecipitation (ChIP) combined with high-throughput sequencing (ChIP-seq) has become the gold standard for whole-genome mapping of protein-DNA interactions. However, conventional ChIP protocols necessitate the use of large numbers of cells, and library preparation steps associated with current high-throughput sequencing platforms require substantial amounts of DNA; both of these factors preclude the application of ChIP-seq technology to many biologically important but rare cell types. Here we describe a nano-ChIP-seq protocol that combines a high-sensitivity small-scale ChIP assay and a tailored procedure for generating high-throughput sequencing libraries from scarce amounts of ChIP DNA. In terms of the numbers of cells required, the method provides two to three orders of magnitude of improvement over the conventional ChIP-seq method and the entire procedure can be completed within 4 d.


Entropy driven spontaneous formation of highly porous films from polymer-nanoparticle composites.
Nanoporous materials have become indispensable in many fields ranging from photonics, catalysis and semiconductor processing to biosensor infrastructure. Rapid and energy efficient process fabrication of these materials is, however, nontrivial. In this communication, we describe a simple method for the rapid fabrication of these materials from colloidal dispersions of Polymethyl Silsesquioxane nanoparticles. Nanoparticle-polymer composites above the decomposition temperature of the polymer are examined and the entropic gain experienced by the nanoparticles in this rubric is harnessed to fabricate novel highly porous films composed of nanoparticles. Optically smooth, hydrophobic films with low refractive indices (as low as 1.048) and high surface areas (as high as 1325 m(2) g(-1)) have been achieved with this approach. In this communication we address the behavior of such systems that are both temperature and substrate surface energy dependent. The method is applicable, in principle, to a variety of nanoparticle-polymer systems to fabricate custom nanoporous materials.


Consequences of occupational asthma.
Seventy-nine patients attending hospital for follow-up of occupational asthma were interviewed, on average 6 years after asthma developed. Although 90% thought their symptoms had improved, 10% had required a hospital admission (apart from for investigation), 72% still took medication and most reported symptoms in the last 3 months. One-third were currently unemployed and 40-73% reported limitation in everyday activities, such as housework or shopping. Symptoms on waking were used as an index of troublesome asthma. Those 31 in whom this occurred at least once a week reported limitation in everyday activities significantly more commonly than others. This relation was more marked in men than women. Limitation in everyday activities was, however, more frequently reported by women than men, who were also more likely than men to be unemployed, suggesting that factors other than impairment of function also contribute to handicap in occupational asthma.


MONITORING POTENTIAL DRUG INTERACTIONS AND REACTIONS VIA NETWORK ANALYSIS OF INSTAGRAM USER TIMELINES.
Much recent research aims to identify evidence for Drug-Drug Interactions (DDI) and Adverse Drug reactions (ADR) from the biomedical scientific literature. In addition to this "Bibliome", the universe of social media provides a very promising source of large-scale data that can help identify DDI and ADR in ways that have not been hitherto possible. Given the large number of users, analysis of social media data may be useful to identify under-reported, population-level pathology associated with DDI, thus further contributing to improvements in population health. Moreover, tapping into this data allows us to infer drug interactions with natural products-including cannabis-which constitute an array of DDI very poorly explored by biomedical research thus far. Our goal is to determine the potential of Instagram for public health monitoring and surveillance for DDI, ADR, and behavioral pathology at large. Most social media analysis focuses on Twitter and Facebook, but Instagram is an increasingly important platform, especially among teens, with unrestricted access of public posts, high availability of posts with geolocation coordinates, and images to supplement textual analysis. Using drug, symptom, and natural product dictionaries for identification of the various types of DDI and ADR evidence, we have collected close to 7000 user timelines spanning from October 2010 to June 2015.We report on 1) the development of a monitoring tool to easily observe user-level timelines associated with drug and symptom terms of interest, and 2) population-level behavior via the analysis of co-occurrence networks computed from user timelines at three different scales: monthly, weekly, and daily occurrences. Analysis of these networks further reveals 3) drug and symptom direct and indirect associations with greater support in user timelines, as well as 4) clusters of symptoms and drugs revealed by the collective behavior of the observed population. This demonstrates that Instagram contains much drug- and pathology specific data for public health monitoring of DDI and ADR, and that complex network analysis provides an important toolbox to extract health-related associations and their support from large-scale social media data.


Overlapping neural circuits for visual attention and eye movements in the human cerebellum.
Previous research in patients with cerebellar damage suggests that the cerebellum plays a role in covert visual attention. One limitation of some of these studies is that they examined patients with heterogeneous cerebellar damage. As a result, the patterns of reported deficits have been inconsistent. In the current study, we used functional neuroimaging (fMRI) in healthy adults (N=14) to examine whether or not the cerebellum plays a role in covert visual attention. Participants performed two covert attention tasks in which they were cued exogenously (with peripheral flashes) or endogenously (using directional arrows) to attend to marked locations in the visual periphery without moving their eyes. We compared BOLD activation in these covert attention conditions to a number of control conditions including: the same attention tasks with eye movements, a target detection task with no cueing, and a self-paced button-press task. Subtracting these control conditions from the covert attention conditions allowed us to effectively remove the contribution of the cerebellum to motor output. In addition to the usual fronto-parietal networks commonly engaged by these attention tasks, lobule VI of the vermis in the cerebellum was also activated when participants performed the covert attention tasks with or without eye movements. Interestingly, this effect was larger for exogenous compared to endogenous cueing. These results, in concert with recent patient studies, provide independent yet converging evidence that the same cerebellar structures that are involved in eye movements are also involved in visuospatial attention.


