Post-traumatic growth among veterans in the USA: results from the National Health and Resilience in Veterans Study.
There is increasing recognition that, in addition to negative psychological consequences of trauma such as post-traumatic stress disorder (PTSD), some individuals may develop post-traumatic growth (PTG) following such experiences. To date, however, data regarding the prevalence, correlates and functional significance of PTG in population-based samples are lacking. Data were analysed from the National Health and Resilience in Veterans Study, a contemporary, nationally representative survey of 3157 US veterans. Veterans completed a survey containing measures of sociodemographic, military, health and psychosocial characteristics, and the Posttraumatic Growth Inventory-Short Form. We found that 50.1% of all veterans and 72.0% of veterans who screened positive for PTSD reported at least 'moderate' PTG in relation to their worst traumatic event. An inverted U-shaped relationship was found to best explain the relationship between PTSD symptoms and PTG. Among veterans with PTSD, those with PTSD reported better mental functioning and general health than those without PTG. Experiencing a life-threatening illness or injury and re-experiencing symptoms were most strongly associated with PTG. In multivariable analysis, greater social connectedness, intrinsic religiosity and purpose in life were independently associated with greater PTG. PTG is prevalent among US veterans, particularly among those who screen positive for PTSD. These results suggest that there may be a 'positive legacy' of trauma that has functional significance for veterans. They further suggest that interventions geared toward helping trauma-exposed US veterans process their re-experiencing symptoms, and to develop greater social connections, sense of purpose and intrinsic religiosity may help promote PTG in this population.


Economic evaluation of an intensified disease management system for patients with type 2 diabetes.
We evaluated the effect of a disease management (DM) program on adherence with recommended laboratory tests, health outcomes, and health care expenditures for patients with type 2 diabetes. The study was a natural experiment in a primary care setting in which the intervention was available to 1 group and then compared to the experience of a matched control group. Univariate analysis and difference in differences analysis were used to test for any significant differences between the 2 groups following a 12-month intervention period. A payer perspective was used to estimate the health care cost consequences based on hospital and physician utilization weighted by Medicare prices. The results were nonsignificant at the .10 level, except for compliance with recommended tests, which showed significant results in the univariate analysis. The intervention increased compliance with testing for HbA1c, microalbuminuria, and lipids, and decreased HbA1c value and the percent of patients with HbA1c >or=9.5%. The point estimates showed small reductions in health care cost; only reductions in costs for office visits were significant at the .10 level. We concluded that while there were signs of improvement in adherence to testing, the low effectiveness may be attributed to existing diabetes management activities in this primary care setting, high compliance rates for testing at the beginning of the study, and a steep learning curve for this complex, information-technology-based DM system. The study raises questions about the incremental gains from complex systems approaches to DM and illustrates a rigorous method to assess DM programs under "real-world" conditions, with control for possible selection bias.


Experimental chronic hepatitis B infection of neonatal tree shrews (Tupaia belangeri chinensis): a model to study molecular causes for susceptibility and disease progression to chronic hepatitis in humans.
Hepatitis B virus (HBV) infection continues to be an escalating global health problem. Feasible and effective animal models for HBV infection are the prerequisite for developing novel therapies for this disease. The tree shrew (Tupaia) is a small animal species evolutionary closely related to humans, and thus is permissive to certain human viral pathogens. Whether tree shrews could be chronically infected with HBV in vivo has been controversial for decades. Most published research has been reported on adult tree shrews, and only small numbers of HBV infected newborn tree shrews had been observed over short time periods. We investigated susceptibility of newborn tree shrews to experimental HBV infection as well as viral clearance over a protracted time period. Forty-six newborn tree shrews were inoculated with the sera from HBV-infected patients or tree shrews. Serum and liver samples of the inoculated animals were periodically collected and analyzed using fluorescence quantitative polymerase chain reaction, enzyme-linked immunosorbent assay, Southern blot, and immunohistochemistry. Six tree shrews were confirmed and four were suspected as chronically HBV-infected for more than 48 (up to 228) weeks after inoculation, including three that had been inoculated with serum from a confirmed HBV-infected tree shrew. Outbred neonatal tree shrews can be long-term chronically infected with HBV at a frequency comparable to humans. The model resembles human disease where also a smaller proportion of infected individuals develop chronic HBV related disease. This model might enable genetic and immunologic investigations which would allow determination of underlying molecular causes favoring susceptibility for chronic HBV infection and disease establishment vs. viral clearance.


Breast ductal lavage for biomarker assessment in high risk women: rationale, design and methodology of a randomized phase II clinical trial with nimesulide, simvastatin and placebo.
Despite positive results from large phase III clinical trials proved that it is possible to prevent estrogen-responsive breast cancers with selective estrogen receptor modulators and aromatase inhibitors, no significant results have been reached so far to prevent hormone non-responsive tumors. The Ductal Lavage (DL) procedure offers a minimally invasive method to obtain breast epithelial cells from the ductal system for cytopathologic analysis. Several studies with long-term follow-up have shown that women with atypical hyperplasia have an elevated risk of developing breast cancer. The objective of the proposed trial is to assess the efficacy and safety of a daily administration of nimesulide or simvastatin in women at higher risk for breast cancer, focused particularly on hormone non-responsive tumor risk. The primary endpoint is the change in prevalence of atypical cells and cell proliferation (measured by Ki67) in DL or fine needle aspirate samples, after 12 months of treatment and 12 months after treatment cessation. METHODS-DESIGN: From 2005 to 2011, 150 women with a history of estrogen receptor negative ductal intraepithelial neoplasia or lobular intraepithelial neoplasia or atypical hyperplasia, or unaffected subjects carrying a mutation of BRCA1 or with a probability of mutation >10% (according to BRCAPRO) were randomized to receive nimesulide 100mg/day versus simvastatin 20mg/day versus placebo for one year followed by a second year of follow-up. This is the first randomized placebo controlled trial to evaluate the role of DL to study surrogate endpoints biomarkers and the effects of these drugs on breast carcinogenesis. In 2007 the European Medicines Agency limited the use of systemic formulations of nimesulide to 15 days. According to the European Institute of Oncology Ethics Committee communication, we are now performing an even more careful monitoring of the study participants. Preliminary results showed that DL is a feasible procedure, the treatment is well tolerated and the safety blood tests do not show any significant liver toxicity. There is an urgent need to confirm in the clinical setting the potential efficacy of other compounds in contrasting hormone non-responsive breast cancer. This paper is focused on the methodology and operational aspects of the clinical trial. (ClinicalTrials.gov Identifier: NCT01500577).


Myocardium-protective effects of Ginkgo biloba extract (EGb 761) in old rats against acute isobaric hypoxia. An electron microscopic morphometric study. I. Protection of cardiomyocytes.
Ginkgo biloba extract EGb 761 was used in hypoxia experiments with old rats to investigate its ultrastructure-preserving effects on the myocardium. Hypoxia was performed by means of a hypoxia chamber combined with a commercial narcosis apparatus. N2O/O2-mixture was applied with O2 at 5 vol.% for 20 minutes under normobaric conditions. Ultrastructural-morphometric analysis revealed that EGb 761-pretreatment was able to diminish hypoxic damage at mitochondrial cristae and matrix and also distension of the sarcoplasmic reticulum during acute hypoxic stress. Whereas formation of vacuoles was depressed below the level of controls, the accumulation of lipid drops was not prevented. The preservation of mitochondrial cristae was confirmed by independent secondary morphometric parameters and by cytophotometrically measured activities of mitochondrial enzymes.


Impact of erythrocyte Duffy antigen genetic polymorphism on the distribution of GroBeta-T, a novel human CXC chemokine.
Grobeta-T, a human CXC chemokine, has been studied for its potential to mobilize stem cells. Chemokines bind specifically to receptors on target immune cells but also to a homologous erythrocyte blood group antigen, the Duffy Antigen/Receptor for Chemokines (DARC)that is subject to genetic polymorphism in humans.A mutation in the DARC gene is common among African Americans and results in lack of expression of the erythrocyte antigen. We used a combination of in vitro studies of Grobeta-DARC interaction and pharmacokinetic simulation to anticipate the potential impact of this polymorphism on the pharmacokinetics of Grobeta-T. [125I]Grobeta-T was incubated in Caucasian blood to characterize the concentration dependence of the blood to plasma concentration ratio (B/P). Affinity and capacity of binding was estimated by Scatchard analysis; specificity was investigated by competitive displacement with a CC chemokine. The B/P value (7 nM) was then determined in blood from 8 African American subjects. Duffy antigen expression was determined by antibody agglutination. A pharmacokinetic model was developed which accounted for blood-cell binding. Simulations were performed to explore effects of dose regimen and DARC expression on the Grobeta-T plasma concentration-time profile. Grobeta-T affinity and capacity for DARC (Caucasian blood)were 23.0 +/- 1.2 and 37.7 +/- 0.6 nM, respectively;excess CC chemokine fully displaced [125I]Grobeta-T. Chemokine binding was highly correlated with the presence or absence of the Duffy antigen (p<0.01) in African American blood; the proportion of subjects for which binding was observed (3/8), was consistent with the reported frequency of DARC expression in this population. Counter to intuition,in the terminal disposition phase at low doses,concentrations of free Grobeta-T in the presence of DARC may be substantially higher than in the absence of DARC. Dissociation from the erythrocyte antigen may lead to greater persistence, at low doses, of free Grobetabeta-T in the blood of individuals expressing the chemokine sink.


Effects of Confinement on the Dielectric Response of Water Extends up to Mesoscale Dimensions.
The extent of confinement effects on water is not clear in the literature. While some properties are affected only within a few nanometers from the wall surface, others are affected over long length scales, but the range is not clear. In this work, we have examined the dielectric response of confined water under the influence of external electric fields along with the dipolar fluctuations at equilibrium. The confinement induces a strong anisotropic effect which is evident up to 100 nm channel width, and may extend to macroscopic dimensions. The root-mean-square fluctuations of the total orientational dipole moment in the direction perpendicular to the surfaces is 1 order of magnitude smaller than the value attained in the parallel direction and is independent of the channel width. Consequently, the isotropic condition is unlikely to be recovered until the channel width reaches macroscopic dimensions. Consistent with dipole moment fluctuations, the effect of confinement on the dielectric response also persists up to channel widths considerably beyond 100 nm. When an electric field is applied in the perpendicular direction, the orientational relaxation is 3 orders of magnitude faster than the dipolar relaxation in the parallel direction and independent of temperature.


