Emerging salt marshes as a source of Trichoderma arenarium sp. nov. and other fungal bioeffectors for biosaline agriculture.
Sustainable agriculture requires effective and safe biofertilizers and biofungicides with low environmental impact. Natural ecosystems that closely resemble the conditions of biosaline agriculture may present a reservoir for fungal strains that can be used as novel bioeffectors. We isolated a library of fungi from the rhizosphere of three natural halotolerant plants grown in the emerging tidal salt marshes on the south-east coast of China. DNA barcoding of 116 isolates based on the rRNA ITS1 and 2 and other markers (tef1 or rpb2) revealed 38 fungal species, including plant pathogenic (41%), saprotrophic (24%) and mycoparasitic (28%) taxa. The mycoparasitic fungi were mainly species from the hypocrealean genus Trichoderma, including at least four novel phylotypes. Two of them, representing the taxa Trichoderma arenarium sp. nov. (described here) and T. asperelloides, showed antagonistic activity against five phytopathogenic fungi, and significant growth promotion on tomato seedlings under the conditions of saline agriculture. Trichoderma spp. of salt marshes play the role of natural biological control in young soil ecosystems with a putatively premature microbiome. The saline soil microbiome is a rich source of halotolerant bioeffectors that can be used in biosaline agriculture.


VIGILANCE: THE IMPORTANCE OF THE ELICITED OBSERVING RATE.
Observing may be elicited by regularly repeated events that occasionally become signals. Such events were presented at rates of either 5 per minute or 30 per minute, and signals averaged 15 per hour during an 80-minute vigil. Observers missed about 10 percent of the signals with the low event rate and about 70 percent of the signals with the high event rate. The experiment supports a decisiontheory approach to observing behavior.


Anxiety sensitivity: the role of conscious awareness and selective attentional bias to physical threat.
Selective attentional biases were examined amongst individuals varying in levels of physical anxiety sensitivity. The dot-probe paradigm was used to examine attention towards anxiety symptomatology, social threat and positive words. Stimuli were presented above (unmasked) and below (masked) the level of conscious awareness. High physical anxiety sensitivity was associated with attentional vigilance for anxiety symptomatology words in both unmasked and masked conditions. For positive words, however, those high in anxiety sensitivity were found to avoid such stimuli when they were masked, whereas they exhibited a relative vigilance when unmasked. If the differences between awareness conditions are reliable, then the impact of the automatic vigilance for threat might be modified by conscious attempts to direct attention towards other types of stimuli.


The Effects of a 2-Year Middle School Physical Education Program on Physical Activity and Its Determinants.
Purpose: This study examines the effects of the middle school SPARK physical education (PE) curriculum on predisposing, enabling, and reinforcing factors for physical activity (PA) as well as self-reported PA in a predominantly low-income, Latinx student population in Los Angeles, CA. Methods: Data were collected from 3763 students of seventh and eighth grades at 2 time points at the 16 middle schools enrolled in the study. Hierarchical logistic regression models were used to assess intervention effects on PA attitudes, PE enjoyment, FitnessGram passing, daily PA, and muscle-strengthening PA, controlling for demographic variables. Results: Although there was no detectable intervention effect on increasing the number of students exercising 60 minutes per day, there was a negative intervention effect detected for muscle-strengthening exercises. A significant positive intervention effect was detected for both PE enjoyment and FitnessGram passing. Deeper analysis of these findings revealed that the positive effect on PE enjoyment occurred only among male students. Conclusion: The SPARK curriculum had mixed effects on students' PA behavior as well as predisposing, enabling, and reinforcing factors for PA. Incorporating student perspectives into the evaluation of intervention efforts to promote PA can facilitate a better understanding of the ways in which these efforts influence PA behaviors and its determinants.


The moderating effect of alcohol use on protective and risky sex behaviors among college students in the Southeast United States.
Objective: College students are a high-risk population for new human immunodeficiency viruses (HIV) diagnoses. Although condom use self-efficacy and HIV knowledge can protect against risky sexual behavior (RSB), these same protective factors have been shown to exacerbate RSB. The influence of alcohol use can further complicate these protective factors to influence RSB. Participants: 689 African American/Black and non-Hispanic White college students attending a public university in the Southeast United States. Method: This study sought to examine the relations between condom use self-efficacy and HIV knowledge with RSB and the moderating effect of alcohol use. Results: Findings showed positive associations between RSB and HIV knowledge and alcohol use. Unexpectedly, low frequency drinkers with high condom use self-efficacy were at increased risk for RSB compared to high frequency drinking counterparts. Conclusions: Findings point to the need to target prevention services for low-risk drinkers in college settings.


Contrast overconstancy.
In foveal vision there is a tendency toward contrast constancy above threshold. Contrast sensitivity varies greatly across different spatial and temporal frequencies and at different luminances, but perception of contrast above threshold varies much less (in logarithmic terms). In parafoveal vision (1-2 degrees eccentricity) the contrast of high-spatial-frequency gratings appeared higher than a 3-cycle per degree (c/deg) comparison grating, even though their threshold sensitivity was lower. I call this overconstancy. For two experienced observers, the effect was greatest at high spatial frequencies (12-18 c/deg) and at contrasts close to threshold. A simple model of contrast coding was able to fit all the data accurately: R' = [(C-T)/(Cnorm-T)]m, where R' is the final response, C is contrast, T is threshold contrast, and Cnorm and m are parameters. Cnorm represents the contrast at which different response functions converge to a common value (R' = 1), while m is the slope of the upper branch of a given function on logarithmic axes. This model, incorporating threshold subtraction, nonlinear compression, and response normalization, was derived from research on contrast matching, magnitude estimation, and discrimination. On this model overconstancy results when C less than Cnorm, and the contrast response for the test condition is more compressive (lower m) than in the comparison condition. In the parafovea m decreased linearly with increasing spatial frequency for both subjects, but Cnorm was approximately constant at 40-50%.