Return of lymphatic function after flap transfer for acute lymphedema.
The goals of this work were to develop animal models of lymphedema and tissue flap transfer, and to observe physiologic changes in lymphatic function that occur in these models over time, both systemically with lymphoscintigraphy (LS) and locally using fluorescence microlymphangiography (FM). Although lymphedema has been managed by a combination of medical and surgical approaches, no effective long-term cure exists. Surgical attempts aimed at reconnecting impaired lymphatic channels or bypassing obstructed areas have failed. The tails of rats (A groups) and mice (B groups) were used because of their different features. Lymphedema was created by ligation of the lymphatics at the tail base and quantified by diameter measurements there. In the experimental group, rectus abdominis myocutaneous flap was transferred across the ligation. In addition to the ligation (A1 and B1) and ligation + flap (A2 and B2) groups, three control groups were included: sham flap with ligation (B4), sham flap alone (B5), and normal (A3 and B3) animals. Observations were made at weekly time points for lymphatic function and continuity. Lymphedema was successfully created in the mouse ligation groups (B1 and B4) and sustained for the entire length of observation (up to 14 weeks). Lymphatic continuity was restored in those animals with transferred flaps across the ligation site (A2 and B2), as seen both by LS and FM. Sham flaps did not visibly affect lymphatic function nor did they cause any visible swelling in the tail. Acute lymphedema developing after ligation of tail lymphatics in mice can be prevented by myocutaneous flap transfer. Restored lymphatic continuity and function were demonstrable using lymphoscintigraphy and fluorescence microlymphangiography.


Mutational phospho-mimicry reveals a regulatory role for the XRCC4 and XLF C-terminal tails in modulating DNA bridging during classical non-homologous end joining.
XRCC4 and DNA Ligase 4 (LIG4) form a tight complex that provides DNA ligase activity for classical non-homologous end joining (the predominant DNA double-strand break repair pathway in higher eukaryotes) and is stimulated by XLF. Independently of LIG4, XLF also associates with XRCC4 to form filaments that bridge DNA. These XRCC4/XLF complexes rapidly load and connect broken DNA, thereby stimulating intermolecular ligation. XRCC4 and XLF both include disordered C-terminal tails that are functionally dispensable in isolation but are phosphorylated in response to DNA damage by DNA-PK and/or ATM. Here we concomitantly modify the tails of XRCC4 and XLF by substituting fourteen previously identified phosphorylation sites with either alanine or aspartate residues. These phospho-blocking and -mimicking mutations impact both the stability and DNA bridging capacity of XRCC4/XLF complexes, but without affecting their ability to stimulate LIG4 activity. Implicit in this finding is that phosphorylation may regulate DNA bridging by XRCC4/XLF filaments.


Stimulus-related activity during conditional associations in monkey perirhinal cortex neurons depends on upcoming reward outcome.
Acquiring the significance of events based on reward-related information is critical for animals to survive and to conduct social activities. The importance of the perirhinal cortex for reward-related information processing has been suggested. To examine whether or not neurons in this cortex represent reward information flexibly when a visual stimulus indicates either a rewarded or unrewarded outcome, neuronal activity in the macaque perirhinal cortex was examined using a conditional-association cued-reward task. The task design allowed us to study how the neuronal responses depended on the animal's prediction of whether it would or would not be rewarded. Two visual stimuli, a color stimulus as Cue1 followed by a pattern stimulus as Cue2, were sequentially presented. Each pattern stimulus was conditionally associated with both rewarded and unrewarded outcomes depending on the preceding color stimulus. We found an activity depending upon the two reward conditions during Cue2, i.e., pattern stimulus presentation. The response appeared after the response dependent upon the image identity of Cue2. The response delineating a specific cue sequence also appeared between the responses dependent upon the identity of Cue2 and reward conditions. Thus, when Cue1 sets the context for whether or not Cue2 indicates a reward, this region represents the meaning of Cue2, i.e., the reward conditions, independent of the identity of Cue2. These results suggest that neurons in the perirhinal cortex do more than associate a single stimulus with a reward to achieve flexible representations of reward information.


Peripheral circadian oscillators: interesting mechanisms and powerful tools.
The lives of plants, animals, and human beings are all regulated by circadian clocks. In mammals, 24-hour rhythms of physiology and behavior are directed by a master clock in the suprachiasmatic nucleus (SCN) of the brain hypothalamus, which in turn entrains "slave" oscillators of similar molecular composition in most cells of the body. These peripheral clocks are interesting not only because they control many aspects of circadian physiology, but also because they are model systems through which we understand how the SCN regulates complex behavior. To this end, peripheral oscillators have been exploited both biochemically to understand the proteins that make up biological clocks, and genetically to decipher the ways in which individual differences in human chronotype might arise.