Comprehensive profiling of free and conjugated estrogens by capillary electrophoresis-time of flight/mass spectrometry.
The biological activity of estrogens is tightly regulated by regioselective phase I/II metabolic transformations that are critical to human health. Current methods for analysis of urinary estrogens are limited by complicated sample pretreatment and/or inadequate specificity for free estrogens and their glucuronide/sulfate conjugates that vary widely in their intrinsic polarity. In this work, direct speciation of intact estrogen conjugates and their regioisomers is demonstrated using capillary electrophoresis-time-of-flight/mass spectrometry (CE-TOF/MS) when using an alkaline buffer system with negative ion mode detection. This method allows for resolution of weakly acidic native estrogens, anionic estrogen conjugates and their positional isomers without significant matrix-induced ion suppression effects in human urine. Identification of unknown estrogen metabolites using CE-TOF/MS is supported by accurate mass together with their characteristic relative migration times, which can be predicted based on two intrinsic physicochemical properties of an ion. CE-TOF/MS offers a promising strategy for comprehensive profiling of estrogens and other classes of steroid conjugates that is needed for deeper insight into the etiology and treatment of chronic disorders associated with impaired estrogen metabolism.


Urinary estrogen metabolites and breast cancer: a case-control study.
Preliminary studies suggest that the estrogen metabolite 16 alpha-hydroxyestrone is associated with breast cancer, whereas 2-hydroxyestrone is not. However, epidemiological studies evaluating this relationship and taking established risk factors for breast cancer into account are lacking. The purpose of this study was to examine the association of the ratio of the urinary estrogen metabolites (2-hydroxyestrone and 16 alpha-hydroxyestrone) and of the individual metabolites with breast cancer. A spot urine sample, a brief history, and clinical data were collected from breast cancer cases (n = 42) and from women coming to the hospital for a routine mammogram or attending a free breast cancer screening (n = 64). 2-Hydroxyestrone and 16 alpha-hydroxyestrone were measured by enzyme immunoassay, and the estrogen metabolite ratio (EMR; 2-hydroxyestrone:16 alpha-hydroxyestrone) was computed. Cases and controls were similar in terms of age (mean age of cases, 53.8 +/- 15.1 years, versus 54.2 +/- 10.4 years for controls; P = 0.9) and demographics. Mean EMR was not associated with breast cancer overall (1.67 +/- 0.80 versus 1.72 +/- 0.66; P = 0.7). However, in postmenopausal women, the mean EMR was significantly lower in cases compared to controls (1.41 +/- 0.73 versus 1.81 +/- 0.71; P = 0.05). The multivariate adjusted odds ratios for the intermediate and lowest tertiles of the EMR relative to the highest among postmenopausal women were 9.73 (95% confidence interval, 1.27-74.84) and 32.74 (95% confidence interval, 3.36-319.09), respectively. The test for trend was highly significant (P = 0.003). Analyses of the individual metabolites indicated that 16 alpha-hydroxyestrone was a strong risk factor. The EMR did not show any consistent associations with age, race/ethnicity, age at first birth, parity, body mass index, family history of breast cancer, smoking, or alcohol intake. These data suggest a strong, inverse association of the EMR and a strong positive association of 16 alpha-hydroxyestrone with breast cancer in postmenopausal women. Larger studies are needed to confirm these results and to assess the relationship of the EMR and of the individual metabolites with breast cancer, with attention to menopausal status and clinical factors and with adjustment for known breast cancer risk factors.


Clinician gate-keeping in clinical research is not ethically defensible: an analysis.
Clinician gate-keeping is the process whereby healthcare providers prevent access to eligible patients for research recruitment. This paper contends that clinician gate-keeping violates three principles that underpin international ethical guidelines: respect for persons or autonomy; beneficence or a favourable balance of risks and potential benefits; and justice or a fair distribution of the benefits and burdens of research. In order to stimulate further research and debate, three possible strategies are also presented to eliminate gate-keeping: partnership with professional researchers; collaborative research design and clinician education.


Cigarette Smoking Among Working Women of Reproductive Age-United States, 2009-2013.
Employers play a vital role in promoting and supporting tobacco use cessation among tobacco-using workers. Cigarette smoking during pregnancy is a preventable cause of complications in pregnancy and adverse infant health outcomes. To estimate cigarette smoking prevalence and attempts to quit among working women of reproductive age in different industries and occupations using a nationally representative survey. The 2009-2013 National Health Interview Survey data for women of reproductive age (18-49 years) who were working in the week prior to the interview (n = 30855) were analyzed. Data were adjusted for nonresponse and weighted to produce nationally representative estimates. During 2009-2013, among working women of reproductive age, an estimated 17.3% (95% confidence interval [CI]: 16.7-17.8) and 12.9% (95% CI: 12.4-13.4) were current and former cigarette smokers, respectively. Of women who smoke daily, 44.5% (95% CI: 42.5-46.5) had made a quit attempt for more than 1 day in the year before the interview. Cigarette smoking prevalence was highest among women working in the construction industry (29.2%; 95% CI: 22.8-35.7) and in construction and extraction occupations (34.6%; 95% CI: 23.4-45.9). Among working women who were pregnant at the time of the interview, 6.8% (95% CI: 4.4-9.2) and 20.4% (95% CI: 16.9-24.0) were current and former cigarette smokers, respectively. Cigarette smoking prevalence varies by industry and occupation. Intensifying tobacco control efforts in high prevalence industries and occupations could result in higher cessation rates and improvements in health among women of reproductive age. This study identified discrepancies in cigarette smoking among women of reproductive age across industries and occupations. In the absence of smoke-free local and state laws, employer-established smoke-free policies and workplace cessation programs are important for achieving reduction of tobacco use among women and for protecting other workers' health. Results in this report may assist in developing educational campaigns targeting women in industries and occupations with high prevalence of cigarette smoking and low percentage of ever-smokers who had quit.


The neurophysiological basis of the discrepancy between objective and subjective sleep during the sleep onset period: an EEG-fMRI study.
Subjective perception of sleep is not necessarily consistent with electroencephalography (EEG) indications of sleep. The mismatch between subjective reports and objective measures is often referred to as "sleep state misperception." Previous studies evince that this mismatch is found in both patients with insomnia and in normal sleepers, but the neurophysiological mechanism remains unclear. The aim of the study is to explore the neurophysiological basis of this mechanism, from the perspective of both EEG power and functional magnetic resonance imaging (fMRI) fluctuations. Thirty-six healthy young adults participated in the study. Simultaneous EEG and fMRI recordings were conducted while the participants were trying to fall asleep in an MRI scanner at approximately 9:00 pm. They were awakened after achieving stable N1 or N2 sleep, or after 90 min without falling into stable sleep. Next they were asked to recall their conscious experiences from the moment immediately prior to awakening. Sixty-one instances of scheduled awakenings were collected: 21 of these after having achieved stable stage N2 sleep; 12, during stage N1 sleep; and, 20 during the waking state. Relative to those awakenings without subjective-objective discrepancy (n = 27), these awakenings with discrepancy (n = 14) were associated with lower θ power, as well as higher α, β, and γ power. Moreover, we found that participants who exhibited the discrepancy, compared with those who did not, evinced a higher amplitude of low-frequency fluctuation levels in the prefrontal cortex. These results lend support to the conjecture that the subjective-objective discrepancy is associated with central nervous system hyperarousal.


Patient and physician preferences for anticancer drugs for the treatment of metastatic colorectal cancer: a discrete-choice experiment.
Many publications describe preferences for colorectal cancer (CRC) screening; however, few studies elicited preferences for anticancer-drug treatment for metastatic CRC (mCRC). This study was designed to elicit preferences and risk tolerance among patients and oncologists in the USA for anticancer drugs to treat mCRC. Patients aged 18 years or older with a self-reported diagnosis of mCRC and board-certified (or equivalent) oncologists who had treated patients with mCRC were recruited by two survey research companies from existing online patient panels in the USA. Additional oncologists were recruited from a list of US physicians. Patients and oncologists completed a discrete-choice experiment (DCE) survey. DCEs offer a systematic method of eliciting preferences and quantifying both the relative importance of treatment attributes and the tradeoffs respondents are willing to make among benefits and risks. Treatment attributes in the DCE were progression-free survival (PFS) and risks of severe papulopustular rash, serious hemorrhage, cardiopulmonary arrest, and gastrointestinal perforation. Patients' and physicians' maximum levels of acceptable treatment-related risks for two prespecified increases in efficacy were estimated. A total of 127 patients and 150 oncologists completed the survey. Relative preferences for the treatment attributes in the study were mostly consistent with the expectation that better clinical outcomes were preferred over worse clinical outcomes. Risk tolerance varied between patients and physicians. On average, physicians were willing to tolerate higher risks than patients, although these differences were mostly not statistically significant. Post hoc latent-class analyses revealed that some patients and physicians were unwilling to forgo any efficacy to avoid toxicities, while others were willing to make such tradeoffs. Differences in preferences between patients and physicians suggest that there is the potential for improvement in patients' well-being. Initiating or enhancing discussions about patient tolerance for toxicities, such as skin rash and gastrointestinal perforations, may help prescribe treatments that entail more appropriate benefit-risk tradeoffs.