Hybrid long-range surface plasmon-polariton modes with tight field confinement guided by asymmetrical waveguides.
A finite width dielectric-metal-dielectric (DMD) waveguide placed on a substrate is numerically investigated near the telecom wavelength lambda = 1550 nm by the finite element method. With proper waveguide sizes, the asymmetrical DMD waveguide can support hybrid long-range surface plasmon-polariton modes which have tight field confinement (approximately 700 nm) and long propagation lengths (L> 300 microm) simultaneously. Compact plasmonic waveguide-ring resonators (WRRs) based on such asymmetrical DMD waveguide show high quality factors compared with dielectric-loaded surface plasmon-polariton, channel plasmon polariton, plasmonic whispering-gallery microcavity, and pure dielectric waveguide cases.


Treatment of schwannomas with an oncolytic recombinant herpes simplex virus in murine models of neurofibromatosis type 2.
Gene therapy for schwannomas was evaluated in two mouse models of neurofibromatosis type 2 (NF2): (1) a transgenic model in which mice express a dominant mutant form of merlin and spontaneously develop schwannomas, and (2) a xenograft model in which human schwannoma tissue is implanted subcutaneously into immune- compromised mice. In both models, schwannoma volumes were monitored by magnetic resonance imaging (MRI) and showed strong gadolinium enhancement typical of these tumors in humans. Both types of tumor were positive for the Schwann cell marker S100, and highly infectable with herpes simplex virus (HSV) vectors. Schwannomas were injected with an oncolytic HSV-1 recombinant virus vector, G47Delta, which has deletions in genes for ribonucleotide reductase (ICP6), gamma34.5, and ICP47. In the NF2 transgenic model, schwannomas were reduced by more than half their original size by 10 days after infection. In the case of subcutaneous schwannoma xenografts, reduction in size after infection occurred more slowly, with a mean reduction of onethird by 42 days after treatment. Schwannomas injected with control vehicles continued to grow slowly over time in both schwannoma models. These studies demonstrate the ability of an oncolytic recombinant HSV vector to reduce the volume of schwannoma tumors in NF2 tumor models in mice and extend the possible therapeutic applications of oncolytic vectors for benign tumors to reduce mass while minimizing nerve damage.


Genome-wide mapping of promoter-anchored interactions with close to single-enhancer resolution.
Although the locations of promoters and enhancers have been identified in several cell types, we still have limited information on their connectivity. We developed HiCap, which combines a 4-cutter restriction enzyme Hi-C with sequence capture of promoter regions. Applying the method to mouse embryonic stem cells, we identified promoter-anchored interactions involving 15,905 promoters and 71,984 distal regions. The distal regions were enriched for enhancer marks and transcription, and had a mean fragment size of only 699 bp--close to single-enhancer resolution. High-resolution maps of promoter-anchored interactions with HiCap will be important for detailed characterizations of chromatin interaction landscapes.


Trends in clinical reproductive medicine research: 10 years of growth.
To study the most important metrics of publication in the field of reproductive medicine over the decade 2003-2012 to aid in discerning the clinical, social, and epidemiologic implications of this relatively new but rapidly emerging area in medical sciences. Bibliometric analysis of most-cited publications from Web of Science databases. Not applicable. None. None. Most productive and frequently cited investigators, institutions, and countries and specific areas of research, scientific collaborations, and comparison of the growth of reproductive medicine research compared with other areas of medical investigation such as obstetrics and gynecology and related science categories. We found that 90 investigators with more than 1,000 citations had jointly published 4,010 articles. A continued rise in the impact factor of reproductive medicine journals was seen. The number of publications in reproductive medicine grew more rapidly compared with other science categories. Presently 22% of highly cited articles in reproductive medicine research are published in journals belonging to science categories outside reproductive medicine. The most-cited study groups are situated in the Netherlands, Belgium, Spain, the United States, and the United Kingdom, and collaborative studies have been increasing. Reproductive medicine research and subsequent clinical development have attained scientific growth and maturity. High-quality research is increasingly being published in high-impact journals. The increase in (inter)national collaborations seems to be key to the field's success.


Isoflavone daidzein regulates immune responses in the B6C3F1 and non-obese diabetic (NOD) mice.
Daidzein (DAZ), a dominant isoflavone in various natural products such as soybeans, has been gaining attention due to the beneficial health effects (e.g., protection against cancer and diabetes) of its metabolites. Our major hypothesis was that dietary exposure to the soy phytoestrogen DAZ could modulate the immune responses toward a protective effect and lead to improved metabolic functions (such as glucose metabolism). In this study, we applied complementary mouse models, the hybrid B6C3F1 and inbred type 1 diabetes prone non-obese diabetic (NOD) mice, to investigate if DAZ exposure modulated the immune responses. The animals were orally administered DAZ at various physiological doses (2-20 mg/kg body weight) during adulthood. DAZ significantly altered the relative organ weights in female B6C3F1 mice and decreased the B cell population (represented by CD3-IgM+), while the T cell populations (represented by CD3+IgM-, CD4+CD8- and CD4-CD8+) were increased. In addition, DAZ dosing produced a decrease in the percentage of late apoptotic thymocytes. However, the activities cytotoxic T cells and natural killer cells were not altered in the B6C3F1 mice. In NOD mice, the blood glucose level and glucose tolerance were not affected by DAZ exposure, but DAZ modulated the antibody production, as shown by increased levels of IgG2b in NOD females and IgG1 in NOD males. Further, DAZ increased CD8+CD25+ splenocytes in NOD females. Taken together, DAZ induced an immunomodulatory effect in both NOD and B6C3F1 mouse strains; however, minimal effects on glucose homeostasis were observed.