Plasmonic waveguides cladded by hyperbolic metamaterials.
Strongly anisotropic media with hyperbolic dispersion can be used for claddings of plasmonic waveguides (PWs). In order to analyze the fundamental properties of such waveguides, we analytically study 1D waveguides arranged from a hyperbolic metamaterial (HMM) in a HMM-Insulator-HMM (HIH) structure. We show that HMM claddings give flexibility in designing the properties of HIH waveguides. Our comparative study on 1D PWs reveals that HIH-type waveguides can have a higher performance than MIM or IMI waveguides.


Ketorolac may control more than pain.
Life-threatening acute respiratory distress syndrome (ARDS) complicates the recovery of patients with burn and inhalation injury. The study by Enkhbaatar and co-workers in this issue of Clinical Science suggests that reducing the early and robust inflammatory cascade may provide patients with protection from developing cardiopulmonary compromise seen early after burn and inhalation injury.


The impact of subcrestal placement on short locking-taper implants placed in posterior maxilla and mandible: a retrospective evaluation on hard and soft tissues stability after 2 years of loading.
Objective of this study was to assess the influence of the subcrestal placement level of short implants with a locking-taper connection design on crestal bone levels and soft tissues health. A clinical retrospective case-control study was conducted between May 2013 and September 2013. The sample was composed of patients who had received at least one 5-to-8-mm-long, plateau-design implant with a locking-taper connection system (Bicon LLC, Boston, MA, USA) in posterior areas of maxilla and mandible, in the period between January 2009 and Dicember 2011. A radiographic evaluation of the degree of subcrestal positioning(t0) was conducted to identify two implant groups: Group 1 was composed of implants placed less than 2 mm under the crestal bone; Group 2 was composed of implants placed 2 mm or more under the crest. The primary outcome variables were the crestal bone levels and the peri-implant bone loss between prosthetic loading and last control visit (t1àt2). Clinical parameters including the keratinized gingival (KG) width, modified bleeding index (mBI), modified plaque index (mPI), and probing depth (PD) were assessed at the follow-up visit. T tests were conducted to identify statistically significant differences between implants groups. Linear regression models were developed to test the dependence of the study variables by the degree of subcrestal surgical implant placement. Significance level was set at P<0.05. One hundred and thirty-seven implants were followed for an average period of 31 months. At the surgery, the implants were placed, on average, 2.04 mm (mesial) and 1.86 mm (distal) subcrestally. Eighty implants were placed less than 2 mm under the crest (average 1.28 mm), while fifty-seven implants were placed more than 2 mm under the crestal bone (average 2.97 mm). At the prosthetic loading (t1), the average crestal bone level was 1.11 mm, 0.79 mm in Shallow group and 1.86 mm in Deep group, with statistically significant differences between implant groups (P<0.05). At the follow-up visit (t2) the mean crestal bone levels were respectively 0.51 mm and 1.35 mm, with statistically significant differences between implant groups (P<0.05). The average peri-implant bone loss between prosthetic loading and control visit (t1àt2) was 0.04 mm in the Group 1 and 0.33 mm in Group 2. The average keratinized mucosa width was 2.16 mm, the average mBI was 0.24 , the average mPI was 0.17 and the average PD was 2.34 mm. Significant difference between groups was observed regarding to keratinized gingival width (Group 1: 1.97 mm; Group 2: 2.41 mm; P<0.05) but not for the other clinical parameters. Linear regression models confirmed the dependence of crestal bone levels by the degree of subcrestal placement (P<0.05). After two years of observation, the implant of this study have shown minimal peri-implant bone resorption. The greater subcrestal implant placement has resulted in a higher level of the peri-implant bone crest, both after the osseointegration period and after the loading period. Both the study implants groups have shown good health of peri-implant soft tissues.


Association between Rheumatoid Arthritis and Apical Periodontitis: A Cross-sectional Study.
The present cross-sectional study aimed to investigate possible association between Rheumatoid Arthritis (RA) and Apical Periodontitis (AP). In table one it is mentioned 48 patients diagnosed with RA were included in the experimental group. Another 48 healthy age- and gender-matched participants who reported no history of any systemic disease were selected to form the control group. All the patients were examined radiographically and clinically to diagnose the presence of AP. The following data was recorded for all patients; the number of teeth present, the number of teeth with AP, the number of patients with AP, the number of patients with root canal treated teeth (RCT) and the number of patients with RCT+AP. The chi-square test and logistic regression analysis were used to determine the possible association between RA and AP. A total of 1026 teeth were examined in the RA group and 45 of them was diagnosed as AP. In the control group, 1025 teeth were examined and 21 teeth were diagnosed as AP. It was found that the prevalence of teeth with AP (4.3%) was significantly higher in the RA group than the control (2%) (odds ratio [OR]=2.193, P=0.003). Logistic regression analysis showed that RA is significantly associated with AP. It can be concluded that patients with RA can be more prone to develop AP.