First Report of Cucumber Black Root Rot Caused by Phomopsis sclerotioides in Italy.
During April 2002 to September 2003 in unheated plastic greenhouses located in Fondi and Sperlonga (Latium Region of central Italy), in which more than 100 ha of cucumber (Cucumis sativus L.) were cultivated, an unusual disease causing decay of roots and plant wilting was observed. Many of the most common cultivars showed susceptibility, and in some farms, severe economic losses occurred. Disease symptoms observed on young plants included stunting, wilting, black root rot, and marked reduction of root development where pseudosclerotial structures were produced. The degree of root symptoms was proportional to the wilting. During periods of high evapotranspiration, wilting was severe in plants at the early stages of disease development, and even lightly infected plants wilted rapidly. Symptoms resembled those caused by vascular wilt fungi and were generally more severe in greenhouses with poorly drained soils. Samples from each of four greenhouses were collected during different periods of the growing season. Each sampling unit consisted of five to eight root pieces that were surface disinfected in 0.1% HgCl2 for 30 s, rinsed in sterile water, placed on petri dishes containing potato dextrose agar (pH 5.5), and incubated for 7 days at 25°C. Phomopsis sclerotioides van Kesteren (1,2) (identification confirmed by R. A. Samson, Centraalbureau voor Schimmelcultures of Utrecht, the Netherlands) was consistently recovered from affected tissues. Subcultures of three isolates were prepared and evaluated for pathogenicity. The experiments were conducted in a greenhouse with a 12-h photoperiod at 25 to 32°C. Seven-week-old seedlings (20 representatives per isolate) of a susceptible hybrid were dipped for 2 min in an agar slurry suspension of the pathogen and then returned to pots. Within 4 to 5 weeks after inoculation, all plants inoculated with each P. sclerotioides isolate showed the same symptoms observed in the field and caused wilting and death of approximately 80% of the inoculated plants. P. sclerotioides was consistently reisolated from the symptomatic test plant, whereas the fungus was never isolated from control plants. Another experiment using naturally infested soil in comparison with sterilized soil confirmed the soilborne nature of the fungus and its pathogenicity. To our knowledge, this is the first report of P. sclerotioides on cucumber in Italy. According to the experience of farmers and agricultural consultants, the disease was first observed in the last 3 to 4 years in unheated plastic greenhouses. However, we cannot exclude the possibility that the disease may have been present in central Italy prior to our observations, since it can be misdiagnosed and the symptoms can be masked by symptoms of other diseases. For these reasons, an accurate monitoring of the pathogen is necessary to determine the magnitude of the problem and its impact on the industry. Management practices that include long-term crop rotation with nonsusceptible hosts, removal and destruction of infected crop debris, and steam soil sterilization are suggested to reduce the economic losses. References: (1) E. Punithalingam et al. No. 461 in: Descriptions of Pathogenic Fungi and Bacteria. CMI, Kew, Surrey, U.K., 1975. (2) H. A. Van Kesteren. Neth. J. Plant Pathol. 73:112, 1967.


The effects of dynamic and three-dimensional environments on chondrogenic differentiation of bone marrow stromal cells.
Articular cartilage is subjected to complex loading, which plays a major role in its growth, development and maintenance. Previously, we found that mechanical stimuli enhanced the development and function of engineered cartilage tissues in elastic mechano-active poly(lactide-co-caprolactone) (PLCL) scaffolds. In addition, it is well known that the three-dimensional spatial organization of cells and extracellular matrices in hydrogels is crucial to chondrogenesis. This study was conducted to enhance the chondrogenic differentiation of bone marrow stromal cells (BMSCs) in the hybrid scaffolds of fibrin gels and PLCL scaffolds in dynamic environments by compression. A highly elastic scaffold was fabricated from very elastic PLCL with 85% porosity and a 300-500 microm pore size using a gel-pressing method. A mixture of rabbit BMSCs and fibrin gels was then seeded onto the PLCL scaffolds and subjected to continuous compressive deformation of 5% strain at 0.1 Hz for 10 days in a chondrogenic medium containing 10 ng ml(-1) TGF-beta(1). The BMSCs-seeded scaffold constructs were then implanted subcutaneously into nude mice. As a control, the cell-PLCL scaffold constructs were cultured under dynamic conditions or the cell-PLCL/fibrin hybrid scaffold constructs and the cell-PLCL scaffold constructs were cultured under static conditions for 10 days in vitro. The results revealed that cells adhered onto the hybrid scaffolds of fibrin gels and PLCL scaffolds cultured under dynamic conditions. In addition, the accumulation of the extracellular matrix of cell-scaffold constructs, which was increased through mechanical stimulation, showed that chondrogenic differentiation was sustained and enhanced significantly in the stimulated hybrid scaffold constructs. Overall, the results of this study indicate that the proper periodic application of dynamic compression and the three-dimensional environments of the hybrid scaffolds composed of fibrin gels and elastic PLCL can encourage BMSCs to differentiate into chondrocytes, maintain their phenotypes and enhance GAGs production, thereby improving the quality of cartilaginous tissue formed in vitro and in vivo.


A randomized, double-blind, phase 2b proof-of-concept clinical trial in early Alzheimer's disease with lecanemab, an anti-Aβ protofibril antibody.
Lecanemab (BAN2401), an IgG1 monoclonal antibody, preferentially targets soluble aggregated amyloid beta (Aβ), with activity across oligomers, protofibrils, and insoluble fibrils. BAN2401-G000-201, a randomized double-blind clinical trial, utilized a Bayesian design with response-adaptive randomization to assess 3 doses across 2 regimens of lecanemab versus placebo in early Alzheimer's disease, mild cognitive impairment due to Alzheimer's disease (AD) and mild AD dementia. BAN2401-G000-201 aimed to establish the effective dose 90% (ED90), defined as the simplest dose that achieves ≥90% of the maximum treatment effect. The primary endpoint was Bayesian analysis of 12-month clinical change on the Alzheimer's Disease Composite Score (ADCOMS) for the ED90 dose, which required an 80% probability of ≥25% clinical reduction in decline versus placebo. Key secondary endpoints included 18-month Bayesian and frequentist analyses of brain amyloid reduction using positron emission tomography; clinical decline on ADCOMS, Clinical Dementia Rating-Sum-of-Boxes (CDR-SB), and Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog14); changes in CSF core biomarkers; and total hippocampal volume (HV) using volumetric magnetic resonance imaging. A total of 854 randomized subjects were treated (lecanemab, 609; placebo, 245). At 12 months, the 10-mg/kg biweekly ED90 dose showed a 64% probability to be better than placebo by 25% on ADCOMS, which missed the 80% threshold for the primary outcome. At 18 months, 10-mg/kg biweekly lecanemab reduced brain amyloid (-0.306 SUVr units) while showing a drug-placebo difference in favor of active treatment by 27% and 30% on ADCOMS, 56% and 47% on ADAS-Cog14, and 33% and 26% on CDR-SB versus placebo according to Bayesian and frequentist analyses, respectively. CSF biomarkers were supportive of a treatment effect. Lecanemab was well-tolerated with 9.9% incidence of amyloid-related imaging abnormalities-edema/effusion at 10 mg/kg biweekly. BAN2401-G000-201 did not meet the 12-month primary endpoint. However, prespecified 18-month Bayesian and frequentist analyses demonstrated reduction in brain amyloid accompanied by a consistent reduction of clinical decline across several clinical and biomarker endpoints. A phase 3 study (Clarity AD) in early Alzheimer's disease is underway. Clinical Trials.gov NCT01767311 .


Plant growth promotion potential is equally represented in diverse grapevine root-associated bacterial communities from different biopedoclimatic environments.
Plant-associated bacteria provide important services to host plants. Environmental factors such as cultivar type and pedoclimatic conditions contribute to shape their diversity. However, whether these environmental factors may influence the plant growth promoting (PGP) potential of the root-associated bacteria is not widely understood. To address this issue, the diversity and PGP potential of the bacterial assemblage associated with the grapevine root system of different cultivars in three Mediterranean environments along a macrotransect identifying an aridity gradient were assessed by culture-dependent and independent approaches. According to 16S rRNA gene PCR-DGGE, the structure of endosphere and rhizosphere bacterial communities was highly diverse (P = 0.03) and was associated with a cultivar/latitudinal/climatic effect. Despite being diverse, the bacterial communities associated with Egyptian grapevines shared a higher similarity with the Tunisian grapevines than those cultivated in North Italy. A similar distribution, according to the cultivar/latitude/aridity gradients, was observed for the cultivable bacteria. Many isolates (23%) presented in vitro multiple stress resistance capabilities and PGP activities, the most frequent being auxin synthesis (82%), insoluble phosphate solubilisation (61%), and ammonia production (70%). The comparable numbers and types of potential PGP traits among the three different environmental settings indicate a strong functional homeostasis of beneficial bacteria associated with grape root.


Postoperative complications and functional results after subtotal gastrectomy with Billroth II reconstruction for primary gastric cancer.
Subtotal gastrectomy is considered the preferred treatment for gastric cancer with antral location. The aim of this study was to assess the incidence of early postoperative complications and late functional results in patients who underwent subtotal gastrectomy with Billroth II reconstruction for primary gastric adenocarcinoma. The results of 310 patients were analyzed with regard to postoperative complications and death rates. Functional results as they relate to the gastric resection were evaluated in 195 disease-free patients. Of the 310 patients, 77 developed postoperative general and surgical complications (24.8%) and 13 consequently died (in-hospital mortality: 4.2%). Although infrequent (6 cases, 1.9%), anastomotic leak was the most serious complication (4 cases died during the postoperative phase). Considering functional results, weight loss continued for the first trimester after surgery, after which it stabilized. Loss of appetite was rarely observed; early after the operation the majority of patients were consuming a normal diet and regularly consumed less than five meals per day (83.6%). Dumping syndrome was uncommon and usually resolved within one year (12.3% at three months, 9.5% after one year, 5.2% after two years). On the other hand, postprandial abdominal fullness was frequently observed (43.1% at three months, 36.1% after one year, 21.3% after three years, and 16.5% after five years). Billroth II reconstruction after subtotal gastrectomy is associated with a limited risk of anastomotic complications. Anastomotic leak, although infrequent, is a life-threatening complaint and requires prompt recognition and aggressive surgical treatment. The incidence of late complications was low and the majority of patients recovered from them within one year after surgery, although the occurrence of postprandial abdominal fullness was not completely irrelevant.