Versatile and Resilient Hydrogen-Bonded Host Frameworks.
Low-density molecular host frameworks, whether equipped with persistent molecular-scale pores or virtual pores that are sustainable only when occupied by guest molecules, have emerged as a promising class of materials owing to the ability to tailor the size, geometry, and chemical character of their free space through the versatility of organic synthesis. As such, molecular frameworks are promising candidates for storage, separations of commodity and fine chemicals, heterogeneous catalysis, and optical and electronic materials. Frameworks assembled through hydrogen bonds, though generally not stable toward collapse in the absence of guests, promise significant chemical and structural diversity, with pores that can be tailored for a wide range of guest molecules. The utility of these frameworks, however, depends on the resilience of n-dimensional hydrogen-bonded motifs that serve as reliable building blocks so that the molecular constituents can be manipulated without disruption of the anticipated global solid-state architecture. Though many hydrogen-bonded frameworks have been reported, few exist that are amenable to systematic modification, thus limiting the design of functional materials. This Account reviews discoveries in our laboratory during the past decade related to a series of host frameworks based on guanidinium cations and interchangeable organosulfonate anions, in which the 3-fold symmetry and hydrogen-bonding complementarity of these ions prompt the formation of a two-dimensional (2-D) quasi-hexagonal hydrogen-bonding network that has proven to be remarkably resilient toward the introduction of a wide range of organic pendant groups attached to the sulfonate. Since an earlier report in this journal that focused primarily on organodisulfonate host frameworks with lamellar architectures, this unusually persistent network has afforded an unparalleled range of framework architectures and hundreds of new crystalline materials with predictable solid-state architectures. These range from the surprising discovery of inclusion compounds in organomonosulfonates (GMS), as well as organodisulfonates (GDS), structural isomerism reminiscent of microstructures observed in soft matter, a retrosynthetic approach to the synthesis of polar crystals, separation of molecular isomers, storage of unstable molecules, formation of a zeolite-like hydrogen-bonded framework, and postsynthetic pathways to inclusion compounds through reversible guest swapping in flexible GS frameworks. Collectively, the examples described in this Account illustrate the potential for hydrogen-bonded frameworks in the design of molecular materials, the prediction of solid-state architecture from simple empirical parameters, and the importance of design principles based on robust high dimensional networks. These and other emerging hydrogen-bonded frameworks promise new advanced materials that capitalize fully on the ability of materials chemists to manipulate solid-state structure through molecular design.


Contribution of the Global Regulator Gene gacA to Persistence and Dissemination of Pseudomonas fluorescens Biocontrol Strain CHA0 Introduced into Soil Microcosms.
Structural and regulatory genes involved in the synthesis of antimicrobial metabolites are essential for the biocontrol activity of fluorescent pseudomonads and, in principle, amenable to genetic engineering for strain improvement. An eventual large-scale release of such bacteria raises the question of whether such genes also contribute to the persistence and dissemination of the bacteria in soil ecosystems. Pseudomonas fluorescens wild-type strain CHA0 protects plants against a variety of fungal diseases and produces several antimicrobial metabolites. The regulatory gene gacA globally controls antibiotic production and is crucial for disease suppression in CHA0. This gene also regulates the production of extracellular protease and phospholipase. The contribution of gacA to survival and vertical translocation of CHA0 in soil microcosms of increasing complexity was studied in coinoculation experiments with the wild type and a gacA mutant which lacks antibiotics and some exoenzymes. Both strains were marked with spontaneous resistance to rifampin. In a closed system with sterile soil, strain CHA0 and the gacA mutant multiplied for several weeks, whereas these strains declined exponentially in nonsterile soil of different Swiss origins. The gacA mutant was less persistent in nonrhizosphere raw soil than was the wild type, but no competitive disadvantage when colonizing the rhizosphere and roots of wheat was found in the particular soil type and during the period studied. Vertical translocation was assessed after strains had been applied to undisturbed, long (60-cm) or short (20-cm) soil columns, both planted with wheat. A smaller number of cells of the gacA mutant than of the wild type were detected in the percolated water and in different depths of the soil column. Single-strain inoculation gave similar results in all microcosms tested. We conclude that mutation in a single regulatory gene involved in antibiotic and exoenzyme synthesis can affect the survival of P. fluorescens more profoundly in unplanted soil than in the rhizosphere.


Mixed-Methods Survey of Healthcare Workers' Experiences of Personal Protective Equipment during the COVID-19 Pandemic in Aotearoa/New Zealand.
There have been widespread issues with the supply and distribution of personal protective equipment (PPE) globally throughout the COVID-19 pandemic, raising considerable public concern. We aimed to understand the experiences of healthcare workers using PPE during the first COVID-19 surge (February-June 2020) in Aotearoa/New Zealand (NZ). This study consisted of an online, voluntary, and anonymous survey, distributed nationwide via multimodal recruitment. Reported domains included PPE supply, sourcing and procurement, fit-testing and fit-checking, perceived protection, trust and confidence in the workplace, mental health, and the likelihood of remaining in the profession. Differences according to demographic variables (e.g., profession and workplace) were examined. We undertook a descriptive analysis of responses to open-text questions to provide explanation and context to the quantitative data. The survey was completed in October-November 2020 by 1411 healthcare workers. Reported PPE shortages were common (26.8%) among healthcare workers during surge one in NZ. This led to respondents personally saving both new (31.2%) and used (25.2%) PPE, purchasing their own PPE (28.2%), and engaging in extended wear practices. More respondents in the public system reported being told not to wear PPE by their organisation compared with respondents in the private sector. Relatively low numbers of respondents who were required to undertake aerosol-generating procedures reported being fit-tested annually (3.8%), a legal requirement in NZ. Healthcare workers in NZ reported a concerning level of unsafe PPE practices during surge one, as well as a high prevalence of reported mental health concerns. As NZ and other countries transition from COVID-19 elimination to suppression strategies, healthcare worker safety should be paramount, with clear communication regarding PPE use and supply being a key priority.