Genomewide Dam Methylation in Escherichia coli during Long-Term Stationary Phase.
DNA methylation in prokaryotes is widespread. The most common modification of the genome is the methylation of adenine at the N-6 position. In Escherichia coli K-12 and many gammaproteobacteria, this modification is catalyzed by DNA adenine methyltransferase (Dam) at the GATC consensus sequence and is known to modulate cellular processes including transcriptional regulation of gene expression, initiation of chromosomal replication, and DNA mismatch repair. While studies thus far have focused on the motifs associated with methylated adenine (meA), the frequency of meA across the genome, and temporal dynamics during early periods of incubation, here we conduct the first study on the temporal dynamics of adenine methylation in E. coli by Dam throughout all five phases of the bacterial life cycle in the laboratory. Using single-molecule real-time sequencing, we show that virtually all GATC sites are significantly methylated over time; nearly complete methylation of the chromosome was confirmed by mass spectroscopy analysis. However, we also detect 66 sites whose methylation patterns change significantly over time within a population, including three sites associated with sialic acid transport and catabolism, suggesting a potential role for Dam regulation of these genes; differential expression of this subset of genes was confirmed by quantitative real-time PCR. Further, we show significant growth defects of the dam mutant during long-term stationary phase (LTSP). Together these data suggest that the cell places a high premium on fully methylating the chromosome and that alterations in methylation patterns may have significant impact on patterns of transcription, maintenance of genetic fidelity, and cell survival. IMPORTANCE While it has been shown that methylation remains relatively constant into early stationary phase of E. coli, this study goes further through death phase and long-term stationary phase, a unique time in the bacterial life cycle due to nutrient limitation and strong selection for mutants with increased fitness. The absence of methylation at GATC sites can influence the mutation frequency within a population due to aberrant mismatch repair. Therefore, it is important to investigate the methylation status of GATC sites in an environment where cells may not prioritize methylation of the chromosome. This study demonstrates that chromosome methylation remains a priority even under conditions of nutrient limitation, indicating that continuous methylation at GATC sites could be under positive selection.


CXCL10/gamma interferon-inducible protein 10-mediated protection against Leishmania amazonensis infection in mice.
Leishmania amazonensis can cause progressive disease in most inbred strains of mice. We have previously shown that L. amazonensis-infected C57BL/6 mice have profound impairments in expression of proinflammatory cytokines and chemokines and in activation of antigen-specific CD4(+) T cells. These impairments are independent of interleukin-4 (IL-4) but partially due to IL-10 production. The precise mechanism of pathogenesis associated with L. amazonensis infection remains largely unresolved. Since chemokines are essential mediators of leukocyte recruitment and effector cell function, we hypothesized that these molecules are important for the initiation of early responses locally and for the eventual control of the infection. In this study, we examined the roles of CXCL10/gamma interferon-inducible protein 10 (IP-10) and CCL2/monocyte chemoattractant protein 1 (MCP-1) in the activation of the macrophage effector function in vitro and their efficacy in ameliorating infection in vivo. Bone marrow-derived macrophages of both BALB/c and C57BL/6 mice were treated with increasing concentrations of recombinant chemokines prior to infection with either stationary-phase promastigotes or tissue-derived amastigotes. We found that treatment with IP-10 or MCP-1 significantly reduced parasite burdens, in a dose-dependent manner, and triggered nitric oxide production. When susceptible C57BL/6 mice were injected locally with IP-10 following L. amazonensis infection, there was a significant delay in lesion development and a reduction in parasite burdens, accompanied by 7- and 3.5-fold increases in gamma interferon and IL-12 secretion, respectively, in restimulated lymph node cells. This study confirms that IP-10 plays a protective role in promoting the reduction of intracellular parasites and thereby opens new avenues for therapeutic control of nonhealing cutaneous leishmaniasis in the New World.


Investigations on DNA intercalation and surface binding by SYBR Green I, its structure determination and methodological implications.
The detection of double-stranded (ds) DNA by SYBR Green I (SG) is important in many molecular biology methods including gel electrophoresis, dsDNA quantification in solution and real-time PCR. Biophysical studies at defined dye/base pair ratios (dbprs) were used to determine the structure-property relationships that affect methods applying SG. These studies revealed the occurrence of intercalation, followed by surface binding at dbprs above approximately 0.15. Only the latter led to a significant increase in fluorescence. Studies with poly(dA)* poly(dT) and poly(dG)* poly(dC) homopolymers showed sequence-specific binding of SG. Also, salts had a marked impact on SG fluorescence. We also noted binding of SG to single-stranded (ss) DNA, although SG/ssDNA fluorescence was at least approximately 11-fold lower than with dsDNA. To perform these studies, we determined the structure of SG by mass spectrometry and NMR analysis to be [2-[N-(3-dimethylaminopropyl)-N-propylamino]-4-[2,3-dihydro-3-methyl-(benzo-1,3-thiazol-2-yl)-methylidene]-1-phenyl-quinolinium]. For comparison, the structure of PicoGreen (PG) was also determined and is [2-[N-bis-(3-dimethylaminopropyl)-amino]-4-[2,3-dihydro-3-methyl-(benzo-1,3-thiazol-2-yl)-methylidene]-1-phenyl-quinolinium]+. These structure-property relationships help in the design of methods that use SG, in particular dsDNA quantification in solution and real-time PCR.