Genetic risk, adherence to a healthy lifestyle, and type 2 diabetes risk among 550,000 Chinese adults: results from 2 independent Asian cohorts.
Whether genetic susceptibility to type 2 diabetes is modified by a healthy lifestyle among Chinese remains unknown. The aim of the study was to determine whether genetic risk and adherence to a healthy lifestyle contribute independently to the risk of developing type 2 diabetes. We defined a lifestyle score using BMI, alcohol intake, smoking, physical activities, and diets in 461,030 participants from the China Kadoorie Biobank and 38,434 participants from the Singapore Chinese Health Study. A genetic risk score was constructed based on type 2 diabetes loci among 100,175 and 16,172 participants in each cohort, respectively. A Cox proportional-hazards model was used to estimate the interaction between genetic and lifestyle factors on the risk of type 2 diabetes. In 2 independent Asian cohorts, we consistently found a healthy lifestyle (the bottom quintile of lifestyle score) was associated with a substantially lower risk of type 2 diabetes than an unhealthy lifestyle (the top quintile of lifestyle score) regardless of genetic risk. In those at a high genetic risk, the risk of type 2 diabetes was 57% lower among participants with a healthy lifestyle than among those with an unhealthy lifestyle in the pooled cohorts. Among participants at high genetic risk, the standardized 10-y incidence of type 2 diabetes was 7.11% in those with an unhealthy lifestyle vs. 2.45% in those with a healthy lifestyle. In 2 independent cohorts involving 558,302 Chinese participants, we did not observe an interaction between genetics and lifestyle with type 2 diabetes risk, but our findings provide replicable evidence to show lifestyle factors and genetic factors were independently associated with the risk of type 2 diabetes. Within any genetic risk category, a healthy lifestyle was associated with a significantly lower risk of type 2 diabetes among the Chinese population.


Valve Replacement in Children with Single Ventricle Physiology.
Severe atrioventricular valve (AVV) or semilunar valve (SLV) regurgitation in the setting of a single ventricle physiology may proceed to valve replacement if repair strategies fail. Outcome data for these children are limited. We present transplant-free survival of a case series of children with single ventricle physiology undergoing either atrioventricular replacement (AVVR) or semilunar valve replacement (SLVR) from a multi-institutional, US-based registry (Pediatric Cardiac Care Consortium-PCCC). Outcomes were derived from PCCC and by linkage with the National Death Index (NDI) and Organ Procurement Transplant Network (OPTN). Fifty children with single ventricle physiology were identified to have received either AVVR (n = 38) or SLVR (n = 12). There were 17 in-hospital deaths including 8 intraoperative deaths (all intraoperative deaths were among children requiring AVVR). The in-hospital mortality was 42% and 8% for AVVR and SLVR, respectively. Among the 33 children surviving to hospital discharge, follow-up was available in 15 (46%). Death or cardiac transplant after hospital discharge occurred in 10-death in 4 (all among those requiring AVVR), cardiac transplant in 6 (2 following AVVR, 4 following SLVR). Valve replacement in children with single ventricle physiology, especially AVVR, is associated with poor outcomes. Alternative palliation strategies should be considered in children with single ventricle physiology with significant AVV or SLV regurgitations.


Acetylation control of the retinoblastoma tumour-suppressor protein.
The retinoblastoma tumour-suppressor protein (pRb) and p300/CBP co-activator proteins are important for control of proliferation and in tumour cells these are sequestered by viral oncoproteins such as E1A. pRb is involved in negatively regulating growth, and p300/CBP proteins have histone acetyltransferase (HAT) activity, which influences gene expression. Although it is known that phosphorylation by G1 cyclin-dependent kinases (CDKs) regulates pRb activity, the nature and role of other post-translational modifications is not understood. Here we identify acetylation as a new type of modification and level of control in pRb function. Adenovirus E1A, which binds p300/CBP through an amino-terminal transformation-sensitive domain, stimulates the acetylation of pRb by recruiting p300 and pRb into a multimeric-protein complex. Furthermore, pRb acetylation is under cell-cycle control, and acetylation hinders the phosphorylation of pRb by cyclin-dependent kinases. pRb binds more strongly when acetylated to the MDM2 oncoprotein, which indicates that acetylation may regulate protein-protein interactions in the pRb pathway. The acetylation of pRb defines a new level of cell-cycle control mediated by HAT. Furthermore, our results establish a relationship between p300, pRb and acetylation in which E1A acts to recruit and target a cellular HAT activity to pRb.


Global transcriptional response of the alkali-tolerant cyanobacterium Synechocystis sp. strain PCC 6803 to a pH 10 environment.
Many cyanobacterial strains are able to grow at a pH range from neutral to pH 10 or 11. Such alkaline conditions favor cyanobacterial growth (e.g., bloom formation), and cyanobacteria must have developed strategies to adjust to changes in CO2 concentration and ion availability. Synechocystis sp. strain PCC 6803 exhibits similar photoautotrophic growth characteristics at pH 10 and pH 7.5, and we examined global gene expression following transfer from pH 7.5 to pH 10 to determine cellular adaptations at an elevated pH. The strategies used to develop homeostasis at alkaline pH had elements similar to those of many bacteria, as well as components unique to phototrophic microbes. Some of the response mechanisms previously identified in other bacteria included upregulation of Na+/H+ antiporters, deaminases, and ATP synthase. In addition, upregulated genes encoded transporters with the potential to contribute to osmotic, pH, and ion homeostasis (e.g., a water channel protein, a large-conductance mechanosensitive channel, a putative anion efflux transporter, a hexose/proton symporter, and ABC transporters of unidentified substrates). Transcriptional changes specific to photosynthetic microbes involved NADH dehydrogenases and CO2 fixation. The pH transition altered the CO2/HCO3(-) ratio within the cell, and the upregulation of three inducible bicarbonate transporters (BCT1, SbtA, and NDH-1S) likely reflected a response to this perturbed ratio. Consistent with this was increased transcript abundance of genes encoding carboxysome structural proteins and carbonic anhydrase. Interestingly, the transition to pH 10 resulted in increased abundance of transcripts of photosystem II genes encoding extrinsic and low-molecular-weight polypeptides, although there was little change in photosystem I gene transcripts.


Development of a novel magnetophoresis-assisted hydrophoresis microdevice for rapid particle ordering.
Focusing and ordering of micro- or nanoparticles is an essential ability in microfluidic platforms for bio-sample processing. Hydrophoresis is an effective method utilising hydrodynamic force to focus microparticles, but it is limited by the fixed operational range and the lack of flexibility. Here, we report a work to tune and improve the dynamic range of hydrophoresis device using magnetophoresis. In this work, a novel approach was presented to fabricate the lateral fluidic ports, which allow the flipped chip to remain stable on the stage of microscope. Diamagnetic polystyrene microparticles suspended in a ferrofluidic medium were repelled to the lower level of the channel by negative magnetophoretic force, and then interact with grooves of microchannel to obtain an excellent hydrophoretic ordering. The effects of (i) flow rate, (ii) particle size, (iii) magnetic susceptibility of the medium, and (iv) number of magnets on the particle focusing efficiency were also reported. As the proposed magnetophorsis-assisted hydrophoretic device is tuneable and simple, it holds great potential to be integrated with other microfluidic components to form an integrated sample-to-answer system.


19F MR imaging golden angle-based capsule tracking for intestinal transit and catheter tracking: initial in vivo experience.
To combine fluorine 19 ((19)F) magnetic resonance (MR) imaging and golden angle radial acquisition and to assess the feasibility of (19)F MR imaging golden angle-based tracking for catheter tracking applications and simultaneous three-dimensional (3D) intestinal tracking of ingested (19)F-labeled capsules in vivo. Approval from the local ethical committee and informed consent from the subject were obtained. In vitro studies were performed to assess (19)F MR imaging golden angle-based tracking reliability with regard to temporal resolution and different tracking strategies (boundary condition-free tracking, composite image-based tracking, and model-based tracking). In vivo performance of the method was investigated in one healthy volunteer on 2 days. On study day 1, a duodenal catheter incorporating five (19)F-labeled capsules was administered nasally, and its 3D movement was tracked inside the stomach and esophagus. On study day 2, three (19)F-labeled capsules were swallowed, and intestinal movement was tracked. Simultaneous in vivo 3D tracking of multiple (19)F-labeled capsules was successfully performed without incorporation of boundary conditions at a temporal resolution of 252 msec. Incorporation of boundary conditions with composite image-based tracking and model-based tracking increased tracking reliability and enabled temporal resolution as high as 108 msec. Use of (19)F MR imaging golden angle-based capsule tracking enables in vivo tracking of (19)F-labeled capsules and catheters at high temporal resolution. The presented method is applicable to physioanatomic studies of the gastrointestinal tract and shows potential for real-time tracking in interventional radiology.


Novel Approaches for Assessing Circadian Rhythmicity in Humans: A Review.
The temporal organization of molecular and physiological processes is driven by environmental and behavioral cycles as well as by self-sustained molecular circadian oscillators. Quantification of phase, amplitude, period, and disruption of circadian oscillators is essential for understanding their contribution to sleep-wake disorders, social jet lag, interindividual differences in entrainment, and the development of chrono-therapeutics. Traditionally, assessment of the human circadian system, and the output of the SCN in particular, has required collection of long time series of univariate markers such as melatonin or core body temperature. Data were collected in specialized laboratory protocols designed to control for environmental and behavioral influences on rhythmicity. These protocols are time-consuming, expensive, and not practical for assessing circadian status in patients or in participants in epidemiologic studies. Novel approaches for assessment of circadian parameters of the SCN or peripheral oscillators have been developed. They are based on machine learning or mathematical model-informed analyses of features extracted from 1 or a few samples of high-dimensional data, such as transcriptomes, metabolomes, long-term simultaneous recording of activity, light exposure, skin temperature, and heart rate or in vitro approaches. Here, we review whether these approaches successfully quantify parameters of central and peripheral circadian oscillators as indexed by gold standard markers. Although several approaches perform well under entrained conditions when sleep occurs at night, the methods either perform worse in other conditions such as shift work or they have not been assessed under any conditions other than entrainment and thus we do not yet know how robust they are. Novel approaches for the assessment of circadian parameters hold promise for circadian medicine, chrono-therapeutics, and chrono-epidemiology. There remains a need to validate these approaches against gold standard markers, in individuals of all sexes and ages, in patient populations, and, in particular, under conditions in which behavioral cycles are displaced.


Quantifying long-term scientific impact.
The lack of predictability of citation-based measures frequently used to gauge impact, from impact factors to short-term citations, raises a fundamental question: Is there long-term predictability in citation patterns? Here, we derive a mechanistic model for the citation dynamics of individual papers, allowing us to collapse the citation histories of papers from different journals and disciplines into a single curve, indicating that all papers tend to follow the same universal temporal pattern. The observed patterns not only help us uncover basic mechanisms that govern scientific impact but also offer reliable measures of influence that may have potential policy implications.