Patients' rights--why the Australian courts have rejected 'Bolam'.
This point of view compares the issue of informed patient consent primarily as it operates in Australia and the United Kingdom. It affords an overview, also, of the applicable law in the United States and Canada. It particularly focuses on the legal test to be applied to patient consent as established in the Bolam case in the United Kingdom. The case, following its approval by the House of Lords, holds that the negligent standard in patient consent situations is to be determined, in cases of dispute, in accordance with standards as viewed by a proper body of competent medical practitioners. By contrast, the law in the United States is premised on the notion of the fundamental right of patients to determine what should or should not be done with their own bodies. In Australia the Bolam test has been rejected by the High Court of Australia following earlier decisions in the State Supreme Courts. The Australian courts did not accept that the setting of standards by the medical profession was an acceptable way of determining the entitlements of a patient who has suffered harm. The author places this discussion in the context of greater community awareness of medical procedures, the heightened accountability of professionals and the increasing practice of having a substantial patient input into medical decisions. He also suggests that the differing social and professional attitudes to authority and fundamental rights to be found between Australia and the United Kingdom have influenced the outcome of the cases in the higher courts of both countries. He suggests that the Bolam test is an illustration of the tendency of authority in the United Kingdom to believe that 'Nanny know best'.


Vitamin D metabolites and/or analogs: which D for which patient?
Numerous drugs with vitamin D activity are available for clinical use and it may not be easy for the nonspecialist to select the most suitable for the individual patient. In this paper we review the main characteristics of the available drugs and provide evidence about any potential specific clinical indications, with special emphasis on renal patients, in order to facilitate the optimal choice. Natural vitamin D products (i.e. those identical to natural metabolites) are first examined, followed by the most frequently used synthetic molecules (i.e. bioengineered molecules not-existing in nature), which are generally indicated as " analogs". Either cholecalciferol, ergocalciferol or calcifediol can be employed in subjects with normal renal function and in CKD stage 3-5 patients to correct vitamin D deficiency and improve, respectively, age- or growth-related bone disease and secondary hyperparathyroidism. Calcifediol can be considered more rapid and effective. In all cases, especially with increasing doses, the risk of hypercalcemia must be taken into account. Calcitriol, which can be regarded as the active hormonal form of vitamin D, has the most potent hypercalcemic effect in both normal and renal failure patients. In renal patients calcitriol is a potent inhibitor of parathyroid activity, but the risk of hypercalcemia, now regarded as harmful, is evident whenever pharmacologic doses are used. Alfacalcidol, requiring 25-hydroxylation to become the active hormonal form of vitamin D3, is prescribed in normal subjects to treat osteoporosis and in renal patients to cure hyperparathyroidism and renal bone disease. Doxercalciferol, transformed into the active hormonal form of vitamin D2 following 25-hydroxylation, is mostly studied in renal patients in whom it cures secondary hyperparathyroidism, possibly with a lower calcemic effect than calcitriol. Paricalcitol, a vitamin D2 analog not requiring activation, has been specifically developed to suppress PTH in renal patients with a limited calcemic effect. As such it is now regarded as a powerful drug useful to treat even severe cases of secondary hyperparathyroidism. Importantly, reno-protective and cardio-protective effects of this analog have been recently evaluated by means of randomized clinical trials in renal patients with partially positive renal effects and negative cardiac results, thus additional studies are needed for confirmation. 22-oxacalcitriol, a vitamin D3 analog with a limited calcemic effect available in Japan, is mostly used in renal patients affected by secondary hyperparathyroidism. The clinical activity of some vitamin D analogs is such that they can be employed in diseases like cancer and autoimmunity. The clinical activity of some vitamin D analogs is such that they can be employed in diseases like cancer and autoimmunity. In summary, available drugs with vitamin D like activity are not all the same either in terms of pharmacological actions, and side-effects. They have specific characteristics that may be useful to know in order to operate the best choice in the individual patient.


Vacuum Assisted Closure- utilization as home based therapy in the management of complex diabetic extremity wounds.
Vacuum assisted closure is a reported technique to manage complex wounds. We have utilized this technique by using simple locally available material in the management of our patients on outpatient basis. The objective of this study is to present our experience. This study was conducted from June 2011 to June 2013 at Dow University Hospital and Aga Khan University Hospital, Karachi. There were 38 patients managed with vacuum assisted closure. Mean age was 56±7.8 years. Twenty three patients presented with necrotizing fasciitis and 15 patients with gangrene. Lower limbs were involved in majority of the patients. Debridement or amputations were done. Vacuum dressing was changed twice weekly in outpatient department. Wounds were closed secondarily if possible or covered with split thickness skin graft in another admission. All the wounds were successfully granulated at the end of vacuum therapy. Mean hospital stay was 7.5 days. Vacuum dressing was applied for a mean of 20 days. There was reduction in the size of the wound. Thirteen patients underwent secondary closure of the wound under local anesthesia, 18 patients required coverage with split thickness skin graft and 7 patients healed with secondary intention. Vacuum assisted closure appeared to be an effective method to manage complex diabetic wounds requiring sterile wound environment.


Analysis on preferential free running laser wavelength and performance modeling of Tm³⁺-doped YAP and YLF.
The preferential free running laser wavelength at room temperature for different axes cuts of Tm³⁺-doped YAP and YLF is comparatively analyzed in this paper. The polarized gain spectrum of Tm:YAP and Tm:YLF with different product values of Tm³⁺-doped concentration and crystal length is theoretically calculated under various cavity output mirror transmissions. From the gain spectrum, it straightforwardly determines the preferential free running laser wavelength for a given light polarization. In addition, a rate equation model is further used to model and compare the laser output performance for both the free running and some common artificially selected oscillating wavelengths, including 1.99 and 1.94 μm of Tm:YAP, and 1.89, 1.91, and 1.94 μm of Tm:YLF, respectively. To achieve an expected laser oscillating wavelength with acceptable output performance, our analysis presented here is very beneficial for one to choose the most suitable axis cut of crystal.