Alcohol Consumption Levels and All-Cause Mortality Among Women Veterans and Non-Veterans Enrolled in the Women's Health Initiative.
To address research gaps regarding women Veterans' alcohol consumption and mortality risk as compared to non-Veterans, the current study evaluated whether alcohol consumption amounts differed between women Veterans and non-Veterans, whether Veterans and non-Veterans within alcohol consumption groups differed on all-cause mortality, and whether Veteran status modified the association between alcohol consumption and all-cause mortality. Six alcohol consumption groups were created using baseline data from the Women's Health Initiative Program (N = 145,521): lifelong abstainers, former drinkers, less than 1 drink/week (infrequent drinkers), 1-7 drinks/week (moderate drinkers), 8-14 drinks/week (moderately heavy drinkers), and 15 or more drinks/week (heavy drinkers). The proportions of Veteran and non-Veteran women within each alcohol consumption category were compared. Mortality rates within each alcohol consumption category were compared by Veteran status. Cox proportional hazard models, including a multiplicative interaction term for Veteran status, were fit to estimate adjusted mortality hazard (rate) ratios for each alcohol consumption category relative to a reference group of either lifelong abstainers or moderate drinkers. Women Veterans were less likely to be lifelong abstainers than non-Veterans. Women Veterans who were former or moderate drinkers had higher age-adjusted mortality rates than did non-Veterans within these alcohol consumption categories. In the fully adjusted multivariate models, Veteran status did not modify the association between alcohol consumption category and mortality with either lifelong abstainers or moderate drinkers as referents. The results suggest that healthcare providers may counsel Veteran and non-Veteran women in similar ways regarding safe and less safe levels of alcohol consumption.


Reactions to ethanol and diazepam in healthy young men.
The reactions to oral ethanol (0.75 ml/kg), IV low-dose diazepam (0.12 mg/kg) and IV high-dose diazepam (0.2 mg/kg) were evaluated over four test sessions in the same 48 healthy young men. The data demonstrated similar subjective feelings after the low-dose diazepam and ethanol, but significantly greater effect after high-dose diazepam. Despite the similarities on subjective feelings, the low-dose diazepam challenge resulted in significantly more impairment than did ethanol on measures of memory, body sway and the evaluation of the passage of time. The similarities in subjective aspects of intoxication for ethanol and low-dose diazepam have potential implications for increasing our understanding of possible enhanced vulnerabilities for abuse of benzodiazepines among alcohol-abusing patients. The trend for similarities in subjective intoxication but greater impairment in motor and cognitive performance after low-dose diazepam compared to ethanol might indicate that subjects might be less aware of their actual levels of performance difficulties after the benzodiazepine. It is hoped that these data will help clinicians understand more about the quality of intoxication with benzodiazepines and the types of impairments likely to be observed.


Identification of amino acids associated with skeletal muscle growth in late gestation and at weaning in lambs of well-nourished sheep.
The objective of this study was to determine the association between intracellular free AA (FAA) profiles in skeletal muscle with muscle growth in twin and singleton fetuses in late pregnancy and at weaning, under an ad libitum feeding regime of the dam. Plasma from singleton- (n = 9) and twin-bearing (n = 10) ewes at d 140 of pregnancy and FAA in the semitendinosus muscle (STM) from the corresponding fetuses were studied. At weaning, intracellular STM FAA concentrations were compared between twins at the same age as singletons (Twin(age); n = 17) and at the same weight as singletons (Twin(wt); n = 17) to that of singletons (n = 20). Twin fetuses were 15% lighter (P = 0.03) with a 20% lighter STM (P = 0.02) compared to singletons. Maternal plasma FAA were similar (P ≥ 0.17) between singleton- and twin-bearing ewes. Twin fetuses had greater (P < 0.05) plasma concentrations of glutamine, histidine, and methionine and lower (P < 0.05) concentrations of aspartate, citrulline, glutamate, and ornithine compared with singletons. In fetal STM, twins had lower (P < 0.05) concentrations of aspartate and valine and greater (P < 0.01) concentration of methionine. Correlations were found between fetal STM weight and intracellular concentrations of arginine (r = 0.66, P < 0.01) and glutamine (r = 0.49, P < 0.01). Compared to singletons at weaning, Twin(age) were 16% lighter (P < 0.01) and the STM weight was proportionately 16% lighter (P < 0.01). For Twin(wt), the magnitude of the difference for STM weight was reduced to 8% lighter (P = 0.02). Compared to singletons, Twin(age) lambs had greater (P < 0.05) intracellular concentrations of glutamine, histidine, threonine, asparagine, alanine, serine, and glutamate but reduced taurine. The differences in FAA concentrations were less between Twin(wt) and singletons than between Twin(age) and singletons. Positive correlations were found between leucine, lysine, methionine, phenylalanine, proline, threonine, and tyrosine muscle concentration and STM weight at weaning. Males differed from females in intracellular FAA both in late pregnancy and at weaning. Twins had reduced RNA content during pregnancy and at weaning, suggesting a lower capacity for protein accretion. These data suggest that specific FAA concentrations are associated with differences in muscle growth during late pregnancy, notably arginine and glutamine, and reduced protein synthesis capacity. However, the relevance of specific FAA varies according to stage of development and sex of the lamb.