Posaconazole exhibits in vitro and in vivo synergistic antifungal activity with caspofungin or FK506 against Candida albicans.
The object of this study was to test whether posaconazole, a broad-spectrum antifungal agent inhibiting ergosterol biosynthesis, exhibits synergy with the β-1,3 glucan synthase inhibitor caspofungin or the calcineurin inhibitor FK506 against the human fungal pathogen Candida albicans. Although current drug treatments for Candida infection are often efficacious, the available antifungal armamentarium may not be keeping pace with the increasing incidence of drug resistant strains. The development of drug combinations or novel antifungal drugs to address emerging drug resistance is therefore of general importance. Combination drug therapies are employed to treat patients with HIV, cancer, or tuberculosis, and has considerable promise in the treatment of fungal infections like cryptococcal meningitis and C. albicans infections. Our studies reported here demonstrate that posaconazole exhibits in vitro synergy with caspofungin or FK506 against drug susceptible or resistant C. albicans strains. Furthermore, these combinations also show in vivo synergy against C. albicans strain SC5314 and its derived echinocandin-resistant mutants, which harbor an S645Y mutation in the CaFks1 β-1,3 glucan synthase drug target, suggesting potential therapeutic applicability for these combinations in the future.


The infected or exposed breast implant: management and treatment strategies.
Among the potential complications associated with the use of breast implants are the risks of periprosthetic infection and device extrusion. There is little published information about the effective management of these situations. Conservative recommendations include antibiotic therapy and removal of the implant until resolution of the infection or until the wound has healed. A retrospective review identified patients with periprosthetic infection or threatened or actual device exposure treated by the senior author. Twenty-four patients encompassing 26 affected prostheses were available for review and were classified into seven groups based on initial presentation as follows: group 1, mild infection (n = 8); group 2, severe infection (n = 4); group 3, threatened exposure without infection (n = 3); group 4, threatened exposure with mild infection (n = 3); group 5, threatened exposure with severe infection (n = 1); group 6, actual exposure without clinical infection (n = 5); and group 7, actual exposure with infection (n = 2). To salvage the prosthesis in these patients, various treatment strategies were utilized. All patients with a suspected infection or device exposure were started immediately on appropriate antibiotic therapy (oral antibiotics for mild infections and parenteral antibiotics for severe infections). Salvage methods included one or more of the following: antibiotic therapy, débridement, curettage, pulse lavage, capsulectomy, device exchange, primary closure, and/or flap coverage. Twenty (76.9 percent) of 26 threatened implants with infection or threatened or actual prosthesis exposure were salvaged after aggressive intervention. The presence of severe infection adversely affected the salvage rate in this series. A statistically significant difference exists among those patients without infection or with mild infection only (groups 1, 3, 4, and 6); successful salvage was achieved in 18 (94.7 percent) of 19 patients, whereas only two of seven of those implants with severe infection (groups 2, 5, and 7) were salvaged (p = 0.0017). Ten (90.9 percent) of 11 devices with threatened or actual exposure, not complicated by severe infection (groups 3, 4, and 6), were salvaged. Several treatment strategies were developed for periprosthetic infection and for threatened or actual implant exposure. Patients with infection were placed on oral or intravenous antibiotics; those who responded completely required no further treatment. For persistent mild infection or threatened or actual exposure, operative intervention was required, including some or all of the following steps: implant removal, pocket curettage, partial or total capsulectomy, débridement, site change, placement of a new implant, and/or flap coverage; the menu of options varied with the precise circumstances. No immediate salvage was attempted in five cases, due to either severe infection, nonresponding infection with gross purulence, marginal tissues, or lack of options for healthy tissue coverage. Based on the authors' experience, salvage attempts for periprosthetic infection and prosthesis exposure may be successful, except in cases of overwhelming infection or deficient soft-tissue coverage. Although an attempt at implant salvage may be offered to a patient, device removal and delayed reinsertion will always remain a more conservative and predictable option.


Indomethacin, prostacyclin, and heparin improve postischemic cerebral blood flow without affecting early postischemic granulocyte accumulation.
Six anesthetized dogs treated with indomethacin, prostacyclin (PGI2), and heparin were compared with 7 anesthetized controls (ischemia without treatment) to determine whether cyclooxygenase inhibition would lead to enhanced granulocyte accumulation because of preferential formation of lipoxygenase products. Cortical somatosensory evoked response, [14C]iodoantipyrine autoradiographic blood flow, and 111In-labelled granulocyte accumulation were compared 4 hours after a 60-minute exposure to multifocal brain ischemia. Treatment with indomethacin, PGI2, and heparin eliminated neuron-disabling brain blood flows without altering early postischemic granulocyte accumulation. Granulocyte accumulation after 4 hours of reperfusion was not significantly different in control and treated dogs. The final amplitude of the cortical somatosensory evoked response in the treated group averaged 38.0 +/- 13.6% (mean +/- SEM) of the corresponding baseline value compared with 21.0 +/- 4.6% in the control group, but this difference was not significant.


Analgesic effects of intraventricular and intrathecal injection of morphine and ketocyclazocine in the infant rat.
Little is known of the neural bases of analgesia in immature animals. This experiment examined the effects of intracerebroventricular (i.c.v.) and intrathecal (i.t.) administration of morphine or ketocyclazocine in tests of antinociception in rats aged 3 to 14 days of age. Analgesia tests were conducted using both thermal and mechanical (pressure) noxious stimuli applied to the forepaw, hindpaw or tail. In the 3-day-old morphine-injected i.c.v. produced analgesia in the forepaws when either the mechanical or thermal noxious stimulus was used. There was no effect when the hindpaw or tail was tested. At 10 days of age, when the mechanical stimulus was used, morphine was analgesic in tests on all three appendages but was only effective in the forepaw when the thermal stimulus was used. Morphine was fully effective in all tests with both stimuli at 14 days of age. Ketocyclazocine had no consistent effect when given i.c.v. When injected i.t., morphine produced analgesia in the forepaws in the thermal test at 4 days of age and in all appendages by 10 days. When the mechanical test was used, morphine was effective in all appendages at all ages tested. Ketocyclazocine was analgesic at all appendages for the mechanical stimulus at all ages but was only transiently effective in the thermal test. The results demonstrate differential development of analgesia mediated at different levels of the neural axis and are consistent with the development of descending inhibitory that may mediate analgesia induced by i.c.v. injections of morphine. Neural mechanisms that are involved in the analgesic effects of these drugs against the two types of stimuli are also developmentally distinct.


Enhanced killing of antibiotic-resistant bacteria enabled by massively parallel combinatorial genetics.
New therapeutic strategies are needed to treat infections caused by drug-resistant bacteria, which constitute a major growing threat to human health. Here, we use a high-throughput technology to identify combinatorial genetic perturbations that can enhance the killing of drug-resistant bacteria with antibiotic treatment. This strategy, Combinatorial Genetics En Masse (CombiGEM), enables the rapid generation of high-order barcoded combinations of genetic elements for high-throughput multiplexed characterization based on next-generation sequencing. We created ∼ 34,000 pairwise combinations of Escherichia coli transcription factor (TF) overexpression constructs. Using Illumina sequencing, we identified diverse perturbations in antibiotic-resistance phenotypes against carbapenem-resistant Enterobacteriaceae. Specifically, we found multiple TF combinations that potentiated antibiotic killing by up to 10(6)-fold and delivered these combinations via phagemids to increase the killing of highly drug-resistant E. coli harboring New Delhi metallo-beta-lactamase-1. Moreover, we constructed libraries of three-wise combinations of transcription factors with >4 million unique members and demonstrated that these could be tracked via next-generation sequencing. We envision that CombiGEM could be extended to other model organisms, disease models, and phenotypes, where it could accelerate massively parallel combinatorial genetics studies for a broad range of biomedical and biotechnology applications, including the treatment of antibiotic-resistant infections.


Need for recovery in relation to effort from work and health in four occupations.
To examine three levels of need for recovery (NFR) after work in relation to effort from work demands, demand compensatory strategies, effort-moderating or -reversing resources, and health including health behaviors. A further purpose was to examine occupational characteristics determining NFR. 5000 engineers, carpenters, nurses, and home care nurses were invited to participate. NFR k-means clusters were calculated from 1289 participants. The effect from three levels of NFR regarding demands, compensatory strategies, resources at work, health, and health behaviors was examined using analysis of variance (ANOVA) and post hoc analysis. Prevalence ratios (PRs) of suboptimal health for three levels of NFR were calculated using Poisson regression. Linear stepwise multiple regression predictors explaining NFR were examined also occupation wise. NFR centroids at 5.8/33, 13.1/33, and 21.0/33 points were identified. ANOVA showed corresponding effects from NFR levels on work demands and compensatory strategies. The inversed proportion concerned levels of resources at work. Only the low NFR cluster negated regular health effects. The other two cluster groups also repeatedly worked while ill and presented PRs concerning health effects from 1.9 to 3.9 when compared to the low NFR group. Making good quality work, recovery opportunities, and thinking of work when off work were the most important predictors of NFR among 1289 participants with also occupation-wise interpretable profiles. Three levels of NFR meant corresponding levels of work demands, work-demand compensatory strategies, and unfavorable health behaviors. An inversed proportion of resources related to the same levels of NFR. Low NFR meant no regular health effects which could guide limit values regarding salutary NFR. Important predictors of NFR were resources making a good quality work, recovery opportunities, and reversely effort from rumination when off work. Occupation-wise predictors could guide interventions.


Dual-Light Photodynamic Therapy Effectively Eliminates Streptococcus Oralis Biofilms.
During cancer treatment, oral mucositis due to radiotherapy or chemotherapy often leads to disruption of the oral mucosa, enabling microbes to invade bloodstream. Viridans streptococcal species are part of the healthy oral microbiota but can be frequently isolated from the blood of neutropenic patients. We have previously shown the antibacterial efficacy of dual-light, the combination of antibacterial blue light (aBL) and indocyanine green photodynamic therapy (aPDT). Here, we investigated the dual-light antibacterial action against four-day Streptococcus oralis biofilm. In addition, while keeping the total radiant exposure constant at 100J/cm2, we investigated the effect of changing the different relative light energies of aBL and aPDT to the antibacterial potential. The dual-light had a significant antibacterial effect in all the tested combinations. Dual-light can be used as an effective disinfectant against S. oralis biofilm.