Preoperative plasma endoglin levels predict biochemical progression after radical prostatectomy.
Endoglin (CD105) is a transmembrane glycoprotein expressed by human vascular endothelial cells thought to play a pivotal role in endothelial cell proliferation. The aim of this study was to evaluate the association of preoperative plasma endoglin levels with established clinical and pathologic features of prostate cancer and disease progression after radical prostatectomy. Preoperative plasma endoglin levels were measured in 425 patients who underwent radical prostatectomy for clinically localized prostate cancer using a commercially available ELISA assay. Multivariate logistic regression was used to test the association of plasma endoglin levels with biochemical progression after radical prostatectomy. Median follow-up for patients alive at the time of analysis was 36.8 months (interquartile range, 44.1). Of 425 patients, 77 patients (18.1%) experienced biochemical progression after radical prostatectomy. Preoperative plasma endoglin levels were significantly elevated in patients with higher preoperative total serum prostate-specific antigen (P < 0.001) and adverse pathologic features. Preoperative plasma endoglin was an independent predictor of biochemical progression after surgery after adjusting for the effects of standard preoperative and postoperative features (P < 0.001 and P = 0.026, respectively). Preoperative plasma endoglin levels are associated with established features of advanced prostate cancer. More importantly, higher preoperative plasma endoglin levels are independent predictors of an increased risk of biochemical progression in patients treated with radical prostatectomy and bilateral pelvic lymphadenectomy.


Obese men have elevated plasma levels of estrone sulfate.
The 24 h mean plasma concentrations of estrone sulfate (ES) were measured in 27 healthy obese and nonobese men (BMI: 21.2-89.5). Plasma levels of ES were found to be elevated in obese men, with ES values significantly correlated to the level of obesity (r = 0.60; P less than 0.001). Thus, an increase in plasma ES concentration (from 524 to 1115 pg/ml), compared to the less than 40 percent increases previously found for estrone and estradiol. Because ES is normally present at an approximately tenfold greater concentration than either estrone or estradiol in men, it may serve as a more easily measurable indicator of adipose tissue aromatization of androstenedione.


[Subset analysis of data in the Japanese patients with NSCLC from IDEAL 1 study on gefitinib].
The multinational, multi-institutional clinical Phase II trial of gefitinib monotherapy, IDEAL (IRESSA Dose Evaluation in Advanced Lung Cancer) 1, included Japanese and non-Japanese patients with advanced non-small-cell lung cancer (NSCLC) pretreated with one or more chemotherapy regimens, at least one including platinum. To investigate whether survival is affected by gender or histological type of cancer, a retrospective, exploratory subset analysis was conducted including only Japanese patients from IDEAL 1 (n = 102 in total, 51 each in 250 and 500 mg/day groups). The median survival time of the 102 patients was 12.0 months and the one year survival rate was 50%. The median survival time was 13.8 months for the 250 mg/day group and 11.2 months for the 500 mg/day group and the one-year survival rate was 57% and 45% respectively. Survival was longer in patients with adenocarcinoma than those with other histological types of cancer, and was longer in those with symptom improvement than without. The median survival time in females was longer than that in males. The results suggest that gefitinib could be superior to classical anticancer agents with regard to not only the response rate but also survival time in patients with NSCLC, particularly adenocarcinoma, previously treated with chemotherapy. Further studies are needed to identify factors affecting survival.


Species diversity of and toxin production by Gibberella fujikuroi species complex strains isolated from native prairie grasses in Kansas.
Fusarium species from agricultural crops have been well studied with respect to toxin production and genetic diversity, while similar studies of communities from nonagricultural plants are much more limited. We examined 72 Fusarium isolates from a native North American tallgrass prairie and found that Gibberella intermedia (Fusarium proliferatum), Gibberella moniliformis (Fusarium verticillioides), and Gibberella konza (Fusarium konzum) dominated. Gibberella thapsina (Fusarium thapsinum) and Gibberella subglutinans (Fusarium subglutinans) also were recovered, as were seven isolates that could not be assigned to any previously described species on the basis of either morphological or molecular characters. In general, isolates from the prairie grasses produced the same toxins in quantities similar to those produced by isolates of the same species recovered from agricultural hosts. The G. konza isolates produce little or no fumonisins (up to 120 micro g/g by one strain), and variable but generally low to moderate amounts of beauvericin (4 to 320 micro g/g) and fusaproliferin (50 to 540 micro g/g). Toxicity to Artemia salina larvae within most species was correlated with the concentration of either beauvericin or fusaproliferin produced. Organic isolates from some cultures of G. moniliformis were highly toxic towards A. salina even though they produced little, if any, beauvericin or fusaproliferin. Thus, additional potentially toxigenic compounds may be synthesized by G. moniliformis strains isolated from prairie grasses. The Fusarium community from these grasses appears to contain some species not found in surrounding agricultural communities, including some that probably are undescribed, and could be capable of serving as a reservoir for strains of potential agricultural importance.


Therapist's practice patterns for subsequent fall/osteoporotic fracture prevention for patients with a distal radius fracture.
Cross-sectional survey. Multifactorial risk factor screening and treatment is needed for subsequent falls/osteoporotic fractures prevention (SFOFP), given the elevated risk among patients with distal radius fracture (DRF). The primary objective was to describe hand therapists' knowledge and clinical practice patterns for assessment, treatment, referral, and education with respect to SFOFP for patients with DRF older than 45 years. Secondary objective was to explore therapist's preferences in content and delivery of knowledge translation tools that would support implementation of SFOFP. A cross-sectional multinational (Canada, the United States, and India) survey was conducted among 272 therapists from August to October 2014. Completed surveys were analyzed descriptively. Surveys were completed by 157 therapists. Most respondents were from the United States (59%), certified hand therapists (54%), and females (87%). Although 65%-90% believed that they had knowledge about SFOFP assessment, treatment, and referral options, 55% did not include it in their routine practice for patients with DRF. Most assessed medication history (82%) and never used a Fracture Risk Assessment Tool (90%) or lower extremity muscle strength testing (54%) to identify those at risk of secondary fractures. With respect to treatment, approximately 33% always used upper extremity muscle strengthening exercises. Most reported rarely (sometimes to never) using balance (79%), lower extremity muscle strengthening (85%), bone strengthening (54%), or community-based physical activity (72%) programs. Similarly, when surveyed about patient education, therapists rarely (sometimes to never) advised patients about web-based resources (94%), regular vision testing (92%), diet for good bone health (87%), bone density evaluation (86%), footwear correction (73%), and hazard identification (67%). Most hand therapists were interested to receive more information on SFOFP for patients with DRF. Nearly one-half preferred to have Web sites for patients, and two-fifth were in favor of pamphlets for patients. Current practice patterns reveal care gaps and limited implementation with respect to SFOFP for patients with DRF. Future research should focus on web-based educational/knowledge translation strategies to promote implementation of multifactorial fall risk screening and hand therapist's engagement in SFOFP for patients with DRF.