Diversity and Activity of Lysobacter Species from Disease Suppressive Soils.
The genus Lysobacter includes several species that produce a range of extracellular enzymes and other metabolites with activity against bacteria, fungi, oomycetes, and nematodes. Lysobacter species were found to be more abundant in soil suppressive against the fungal root pathogen Rhizoctonia solani, but their actual role in disease suppression is still unclear. Here, the antifungal and plant growth-promoting activities of 18 Lysobacter strains, including 11 strains from Rhizoctonia-suppressive soils, were studied both in vitro and in vivo. Based on 16S rRNA sequencing, the Lysobacter strains from the Rhizoctonia-suppressive soil belonged to the four species Lysobacter antibioticus, Lysobacter capsici, Lysobacter enzymogenes, and Lysobacter gummosus. Most strains showed strong in vitro activity against R. solani and several other pathogens, including Pythium ultimum, Aspergillus niger, Fusarium oxysporum, and Xanthomonas campestris. When the Lysobacter strains were introduced into soil, however, no significant and consistent suppression of R. solani damping-off disease of sugar beet and cauliflower was observed. Subsequent bioassays further revealed that none of the Lysobacter strains was able to promote growth of sugar beet, cauliflower, onion, and Arabidopsis thaliana, either directly or via volatile compounds. The lack of in vivo activity is most likely attributed to poor colonization of the rhizosphere by the introduced Lysobacter strains. In conclusion, our results demonstrated that Lysobacter species have strong antagonistic activities against a range of pathogens, making them an important source for putative new enzymes and antimicrobial compounds. However, their potential role in R. solani disease suppressive soil could not be confirmed. In-depth omics'-based analyses will be needed to shed more light on the potential contribution of Lysobacter species to the collective activities of microbial consortia in disease suppressive soils.


Glasdegib: A Novel Hedgehog Pathway Inhibitor for Acute Myeloid Leukemia.
Acute myeloid leukemia (AML) is an aggressive myeloid disorder that is associated with a generally poor prognosis. Effective treatment options have been limited for older patients with AML who are not able to undergo intensive remission induction chemotherapy due to advanced age or comorbidities. New and novel agents are needed to improve treatment outcomes for this patient population. Glasdegib is a novel Hedgehog signaling pathway inhibitor approved by the U.S. Food & Drug Administration for the treatment of patients with newly diagnosed AML who are 75 years of age or older or who have comorbidities that preclude intensive induction chemotherapy. Glasdegib is approved in combination with low-dose cytarabine (LDAC). This approval is based on the results of a multicenter, open-label, randomized trial of glasdegib plus LDAC vs. LDAC monotherapy in which the addition of glasdegib resulted in an improvement in median overall survival.


Cluster Analysis of Cardiovascular Phenotypes in Patients With Type 2 Diabetes and Established Atherosclerotic Cardiovascular Disease: A Potential Approach to Precision Medicine.
Phenotypic heterogeneity among patients with type 2 diabetes mellitus (T2DM) and atherosclerotic cardiovascular disease (ASCVD) is ill defined. We used cluster analysis machine-learning algorithms to identify phenotypes among trial participants with T2DM and ASCVD. We used data from the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) study (n = 14,671), a cardiovascular outcome safety trial comparing sitagliptin with placebo in patients with T2DM and ASCVD (median follow-up 3.0 years). Cluster analysis using 40 baseline variables was conducted, with associations between clusters and the primary composite outcome (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina) assessed by Cox proportional hazards models. We replicated the results using the Exenatide Study of Cardiovascular Event Lowering (EXSCEL) trial. Four distinct phenotypes were identified: cluster I included Caucasian men with a high prevalence of coronary artery disease; cluster II included Asian patients with a low BMI; cluster III included women with noncoronary ASCVD disease; and cluster IV included patients with heart failure and kidney dysfunction. The primary outcome occurred, respectively, in 11.6%, 8.6%, 10.3%, and 16.8% of patients in clusters I to IV. The crude difference in cardiovascular risk for the highest versus lowest risk cluster (cluster IV vs. II) was statistically significant (hazard ratio 2.74 [95% CI 2.29-3.29]). Similar phenotypes and outcomes were identified in EXSCEL. In patients with T2DM and ASCVD, cluster analysis identified four clinically distinct groups. Further cardiovascular phenotyping is warranted to inform patient care and optimize clinical trial designs.


Gastric cancer: epidemiology, pathology and treatment.
Gastric cancer incidence and mortality has fallen dramatically over the last 50 years in many regions, but remains the second most common cancer worldwide. Despite a marked decline in fundic and distal tumors, there is a rising incidence of adenocarcinomas of the gastroesophageal junction and gastric cardia, particularly in Western nations. This may imply that there are in fact two diseases differing from each other in epidemiology, etiology, pathology and clinical expression. While surgical resection remains the cornerstone of gastric cancer treatment, the optimum extent of nodal resection remains controversial, with randomized studies failing to show that the D2 procedure improves survival when compared with D1 dissection. The high rate of recurrence and poor survival following surgery provides a rationale for the early use of adjuvant treatment. Adjuvant chemotherapy or adjuvant radiotherapy, when used alone, do not improve survival following resection. However, the results of the recent Intergroup 0116 study are promising in showing that the combination of 5-fluorouracil (5-FU)-based chemotherapy with radiotherapy significantly prolongs disease-free and overall survival when compared with no adjuvant treatment. In advanced gastric cancer, chemotherapy enhances quality of life and prolongs survival when compared with best supportive care. There is no agreed standard of treatment in this setting. Of the commonly used regimens, epirubicin plus cisplatin and 5-FU (ECF) probably has the strongest claim to this role. However, there is a pressing need for new agents, both cytotoxic and molecularly targeted, to be assessed in both the advanced and adjuvant settings.