Number of comorbidities and their impact on perioperative outcome and costs - a single centre cohort study.
Multimorbidity is a growing global health problem, resulting in an increased perioperative risk for surgical patients. Data on both the prevalence of multimorbidity and its impact on perioperative outcome are limited. The American Society of Anesthesiologists (ASA) classification uses only the single most severe systemic disease to define the ASA class and ignores multimorbidity. This study aimed to assess the number and type of all anaesthesia-relevant comorbidities and to analyse their impact on outcome and hospital costs. This cohort study is nested in the ClassIntra® validation study and includes only patients enrolled at the University Hospital of Basel. Approximately 30 patients per surgical discipline undergoing any type of in-hospital surgery were followed up until hospital discharge to record all intra- and postoperative adverse events. In addition, the type and severity of all perioperatively relevant comorbidities were extracted from the electronic medical record according to a predefined list. The primary endpoint was the number of all anaesthesia-relevant comorbidities by ASA class. Using structural equation models, the direct and indirect effects of comorbidities on costs were estimated after adjustment for the ASA class and further relevant confounders and mediators. Of 320 enrolled patients, 27 were ASA I (8%), 150 ASA II (47%), 116 ASA III (36%) and 27 ASA IV (8%). The median number of comorbidities per patient was 5 (range 0-18), this number significantly increasing with higher ASA class: 1 comorbidity (95% CI 0.0-2.0) in ASA I, 4 comorbidities (3.8-4.2) in ASA II, 9 (8.1-9.9) in ASA III and 12 (10-14) in ASA IV patients. Independent of ASA class, each additional comorbidity increased hospital costs by EUR 1,198 (95% CI 288-2108) with almost identical proportions of direct and indirect effects. The number of anaesthesia-relevant comorbidities also increased postoperative complications and postoperative length of hospital stay. Multimorbidity in perioperative patients is highly prevalent and has a relevant impact on hospital costs, independent of the ASA class. Incorporating multimorbidity into the ASA classification might be warranted to improve its predictive ability and support adequate reimbursement.


Minimally invasive removal of lumbar intradural extramedullary lesions using the interlaminar approach.
OBJECT Posterior midline laminectomy or hemilaminectomy has been successfully applied as the standard microsurgical technique for the treatment of spinal intradural pathologies. However, the associated risks of postoperative spinal instability increase the need for subsequent fusion surgery to prevent potential long-term spinal deformity. Continuous efforts have been made to minimize injuries to the surrounding tissue resulting from surgical manipulations. The authors report here their experiences with a novel minimally invasive surgical approach, namely the interlaminar approach, for the treatment of lumbar intraspinal tumors. METHODS A retrospective review was conducted of patients at the Second Affiliated Hospital of Zhejiang University School of Medicine who underwent minimally invasive resection of lumbar intradural-extramedullary tumors. By using an operative microscope, in addition to an endoscope when necessary, the authors were able to treat all patients with a unilateral, paramedian, bone-sparing interlaminar technique. Data including preoperative neurological status, tumor location, size, pathological diagnosis, extension of resections, intraoperative blood loss, length of hospital stay, and clinical outcomes were obtained through clinical and radiological examinations. RESULTS Eighteen patients diagnosed with lumbar intradural-extramedullary tumors were treated from October 2013 to March 2015 by this interlaminar technique. A microscope was used in 15 cases, and the remaining 3 cases were treated using a microscope as well as an endoscope. There were 14 schwannomas, 2 ependymomas, 1 epidermoid cyst, and 1 enterogenous cyst. Postoperative radiological follow-up revealed complete removal of all the lesions and no signs of bone defects in the lamina. At clinical follow-up, 14 of the 18 patients had less pain, and patients' motor/sensory functions improved or remained normal in all cases except 1. CONClUSIONS When meeting certain selection criteria, intradural-extramedullary lumbar tumors, especially schwannomas, can be completely and safely resected through a less-invasive interlaminar approach using a microscope, or a microscope in addition to an endoscope when necessary. This approach was advantageous because it caused even less bone destruction, resulting in better postoperative spinal stability, no need for facetectomy and fusion, and quicker functional recovery for the patients. Individualized surgical planning according to preoperative radiological findings is key to a successful microsurgical resection of these lesions through the interlaminar space.


Cohort Profile: LifeLines, a three-generation cohort study and biobank.
The LifeLines Cohort Study is a large population-based cohort study and biobank that was established as a resource for research on complex interactions between environmental, phenotypic and genomic factors in the development of chronic diseases and healthy ageing. Between 2006 and 2013, inhabitants of the northern part of The Netherlands and their families were invited to participate, thereby contributing to a three-generation design. Participants visited one of the LifeLines research sites for a physical examination, including lung function, ECG and cognition tests, and completed extensive questionnaires. Baseline data were collected for 167 729 participants, aged from 6 months to 93 years. Follow-up visits are scheduled every 5 years, and in between participants receive follow-up questionnaires. Linkage is being established with medical registries and environmental data. LifeLines contains information on biochemistry, medical history, psychosocial characteristics, lifestyle and more. Genomic data are available including genome-wide genetic data of 15 638 participants. Fasting blood and 24-h urine samples are processed on the day of collection and stored at -80 °C in a fully automated storage facility. The aim of LifeLines is to be a resource for the national and international scientific community. Requests for data and biomaterials can be submitted to the LifeLines Research Office [email@example.com].


Bacterial strain-specific induction of Foxp3+ T regulatory cells is protective in murine allergy models.
The incidence of atopic disease has increased dramatically during recent decades and the potential immunoregulatory influence of the microbiota in these individuals is under investigation. The aim of our study was to identify a bacterial strain that is protective in murine allergy models and to determine if microbial induction of T regulatory cells was associated with protection from allergic inflammation. Three microbes (Bifidobacterium breve AH1205, B. longum AH1206 and Lactobacillus salivarius AH102) of human origin were fed to newborn, adult and germ-free animals. Induction of Foxp3(+) T regulatory cells was assessed by flow cytometry. Gene array analysis was performed on Peyer's patches. Strains were also examined for their protective effects in the ovalbumin (OVA) respiratory allergy model and the OVA-cholera toxin dietary allergy model. Bifidobacterium longum AH1206 consumption resulted in increased numbers of Foxp3(+) T regulatory cells in infant, adult and germ-free animals. B. breve AH1205 induced Foxp3(+) T regulatory cell expansion only in infant mice while L. salivarius AH102 did not alter T regulatory cell numbers in any animal model tested. B. longum AH1206 reduced the Peyer's patch gene expression associated with antigen presentation, TLR signalling and cytokine production while increasing the expression of genes associated with retinoic acid metabolism. B. longum AH1206 protected against airway inflammation in OVA-sensitized animals and B. longum AH1206 blocked the induction of IgE to orally administered OVA. Neither B. breve AH1205 nor L. salivarius AH102 had a protective effect in either model. Bacterial strain-specific induction of Foxp3(+) T regulatory cells in vivo is associated with protection from respiratory and oral allergy.


Diagnostic Accuracy of Cerebrospinal Fluid (CSF) Cytology in Metastatic Tumors: An Analysis of Consecutive CSF Samples.
Cerebrospinal fluid (CSF) examination can be used to verify the presence of primary malignancies as well as cases of central nervous system (CNS) metastasis. Because of its importance, there have been several studies concerning the sensitivity of CSF cytology. To determine the practical use and reproducibility of diagnoses based on CSF cytology, we evaluated this test by analyzing cytology results from consecutive CSF samples. Between July 2010 and June 2013, 385 CSF cytology samples from 42 patients were collected. The samples were gathered using a ventricular catheter and reservoir. CSF cytology of all patients was examined more than two times with immunocytochemistry for cytokeratin. Primary neoplastic sites and histologic types of patients' metastatic cancer were diverse. The overall sensitivity for detecting malignancy was 41.3%. Even within short-term intervals, diagnoses frequently changed. Our results were inconsistent, with low sensitivity, when compared to the results of previous studies. However, CSF evaluation can still provide valuable diagnostic and prognostic information because adjuvant treatments are now routinely performed in patients with CNS metastasis. Negative CSF cytology results should not be ignored, and continuous CSF follow-up is essential for following the clinical course of patients with metastatic cancer involving the CNS.


Prospective, Randomized Intervention Study Comparing Retinal Pigment Epithelium-Choroid Graft Surgery and Anti-VEGF Therapy in Patients with Exudative Age-Related Macular Degeneration.
To investigate whether patients with exudative age-related macular degeneration and a submacular hemorrhage, retinal pigment epithelium (RPE) tear or nonresponders to anti-vascular endothelial growth factor (VEGF) benefit more from a free RPE-choroid graft transplantation surgery than from (continuation of) anti-VEGF treatment. A total of 20 patients were included in this prospective, international, multicenter, randomized intervention study. The change in the mean number of Early Treatment of Diabetic Retinopathy Study (ETDRS) letters in the graft group 1 year postoperatively was -15 (range -54 to +26), whilst 2 patients experienced a gain of >10 letters. The median preoperative visual acuity (VA) was 0.75 logMAR (range 0.46-2.8), and the mean postoperative VA was 1.48 logMAR (range 0.14-2.8). The change in the mean number of ETDRS letters in the anti-VEGF group was -8 (range -26 to +6); no patients experienced a >10 letter gain. The median preoperative VA was 1.36 logMAR (range 0.58-1.6), and the median postoperative VA was 1.42 logMAR (range 0.44-1.66). The included patient group is far too small to draw conclusions. However, both gain and loss of VA may be experienced by patients undergoing either treatment method; more gain might be possible for patients with a graft in the absence of complications.