Gender differences in childhood trauma in first episode psychosis: Association with symptom severity over two years.
Early life adversity is associated with increased risk for psychosis onset and poor clinical outcome. Male compared to female patients often show a more severe course of psychotic illness. The aim of the present study was to investigate gender differences in childhood trauma (CT) and their impact on symptomatic and functional outcome following psychosis onset. The study included 210 patients (144 men, 66 women) diagnosed with a first-episode of psychosis (FEP). Early adversity was assessed with the Childhood Trauma Questionnaire. Psychotic symptoms and general functioning were rated with the Brief Psychiatric Rating Scale and Global Assessment of Functioning scale at baseline, 12 and 24 months of follow-up in an established early intervention service. Male patients reported higher rates of physical or emotional neglect, whereas female patients indicated significantly higher rates of emotional abuse. More severe CT was related to higher levels of depression in women and to negative symptoms in men. Distinct CT effects were observed on positive and negative symptom severity and global functioning in male patients at 24 months. Emotional abuse was the strongest predictor of depression in both genders. In male patients only, emotional abuse predicted positive symptom severity and impaired global functioning, whereas emotional neglect predicted more severe negative symptoms. Our results suggest differences in CT experiences in male and female FEP patients, with a more pronounced impact on longer-term outcome in male patients. The findings support the notion that sex differences in stress vulnerability account for the relatively poor illness course in male psychosis patients.


Cerebral Responses to Stationary Emotional Stimuli Measured by fMRI in Women with Persistent Postural-Perceptual Dizziness.
Introduction Persistent postural-perceptual dizziness (PPPD) is a functional vestibular disorder characterized by chronic dizziness, unsteadiness, and hypersensitivity to motion. Preexisting anxiety disorders and neurotic personality traits confer vulnerability to PPPD. High anxiety during acute vertigo or dizziness incites it. A functional magnetic resonance imaging (fMRI) study of chronic subjective dizziness found unexpectedly hypoactive responses to vestibular stimulation in cortical regions that integrate threat assessment and spatial perception. Objective This fMRI study used non-moving, but emotionally charged visual stimuli to investigate the brain's activity of PPPD patients and control subjects. Methods The participants included 16 women with PPPD and 16 age-matched women who recovered completely from acute episodes of vertigo or dizziness capable of triggering PPPD. Brain responses to positive, neutral, and negative figures from the International Affective Picture System were measured with fMRI and compared between the groups. Dizziness handicap, anxiety, and depression were assessed with validated questionnaires. Results Between group analyses: Participants with PPPD showed reduced activity in anterior cingulate cortex and increased activity in left angular gyrus in response to negative versus positive stimuli, which was not observed in recovered individuals. Within group analyses: Participants with PPPD had increased activity in visuospatial areas (parahippocampal gyrus, intraparietal sulcus) in negative versus positive and negative versus neutral contrasts, whereas recovered individuals had increased activity in anxiety regions (amygdala, orbitofrontal cortex). Conclusion Patients with PPPD may be more attuned to spatial elements than to the content of emotionally charged visual stimuli.


Relation between vitamin D status and body composition in collegiate athletes.
Excess body fat or obesity is known to increase risk of poor vitamin D status in nonathletes but it is not known if this is the case in athletes. Furthermore, the reason for this association is not understood, but is thought to be due to either sequestration of the fat-soluble vitamin within adipose tissue or the effect of volume dilution related to obese individuals' larger body size. Forty two US college athletes (24 men 18 women, 20.7 ± 1.6 years, 85.0 ± 28.7 kg, BMI = 25.7 ± 6.1 kg/m2) provided blood samples during the fall and underwent measurement of body composition via dual energy X-ray absorptiometry. Serum samples were evaluated for 25-hydroxyvitamin D (25(OH)D) concentration to assess vitamin D status using Diasorin 25(OH)D radioiodine assay. Serum 25(OH)D concentration was negatively associated with height (r = -0.45), total body mass (r = -0.57), BMI (r = -0.57), body fat percentage (r = -0.45), fat mass (r = -0.60) and fat-free mass (r = -0.51) (p < .05). These associations did not change after controlling for sex. In a linear regression mixed model, fat mass (coefficient -0.47, p = .01), but not fat-free mass (coefficient -0.18, p = .32) significantly predicted vitamin D status and explained approximately 36% of the variation in serum 25(OH)D concentration. These results suggest that athletes with a large body size and/or excess adiposity may be at higher risk for vitamin D insufficiency and deficiency. In addition, the significant association between serum 25(OH)D concentration and fat mass in the mixed model, which remained after controlling for sex, is in support of vitamin D sequestration rather than volume dilution as an explanation for such association.