Micromethods for the simultaneous measurement of intracellular potassium and corticosterone output of isolated adrenal cortical cells.
1. A technique is described for the measurement of potassium and water spaces in less than 1 mul of packed cells. 2. The total potassium content of cell pellets is measured in a perchloric and nitric acid extract by flame spectrophotometry. The potassium in trapped medium is estimated from the distribution space of hydroxy[-14C]methylinulin and subtracted from the total potassium content to give intracellular potassium content. Corticosterone output was measured by radioimmunoassay. 3. The simultaneous measurement of total water from the [-3H]water space allows calculation of the intracellular water space. 4. Values obtained for intracellular potassium content, intracellular water space and calculated intracellular potassium concentration are presented for different preparations of isolated adrenal cortical cells.


Hepatitis C virus infection among HIV-positive men who have sex with men: protocol for a systematic review and meta-analysis.
Outbreaks of hepatitis C virus (HCV) infection have been reported in HIV-positive men who have sex with men (MSM) in North America, Europe and Asia. Transmission is believed to be the result of exposure to blood during sexual contact. In those infected with HIV, acute HCV infection is more likely to become chronic, treatment for both HIV and HCV is more complicated and HCV disease progression may be accelerated. There is a need for systematic reviews and meta-analyses to synthesize the epidemiology, prevention and methods to control HCV infection in this population. Eligible studies will include quantitative empirical data related to sexual transmission of HCV in HIV-positive MSM, including data describing incidence or prevalence, and associations between risk factors or interventions and the occurrence or progression of HCV disease. Care will be taken to ensure that HCV transmission related to injection drug use is excluded from the incidence estimates. Scientific databases will be searched using a comprehensive search strategy. Proceedings of scientific conferences, reference lists and personal files will also be searched. Quality ratings will be assigned to each eligible report using the Newcastle-Ottawa scale. Pooled estimates of incidence rates and measures of association will be calculated using random effects models. Heterogeneity will be assessed at each stage of data synthesis. HIV-positive MSM are a key HCV-affected population in the US and other high-income countries. This review seeks to identify modifiable risk factors and settings that will be the target of interventions, and will consider how to constitute a portfolio of interventions to deliver the greatest health benefit. This question must be considered in relation to the magnitude of HCV infection and its consequences in other key affected populations, namely, young prescription opioid users who have transitioned to illicit opiate injection, and older injection drug users among whom HCV prevalence and incidence are extremely high. This review is part of a series of systematic reviews and meta-analyses that will synthesize the evidence across all these population groups and develop recommendations and decision tools to guide public health resource allocation. PROSPERO registration number: CRD42013006462.


A brief history of asthma and its mechanisms to modern concepts of disease pathogenesis.
The original concept of asthma being primarily a disease of airways smooth muscle drove the development of bronchodilator drugs. However when it was realised that airway inflammation underpinned the disordered airway function, this gave way to the development of controller therapies such as inhaled cromones and corticosteroids. More recently the discovery of complex interconnecting cytokine and chemokine networks has stimulated the development of biologics with varying success. With the recognition that airway wall "remodelling" is present early in asthma inception and is in part driven by aberrant epithelial-mesenchymal communication both genetic and environmental factors beyond allergen exposure such as virus infection and air pollution are being seen as being increasingly important not only in asthma exacerbations but in the origins of asthma and its evolution into different sub-phenotypes. This brings us round full circle to once again considering that the origins of asthma lie in defects in the formed elements of the airway; the epithelium, smooth muscle, and vasculature. Over the last 25 years Professor You Young Kim has engaged in the exciting discovery science of allergy and asthma and has made an enormous contribution in bringing Korea to the forefront of disease management and research, a position that both he and his colleagues can justly be proud of.


A pilot study evaluating multiple risk factor interventions by community pharmacists to prevent cardiovascular disease: the PAART CVD pilot project.
There is insufficient evidence for the efficacy of comprehensive multiple risk factor interventions by pharmacists in the primary prevention of cardiovascular disease (CVD). Given the proven benefits of pharmacist interventions for individual risk factors, it is essential that evidence for a comprehensive approach to care be generated so that pharmacists remain key members of the health care team for individuals at risk of initial onset of CVD. To establish the feasibility of an intervention delivered by community pharmacists to reduce the risk of primary onset of CVD. A single-cohort intervention study was undertaken in 2008-2009. Twelve community pharmacists from 10 pharmacies who were trained to provide lifestyle and medicine management support to reduce CVD risk recruited 70 at-risk participants aged 50-74 years who were free from diabetes or CVD. Participants received a baseline assessment to establish CVD risk and health behaviors. An assessment report provided to patients and pharmacists was used to collaboratively establish treatment goals and, over 5 sessions, implement treatment strategies. Follow-up assessment at 6 months measured changes in baseline parameters. The primary outcome was the average change to overall 5-year risk of CVD onset. Sixty-seven participants were included in the analysis. The mean participant age was 60 years and 73% were female. We observed a 25% (95% CI 17 to 33) proportional risk reduction in overall CVD risk. Significant reductions also occurred in mean blood pressure (-11/-5 mm Hg) and waist circumference (-1.3 cm), with trends toward improvement for most other observed risk factors. Findings support previous evidence of positive cardiovascular health outcomes following pharmacist intervention in other patient groups; we recommend generating randomized controlled trial evidence for a primary prevention population.