Effect of Prolonged Fasting Duration on 50 Gram Oral Glucose Challenge Test in the Diagnosis of Gestational Diabetes Mellitus.
The aim of this study was to investigate the association between fasting duration before screening with 50 g glucose challenge test (GCT) and the test outcome. For this cross-sectional study, we enrolled 508 low-risk pregnant women who underwent 50 g GCT between the 24 and 28 weeks of gestation. We excluded women with pregestational diabetes, multiple gestations or a history of gestational diabetes mellitus (GDM), and macrosomia. We evaluated fasting durations, GCT results, and demographic features. A significant positive correlation was found between fasting duration and 50 g GCT values (r=0.122; p=0.006), and the best cut-off value was found to be 6.5 h, with 85.85% sensitivity and 38.61% specificity (relative risk, 2.73; 95% CI, 1.893-3.936; p<0.0001). Further, we divided the patients into two groups: study (fasting, <6.5 h; n=146) and control (fasting,>6.5 h; n=362) groups. Notably, the mean glucose levels, number of patients with GCT>140 mg/dl, and rates of unnecessary 100 g loadings were significantly higher in the study group. We found no significant differences between the groups in terms of the fasting plasma glucose levels and GDM prevalence. According to our findings, fasting duration of>6.5 h resulted in 2.7 times more unnecessary 100 g glucose tolerance tests (GTT). We recommend that patients having fasted for>6.5 h receive a one-step 75 g GTT after completing 8-h fasting.


Effectiveness of a Multifaceted Intervention for Potentially Inappropriate Prescribing in Older Patients in Primary Care: A Cluster-Randomized Controlled Trial (OPTI-SCRIPT Study).
Potentially inappropriate prescribing (PIP) is common in older people and can result in increased morbidity, adverse drug events, and hospitalizations. The OPTI-SCRIPT study (Optimizing Prescribing for Older People in Primary Care, a cluster-randomized controlled trial) tested the effectiveness of a multifaceted intervention for reducing PIP in primary care. We conducted a cluster-randomized controlled trial among 21 general practitioner practices and 196 patients with PIP. Intervention participants received a complex, multifaceted intervention incorporating academic detailing; review of medicines with web-based pharmaceutical treatment algorithms that provide recommended alternative-treatment options; and tailored patient information leaflets. Control practices delivered usual care and received simple, patient-level PIP feedback. Primary outcomes were the proportion of patients with PIP and the mean number of potentially inappropriate prescriptions. We performed intention-to-treat analysis using random-effects regression. All 21 practices and 190 patients were followed. At intervention completion, patients in the intervention group had significantly lower odds of having PIP than patients in the control group (adjusted odds ratio = 0.32; 95% CI, 0.15-0.70; P = .02). The mean number of PIP drugs in the intervention group was 0.70, compared with 1.18 in the control group (P = .02). The intervention group was almost one-third less likely than the control group to have PIP drugs at intervention completion, but this difference was not significant (incidence rate ratio = 0.71; 95% CI, 0.50-1.02; P = .49). The intervention was effective in reducing proton pump inhibitor prescribing (adjusted odds ratio = 0.30; 95% CI, 0.14-0.68; P = .04). The OPTI-SCRIPT intervention incorporating academic detailing with a pharmacist, and a review of medicines with web-based pharmaceutical treatment algorithms, was effective in reducing PIP, particularly in modifying prescribing of proton pump inhibitors, the most commonly occurring PIP drugs nationally.


Unimpeded permeation of water through helium-leak-tight graphene-based membranes.
Permeation through nanometer pores is important in the design of materials for filtration and separation techniques and because of unusual fundamental behavior arising at the molecular scale. We found that submicrometer-thick membranes made from graphene oxide can be completely impermeable to liquids, vapors, and gases, including helium, but these membranes allow unimpeded permeation of water (H(2)O permeates through the membranes at least 10(10) times faster than He). We attribute these seemingly incompatible observations to a low-friction flow of a monolayer of water through two-dimensional capillaries formed by closely spaced graphene sheets. Diffusion of other molecules is blocked by reversible narrowing of the capillaries in low humidity and/or by their clogging with water.


The social dilemma of autonomous vehicles.
Autonomous vehicles (AVs) should reduce traffic accidents, but they will sometimes have to choose between two evils, such as running over pedestrians or sacrificing themselves and their passenger to save the pedestrians. Defining the algorithms that will help AVs make these moral decisions is a formidable challenge. We found that participants in six Amazon Mechanical Turk studies approved of utilitarian AVs (that is, AVs that sacrifice their passengers for the greater good) and would like others to buy them, but they would themselves prefer to ride in AVs that protect their passengers at all costs. The study participants disapprove of enforcing utilitarian regulations for AVs and would be less willing to buy such an AV. Accordingly, regulating for utilitarian algorithms may paradoxically increase casualties by postponing the adoption of a safer technology.


Communicating alcohol narratives: creating a healthier relationship with alcohol.
Alcohol, like mental health, is a neglected topic in public health discussions. However, it should be defined as a priority public health area because the evidence available to support this is very persuasive. Although only half the world's population drinks alcohol, it is the world's third leading cause of ill health and premature death, after low birth weight and unsafe sex, and the world's greatest cause of ill health and premature death among individuals between 25 and 59 years of age. This article aims to outline current global experiences with alcohol policies and suggests how to communicate better evidence-based policy responses to alcohol-related harm using narratives. The text summarizes 6 actions to provide incentives that would favor a healthier relationship with alcohol in contemporary society. Actions include price and availability changes, marketing regulations, changes in the format of drinking places and on the product itself, and actions designed to nudge people at the time of their purchasing decisions. Communicating alcohol narratives to policymakers more successfully will likely require a discourse emphasizing the reduction of heavy drinking occasions and the protection of others from someone else's problematic drinking.


Olprinone, a phosphodiesterase III inhibitor, reduces gut mucosal injury and portal endotoxin level during acute hypoxia in rabbits.
Preservation of gut integrity has become a therapeutic goal to obviate bacterial translocation in the critically ill. The authors examined whether olprinone, a phosphodiesterase III inhibitor, protected functional and structural integrity of gut mucosa against acute progressive hypoxia. Thirty-two animals were randomly allocated to a control group (n = 12), a low-dose group (0.2 microg x kg-1 x min-1 olprinone; n = 10), or a high-dose group (0.6 microg x kg-1 x min-1 olprinone; n = 10) after preparatory surgery. Ascending aortic and portal blood flow, intramural pH of the ileum, and portal endotoxin levels were measured at normoxia and through three stages of progressive hypoxia (fraction of inspired oxygen = 0.17, 0.13, and 0.10). At normoxia, ascending aortic flow in the high-dose group was approximately 20% higher than in the control and low-dose groups. During progressive hypoxia, both ascending aortic and portal flow in the control group were depressed, whereas olprinone infusion attenuated such alterations and redistributed blood to the splanchnic area in a dose-dependent manner. On the contrary, the reduction of intramural pH of the ileum and the elevation of portal endotoxin levels observed in the control group were significantly minimized in both the low- and high-dose groups to a similar extent during acute hypoxia. Histopathologic alterations of gut mucosa observed in the control group were minimized by olprinone infusion dose-independently, accompanied by reduction of mortality rate of the animals. Olprinone slows progression of intestinal mucosal acidosis and gut barrier dysfunction, concurrently with preservation of microscopic structures, through both flow-dependent and -independent mechanisms under acute hypoxia. Such properties of olprinone may serve to protect the host under insult.


Methylated DNA immunoprecipitation (MeDIP) from low amounts of cells.
Methylated DNA immunoprecipitation (MeDIP) is an immunocapturing approach for unbiased enrichment of DNA that is methylated on cytosines. The principle is that genomic DNA is randomly sheared by sonication and immunoprecipitated with an antibody that specifically recognizes 5-methylcytidine (5mC), which can be combined with PCR or high-throughput analysis (microarrays, deep sequencing). The MeDIP technique has been originally used to generate DNA methylation profiles on a genome scale in mammals and plants. Here we provide an optimized version of the MeDIP protocol suitable for low amounts of DNA, which can be used to study DNA methylation in cellular populations available in small quantities.


Neurophysiological correlates of bradykinesia in Parkinson's disease.
Many neurophysiological abnormalities have been described in the primary motor cortex of patients with Parkinson's disease. However, it is unclear whether there is any relationship between them and bradykinesia, one of the cardinal motor features of the condition. In the present study we aimed to investigate whether objective measures of bradykinesia in Parkinson's disease have any relationship with neurophysiological measures in primary motor cortex as assessed by means of transcranial magnetic stimulation techniques. Twenty-two patients with Parkinson's disease and 18 healthy subjects were enrolled. Objective measurements of repetitive finger tapping (amplitude, speed and decrement) were obtained using a motion analysis system. The excitability of primary motor cortex was assessed by recording the input/output curve of the motor-evoked potentials and using a conditioning-test paradigm for the assessment of short-interval intracortical inhibition and facilitation. Plasticity-like mechanisms in primary motor cortex were indexed according to the amplitude changes in motor-evoked potentials after the paired associative stimulation protocol. Patients were assessed in two sessions, i.e. OFF and ON medication. A canonical correlation analysis was used to test for relationships between the kinematic and neurophysiological variables. Patients with Parkinson's disease tapped more slowly and with smaller amplitude than normal, and displayed decrement as tapping progressed. They also had steeper input/output curves, reduced short-interval intracortical inhibition and a reduced response to the paired associative stimulation protocol. Within the patient group, bradykinesia features correlated with the slope of the input/output curve and the after-effects of the paired associative stimulation protocol. Although dopaminergic therapy improved movement kinematics as well as neurophysiological measures, there was no relationship between them. In conclusion, neurophysiological changes in primary motor cortex relate to bradykinesia in patients with Parkinson's disease, although other mechanisms sensitive to dopamine levels must also play a role.


Morphological rational operator for contrast enhancement.
Contrast enhancement is an important task in image processing that is commonly used as a preprocessing step to improve the images for other tasks such as segmentation. However, some methods for contrast improvement that work well in low-contrast regions affect good contrast regions as well. This occurs due to the fact that some elements may vanish. A method focused on images with different luminance conditions is introduced in the present work. The proposed method is based on morphological transformations by reconstruction and rational operations, which, altogether, allow a more accurate contrast enhancement resulting in regions that are in harmony with their environment. Furthermore, due to the properties of these morphological transformations, the creation of new elements on the image is avoided. The processing is carried out on luminance values in the u'v'Y color space, which avoids the creation of new colors. As a result of the previous considerations, the proposed method keeps the natural color appearance of the image.