Antifolate resistance associated with loss of MRP1 expression and function in Chinese hamster ovary cells with markedly impaired export of folate and cholate.
Export of folates from a Chinese hamster ovary PyrR100 cell line is markedly impaired, resulting in expansion of cellular folate pools and high-level antifolate resistance. We now report that MRP1 expression is absent in PyrR100 cells along with a marked decrease in MRP5 expression with 3-fold cross-resistance to thiopurines. PyrR100 and wild-type cells had comparable low levels of MRP2 expression; both lacked the breast cancer resistance protein. PyrR100 cells showed a 4-fold decrease in cholate (an MRP substrate) efflux with a 6-fold increase in cellular cholate accumulation compared with wild-type cells. Prostaglandin A1 increased cholate accumulation in wild-type cells to levels comparable with PyrR100 cells. Calcein (an MRP1 substrate) fluorescence increased 5-fold in PyrR100 cells; probenecid increased the intracellular calcein level in wild-type cells to that of PyrR100 cells. Consistent with the loss of MRP1 expression, PyrR100 cells showed modest collateral sensitivity to cholate, etoposide, doxorubicin, and vincristine. Transfection of MRP5 into PyrR100 cells did not alter sensitivity to pyrimethamine or MTX but restored sensitivity to mercaptopurines, indicating that decreased MRP5 expression did not play a role in antifolate resistance. Hence, although MRP-mediated anticancer drug resistance has been associated with gain of function (i.e., overexpression), this is the first report that loss of MRP1 efflux function can expand intracellular folate pools to result in acquired antifolate resistance. The data also suggest that MRP1, and possibly other MRPs that transport folates, can play a role in the maintenance of cellular folate homeostasis.


Uptake of tritium-labeled norepinephrine in brain and other tissues of cat in vitro.
Slices of cat cerebral cortex, heart, and spleen that have been incubated in media containing approximately 5 to 25 mmicrog of dl-norepinephrine-7H(8) per milliliter contain levels of isotopic amine greater than those in the medium. The effects of norepinephrine concentration, reserpine, and ouabain on the uptake suggest that the amine enters cells both by diffusion and by a concentrating miechanism that is saturated at low levels of norepinephrine. The drugs inhibit the latter.


Reversible anonymization of DICOM images using automatically generated policies.
Many real-world applications in the area of medical imaging like case study databases require separation of identifying (IDATA) and non-identifying (MDATA) data, specifically those offering Internet-based data access. These kinds of projects also must provide a role-based access system, controlling, how patient data must be organized and how it can be accessed. On DICOM image level, different image types support different kind of information, intermixing IDATA and MDATA in a single object. To separate them, it is possible to reversibly anonymize DICOM objects by substituting IDATA by a unique anonymous token. In case that later an authenticated user needs full access to an image, this token can be used for re-linking formerly separated IDATA and MDATA, thus resulting in a dynamically generated, exact copy of the original image. The approach described in this paper is based on the automatic generation of anonymization policies from the DICOM standard text, providing specific support for all kinds of DICOM images. The policies are executed by a newly developed framework based on the DICOM toolkit DCMTK and offer a reliable approach to reversible anonymization. The implementation is evaluated in a German BMBF-supported expert network in the area of skeletal dysplasias, SKELNET, but may generally be applicable to related projects, enormously improving quality and integrity of diagnostics in a field focused on images. It performs effectively and efficiently on real-world test images from the project and other kind of DICOM images.


Isolation and characterization of a metalloproteinase with weak hemorrhagic activity from the venom of the snake Bothrops asper (terciopelo).
A metalloproteinase, named BaP1, was purified to homogeneity from the venom of Bothrops asper (Pacific region) of Costa Rica by ion-exchange chromatography on CM-Sephadex and gel filtration on Sephacryl S-200. The enzyme has a mol. wt of 24,000 and contains few Cys and high numbers of Asp, Leu, Ser and Glu. BaP1 hydrolyzes casein, hide powder azure and fibrinogen, having an optimal pH of 8.0. It rapidly digests the A alpha-chain of fibrinogen and, later on, the B beta-chain, leaving the gamma-chain unaffected. Chelating agents (EDTA and 1,10-phenanthroline) inhibited proteolytic activity, whereas 2-mercaptoethanol and soybean trypsin inhibitor did not affect this activity. BaP1 has a weak hemorrhagic activity, with a minimum hemorrhagic dose of 20 micrograms; this activity was inhibited by EDTA and was abolished after incubation at 60 degrees C. In addition, BaP1 induces edema and a mild myotoxic effect, lacking coagulant, defibrinating and lethal effects.


Living apart together: crosstalk between the core and supernumerary genomes in a fungal plant pathogen.
Eukaryotes display remarkable genome plasticity, which can include supernumerary chromosomes that differ markedly from the core chromosomes. Despite the widespread occurrence of supernumerary chromosomes in fungi, their origin, relation to the core genome and the reason for their divergent characteristics are still largely unknown. The complexity of genome assembly due to the presence of repetitive DNA partially accounts for this. Here we use single-molecule real-time (SMRT) sequencing to assemble the genome of a prominent fungal wheat pathogen, Fusarium poae, including at least one supernumerary chromosome. The core genome contains limited transposable elements (TEs) and no gene duplications, while the supernumerary genome holds up to 25 % TEs and multiple gene duplications. The core genome shows all hallmarks of repeat-induced point mutation (RIP), a defense mechanism against TEs, specific for fungi. The absence of RIP on the supernumerary genome accounts for the differences between the two (sub)genomes, and results in a functional crosstalk between them. The supernumerary genome is a reservoir for TEs that migrate to the core genome, and even large blocks of supernumerary sequence (>200 kb) have recently translocated to the core. Vice versa, the supernumerary genome acts as a refuge for genes that are duplicated from the core genome. For the first time, a mechanism was determined that explains the differences that exist between the core and supernumerary genome in fungi. Different biology rather than origin was shown to be responsible. A "living apart together" crosstalk exists between the core and supernumerary genome, accelerating chromosomal and organismal evolution.


Genome-Wide Screens Reveal that Resveratrol Induces Replicative Stress in Human Cells.
Resveratrol is a natural product associated with wide-ranging effects in animal and cellular models, including lifespan extension. To identify the genetic target of resveratrol in human cells, we conducted genome-wide CRISPR-Cas9 screens to pinpoint genes that confer sensitivity or resistance to resveratrol. An extensive network of DNA damage response and replicative stress genes exhibited genetic interactions with resveratrol and its analog pterostilbene. These genetic profiles showed similarity to the response to hydroxyurea, an inhibitor of ribonucleotide reductase that causes replicative stress. Resveratrol, pterostilbene, and hydroxyurea caused similar depletion of nucleotide pools, inhibition of replication fork progression, and induction of replicative stress. The ability of resveratrol to inhibit cell proliferation and S phase transit was independent of the histone deacetylase sirtuin 1, which has been implicated in lifespan extension by resveratrol. These results establish that a primary impact of resveratrol on human cell proliferation is the induction of low-level replicative stress.