Seroprevalence of leptospirosis among high-risk population of Andaman Islands, India.
Leptospirosis is a severe spirochetal zoonosis in the world. It is considered an occupational disease of persons engaged in agriculture, sewage works, forestry, and animal slaughtering. A study was conducted with an objective of assessing the seroprevalence of leptospirosis among the high-risk groups of Andaman Islands. A total of 611 sera samples from different high-risk populations were collected and tested by microscopic agglutination test (MAT). Genetic characterization of the isolate was done by randomly amplified polymorphic DNA (RAPD) fingerprinting, and serological characterization was done using monoclonal antibody technique. Antibodies to leptospires were detected in 322 samples giving an overall seroprevalence of 52.7%. The seroprevalence was highest among agriculture workers (62.5%) followed by sewage workers (39.4%), animal handlers (37.5%), forest workers (27.3%), and butchers (30.0%). Seroprevalence among control population was 14.7%, which was comparatively less than that of the high-risk population groups. Subject sera were most commonly reacted with organisms of the serogroup Grippotyphosa followed by Australis, and the pattern was similar in control group. Four leptospires were isolated from agriculture workers who were admitted to the public health center (PHC) with complaints of fever and body ache. Human isolates were compared with two rodent (Rattus norvegicus) isolates from the same area of agriculture workers to get initial information about the transmission cycle of leptospirosis in the study community. Randomly amplified polymorphic DNA fingerprinting pattern of the strains recovered from the rodents and human patients were identified as belonged to genomo-species Leptospira interrogans. The antigenic characterization of the strains recovered from them belonged to serovar Valbuzzi of serogroup Grippotyphosa. The study showed that people engaged in high-risk activities such as agriculture, sewage cleaning, animal handling, animal slaughtering, and forestry are frequently exposed to leptospirosis, and hence control strategies targeting these populations could be more effective.


Association of Symptoms of Depression With Cardiovascular Disease and Mortality in Low-, Middle-, and High-Income Countries.
Depression is associated with incidence of and premature death from cardiovascular disease (CVD) and cancer in high-income countries, but it is not known whether this is true in low- and middle-income countries and in urban areas, where most people with depression now live. To identify any associations between depressive symptoms and incident CVD and all-cause mortality in countries at different levels of economic development and in urban and rural areas. This multicenter, population-based cohort study was conducted between January 2005 and June 2019 (median follow-up, 9.3 years) and included 370 urban and 314 rural communities from 21 economically diverse countries on 5 continents. Eligible participants aged 35 to 70 years were enrolled. Analysis began February 2018 and ended September 2019. Four or more self-reported depressive symptoms from the Short-Form Composite International Diagnostic Interview. Incident CVD, all-cause mortality, and a combined measure of either incident CVD or all-cause mortality. Of 145 862 participants, 61 235 (58%) were male and the mean (SD) age was 50.05 (9.7) years. Of those, 15 983 (11%) reported 4 or more depressive symptoms at baseline. Depression was associated with incident CVD (hazard ratio [HR], 1.14; 95% CI, 1.05-1.24), all-cause mortality (HR, 1.17; 95% CI, 1.11-1.25), the combined CVD/mortality outcome (HR, 1.18; 95% CI, 1.11-1.24), myocardial infarction (HR, 1.23; 95% CI, 1.10-1.37), and noncardiovascular death (HR, 1.21; 95% CI, 1.13-1.31) in multivariable models. The risk of the combined outcome increased progressively with number of symptoms, being highest in those with 7 symptoms (HR, 1.24; 95% CI, 1.12-1.37) and lowest with 1 symptom (HR, 1.05; 95% CI, 0.92 -1.19; P for trend < .001). The associations between having 4 or more depressive symptoms and the combined outcome were similar in 7 different geographical regions and in countries at all economic levels but were stronger in urban (HR, 1.23; 95% CI, 1.13-1.34) compared with rural (HR, 1.10; 95% CI, 1.02-1.19) communities (P for interaction = .001) and in men (HR, 1.27; 95% CI, 1.13-1.38) compared with women (HR, 1.14; 95% CI, 1.06-1.23; P for interaction < .001). In this large, population-based cohort study, adults with depressive symptoms were associated with having increased risk of incident CVD and mortality in economically diverse settings, especially in urban areas. Improving understanding and awareness of these physical health risks should be prioritized as part of a comprehensive strategy to reduce the burden of noncommunicable diseases worldwide.