Laparoscopic donor nephrectomy versus open donor nephrectomy: recipient's perspective.
Effects of laparoscopic donor nephrectomy (LDN) on graft function, especially early post-transplant, have been controversial. To assess and compare early and late graft function in kidneys procured by open and laparoscopic methods, a retrospective observational study was carried out on 37 recipients-donors who underwent LDN after introduction of this technique in February 2007 at our center, a tertiary care nephrology referral center. Demographic, immunological and intraoperative variables as well as immunosuppressive protocols and number of human leukocyte antigen (HLA) mismatches were noted. Early graft function was assessed by serum creatinine on Days two, five, seven, 14 and 28 and at the time of discharge. Serum creatinine values at three months and at one year post-transplant were considered as the surrogates of late graft function. Data obtained were compared with the data from 33 randomly selected kidney transplants performed after January 2000 by the same surgical team, in whom open donor nephrectomy was used. Pearson's chi square test, Student's t test and Mann-Whitney U test were used for statistical analysis. Early graft function (serum creatinine on Day five 2.15 mg/dL vs 1.49 mg/dL, P = 0.027) was poorer in the LDN group. Late graft function as assessed by serum creatinine at three months (1.45 mg/dL vs 1.31 mg/dL, P = 0.335) and one year (1.56 mg/dL vs 1.34 mg/dL, P = 0.275) was equivalent in the two groups. Episodes of early acute graft dysfunction due to acute tubular necrosis were significantly higher in the LDN group (37.8% vs 12.1%, Z score 2.457, P = 0.014). Warm ischemia time was significantly prolonged in the LDN group (255 s vs 132.5 s, P = 0.002). LDN is associated with slower recovery of graft function and higher incidence of early acute graft dysfunction due to acute tubular necrosis. Late graft function at one year is however comparable.


Nanoelectronic three-dimensional (3D) nanotip sensing array for real-time, sensitive, label-free sequence specific detection of nucleic acids.
The improvements in our ability to sequence and genotype DNA have opened up numerous avenues in the understanding of human biology and medicine with various applications, especially in medical diagnostics. But the realization of a label free, real time, high-throughput and low cost biosensing platforms to detect molecular interactions with a high level of sensitivity has been yet stunted due to two factors: one, slow binding kinetics caused by the lack of probe molecules on the sensors and two, limited mass transport due to the planar structure (two-dimensional) of the current biosensors. Here we present a novel three-dimensional (3D), highly sensitive, real-time, inexpensive and label-free nanotip array as a rapid and direct platform to sequence-specific DNA screening. Our nanotip sensors are designed to have a nano sized thin film as their sensing area (~ 20 nm), sandwiched between two sensing electrodes. The tip is then conjugated to a DNA oligonucleotide complementary to the sequence of interest, which is electrochemically detected in real-time via impedance changes upon the formation of a double-stranded helix at the sensor interface. This 3D configuration is specifically designed to improve the biomolecular hit rate and the detection speed. We demonstrate that our nanotip array effectively detects oligonucleotides in a sequence-specific and highly sensitive manner, yielding concentration-dependent impedance change measurements with a target concentration as low as 10 pM and discrimination against even a single mismatch. Notably, our nanotip sensors achieve this accurate, sensitive detection without relying on signal indicators or enhancing molecules like fluorophores. It can also easily be scaled for highly multiplxed detection with up to 5000 sensors/square centimeter, and integrated into microfluidic devices. The versatile, rapid, and sensitive performance of the nanotip array makes it an excellent candidate for point-of-care diagnostics, and high-throughput DNA analysis applications.


Susceptibility of the Stem Pull Area of Mechanically Harvested Apples to Blue Mold Decay and Its Control with a Biocontrol Agent.
A new harvester, which uses a rapid displacement actuator on the main scaffolds to remove apples from trees with narrow-inclined trellises, has shown good potential. With this technique, stem loss (stempulls) during harvest ranges from 20 to 57%, depending on the cultivar. This can create a potential point of entry for pathogens. We evaluated the susceptibility of the stem cavity area, with and without stems, to blue mold decay (Penicillium expansum) on three cultivars of mechanically harvested apples, and tested the effectiveness of the antagonist Pseudomonas syringae (used in BioSave 110) in controlling decay. Fruit with stempulls were more susceptible to blue mold decay than fruit with stems. On fruit with stempulls inoculated with P. expansum and stored for 2 months at 1°C, decay incidence was 0% on 'Pink Lady', 8.3% on 'Ace Spur Delicious', and 41% on 'Empire'. On fruit with stems, there was no decay on all three cultivars. P. syringae reduced decay on 'Empire' with stempulls to 3.3%, and no decay occurred on the other two cultivars. Similar trends were observed on fruit stored at 22°C for 14 days, but the incidence of decay was higher, and only 'Pink Lady' had no decay on the antagonist-treated fruit. Although mechanical harvesting can predispose the stem cavity to decay in some cultivars, this problem can be alleviated using biological control without resorting to the use of synthetic pesticides.


A reverse shoulder arthroplasty with increased offset for the treatment of cuff-deficient shoulders with glenohumeral arthritis.
Inherent disadvantages of reverse shoulder arthroplasty designs based on the Grammont concept have raised a renewed interest in less-medialised designs and techniques. The aim of this study was to evaluate the outcome of reverse shoulder arthroplasty (RSA) with the fully-constrained, less-medialised, Bayley-Walker prosthesis performed for the treatment of rotator-cuff-deficient shoulders with glenohumeral arthritis. A total of 97 arthroplasties in 92 patients (53 women and 44 men, mean age 67 years (standard deviation (sd) 10, (49 to 85)) were retrospectively reviewed at a mean follow-up of 50 months ((sd 25) (24 to 96)). The mean Oxford shoulder score and subjective shoulder value improved from 47 (sd 9) and 24 points (sd 18) respectively before surgery to 28 (sd 11) and 61 (sd 24) points after surgery (p < 0.001). The mean pain at rest decreased from 5.3 (sd 2.8) to 1.5 (sd 2.3) (p < 0.001). The mean active forward elevation and external rotation increased from 42(°)(sd 30) and 9(°) (sd 15) respectively pre-operatively to 78(°) (sd 39) and 24(°) (sd 17) post-operatively (p < 0.001). A total of 20 patients required further surgery for complications; 13 required revision of components. No patient developed scapular notching. The Bayley-Walker prosthesis provides reliable pain relief and reasonable functional improvement for patients with symptomatic cuff-deficient shoulders. Compared with other designs of RSA, it offers a modest improvement in forward elevation, but restores external rotation to some extent and prevents scapular notching. A longer follow-up is required to assess the survival of the prosthesis and the clinical performance over time.


Daily stressors facilitate giving and receiving of emotional support in adulthood.
The aims of the present study were to examine whether daily stressors are associated with engagement in emotional support and whether these associations differ by gender. Analyses were conducted using Wave 2 of Midlife in the United States data and its subproject National Study of Daily Experiences. The sample consisted of adults aged 33 to 84 (N = 1,622). Using multinomial multilevel analysis, we looked at the associations between lagged and concurrent daily stressors with engagement in emotional support. For concurrent associations, people who experienced stressors were more likely to both give and receive, solely give, and solely receive emotional support compared with those who did not have any stressors. Women were more likely to engage in both giving and receiving of emotional support compared with men when they experienced stressors during the same day. In terms of the lagged associations, both men and women who experienced stressors during the previous day were more likely to both give and receive emotional support the next day compared with those who did not experience any stressors during the previous day. These results suggest that experiencing daily stressors facilitates giving and receiving of emotional support at daily level in adulthood.


The centrosome-specific phosphorylation of Cnn by Polo/Plk1 drives Cnn scaffold assembly and centrosome maturation.
Centrosomes are important cell organizers. They consist of a pair of centrioles surrounded by pericentriolar material (PCM) that expands dramatically during mitosis-a process termed centrosome maturation. How centrosomes mature remains mysterious. Here, we identify a domain in Drosophila Cnn that appears to be phosphorylated by Polo/Plk1 specifically at centrosomes during mitosis. The phosphorylation promotes the assembly of a Cnn scaffold around the centrioles that is in constant flux, with Cnn molecules recruited continuously around the centrioles as the scaffold spreads slowly outward. Mutations that block Cnn phosphorylation strongly inhibit scaffold assembly and centrosome maturation, whereas phosphomimicking mutations allow Cnn to multimerize in vitro and to spontaneously form cytoplasmic scaffolds in vivo that organize microtubules independently of centrosomes. We conclude that Polo/Plk1 initiates the phosphorylation-dependent assembly of a Cnn scaffold around centrioles that is essential for efficient centrosome maturation in flies.


Temperature scanning FTIR analysis of hydrogen bonding states of various saccharides in amorphous matrixes below and above their glass transition temperatures.
Temperature scanning Fourier transform infrared, TS-FTIR, spectroscopy of various amorphous sugar matrixes was conducted to investigate the relationship between the glass transition temperature, T(g), of an amorphous sugar matrix and the nature of the hydrogen bonds in the matrix. An amorphous sugar matrix was prepared by air-drying an aqueous solution of sugar, and the degree of formation of hydrogen bonds in the matrix was evaluated at different temperatures using the peak positions of the IR band corresponding to the O-H stretching vibration at around 3400 cm(-1). The T(g) value increased with increasing peak position of the O-H stretching vibration at T(g) and were correlated reasonably well with the magnitude of the peak shift by the temperature increase (from 25 degrees C) to the T(g) value. This demonstrates that the amorphous sugar matrix, in which the segments are fixed by fewer hydrogen bonds, has a higher thermal resistance. The glycosidic linkage largely contributes to the restriction of the segments, pyranose ring, rather than a hydrogen bond. As the degree of polymerization of pyranose rings increases, the degree of hydrogen bond formation needed to hold the matrix in a fixed position decreases. However, the magnitude of the restriction of pyranose rings by a glycosidic linkage changes depending on the type: the restrictions imposed by alpha-1,1 and -1,6 glycosidic linkages are the tightest and most flexible of all of the types of glycosidic linkages, respectively.


The efficacy of tourniquets as a first-aid measure for Russell's viper bites in Burma.
The efficacy of the tourniquets commonly used by Russell's viper bite victims in retarding venom movement from the bite was studied in 37 cases by measuring venom antigen levels by enzyme-linked immunosorbent assay in venous samples taken proximal and distal to the tourniquets and also before and after release of tourniquets. In most cases, the tourniquet did not prevent proximal spread of venom. In 8/37 cases, however, venom antigen assays suggested but did not prove that venom absorption was being delayed by the tourniquet.