Real-time dispersion-compensated image reconstruction for compressive sensing spectral domain optical coherence tomography.
In this work, we propose a novel dispersion compensation method that enables real-time compressive sensing (CS) spectral domain optical coherence tomography (SD OCT) image reconstruction. We show that dispersion compensation can be incorporated into CS SD OCT by multiplying the dispersion-correcting terms by the undersampled spectral data before CS reconstruction. High-quality SD OCT imaging with dispersion compensation was demonstrated at a speed in excess of 70 frames per s using 40% of the spectral measurements required by the well-known Shannon/Nyquist theory. The data processing and image display were performed on a conventional workstation having three graphics processing units.


Steerable features for statistical 3D dendrite detection.
Most state-of-the-art algorithms for filament detection in 3-D image-stacks rely on computing the Hessian matrix around individual pixels and labeling these pixels according to its eigenvalues. This approach, while very effective for clean data in which linear structures are nearly cylindrical, loses its effectiveness in the presence of noisy data and irregular structures. In this paper, we show that using steerable filters to create rotationally invariant features that include higher-order derivatives and training a classifier based on these features lets us handle such irregular structures. This can be done reliably and at acceptable computational cost and yields better results than state-of-the-art methods.


Evaluation of the referral system in Iran's rural family physician program; a study of Jiroft University of Medical Sciences.
Referral systems are relatively easy in terms of design, but implementing them is extremely difficult. Considering the three levels of primary healthcare, access of people to specialized services through a referral system is possible. With regard to the importance of a referral system in a family physician program, this study was performed to assess the function of the referral system in the family physician program in Jiroft University of Medical Sciences. This cross-sectional study was performed in the first half of 2014. The sample size included 700 patients selected using multistage sampling. Firstly 30% of health centers were randomly selected as a cluster. Then, the patients were randomly selected from each cluster. The study data were collected through a questionnaire consisting of 2 parts - demographic variables and the rules of the referral system. Data were analyzed using descriptive statistics, Chi Square, and Logistic Regression. From 700 patients who received the level 2 services, 69% of cases were female and 31% were male. One hundred eighty-two cases (26%) had referral form from health house. Only 56.4% of persons referred to the centers because of diagnosis of the family physician. For 34% of cases, the specialists wrote the results of their evaluation in feedback form. Four hundred sixty-three patients did not return to their family physician because of lack of knowledge. The referral situation to level 2, in the present study was poor. Ease of access to specialized services level 2, and educational intervention for healthcare staff and familiarizing people with the objectives of the family physician program and referral system are recommended.


The impact of the recent financial crisis on 401(k) account balances.
401(K) LOSSES FROM THE ECONOMIC CRISIS: During 2008, major U.S. equity indexes were sharply negative, with the S&P 500 Index losing 37.0 percent for the year, which translated into corresponding losses in 401(k) retirement plan assets. But how individual 401(k) participants are affected by the crisis is largely determined by their account balance, age, and job tenure. IMPACT VARIES BY ACCOUNT BALANCE: This Issue Brief estimates changes in average 401(k) balances from Jan. 1, 2008, to Jan. 20, 2009, using the EBRI/ICI 401(k) database of more than 21 million participants. Not surprisingly, how the recent financial market losses affect individual 401(k) account balances is strongly affected by the size of a participant's account balance. Those with low account balances relative to contributions experienced minimal investment losses that were typically more than made up by contributions: Those with less than $10,000 in account balances had an average growth of 40 percent during 2008, since contributions had a bigger impact than investment losses. However, those with more than $200,000 in account balances had an average loss of more than 25 percent. IMPACT VARIES BY AGE AND JOB TENURE: 401(k) participants on the verge of retirement (ages 56-65) had average changes during this period that varied between a positive 1 percent for short-tenure individuals (one to four years with the current employer) to more than a 25 percent loss for those with long tenure (with more than 20 years). SHORT-TERM VS. LONG-TERM: While much of the focus has been on market fluctuations in the last year, investing for retirement security is (or should be) a long-term proposition. When a consistent sample of 2.2 million participants who had been with the same 401(k) plan sponsor for the seven years from 1999-2006 was analyzed, the average estimated growth rates for the period from Jan. 1, 2000 through Jan. 20, 2009, ranged from +29 percent for long-tenure older participants to more than +500 percent for short-tenure younger participants. RECOVERY TIME AND FUTURE STOCK MARKET PERFORMANCE: This analysis also calculates how long it might take for end-of-year 2008 401(k) balances to recover to their beginning-of-year 2008 levels, before the sharp stock market declines. Because future performance is unknown, this analysis provides a range of equity returns: At a 5 percent equity rate-of-return assumption, those with longest tenure with their current employer would need nearly two years at the median to recover, but approximately five years at the 90th percentile. If the equity rate of return is assumed to drop to zero for the next few years, this recovery time increases to approximately 2.5 years at the median and nine to 10 years at the 90th percentile. NEAR-ELDERLY WITH VERY HIGH EQUITY EXPOSURE: Estimates from the EBRI/ICI 401(k) database show that many participants near retirement had exceptionally high exposure to equities: Nearly 1 in 4 between ages 56-65 had more than 90 percent of their account balances in equities at year-end 2007, and more than 2 in 5 had more than 70 percent. As a result of the Pension Protection Act of 2006, many 401(k) plan sponsors appear to be offering lifecycle/ target-date funds, which automatically rebalance asset investments into more "age appropriate" allocations. Had all 401(k) participants been in the average target date fund at the end of 2007, 40 percent of the participants would have had at least a 20 percent decrease in their equity concentrations, and consequently, may have mitigated their losses, sometimes to an appreciable extent.


How fun are your meetings? Investigating the relationship between humor patterns in team interactions and team performance.
Research on humor in organizations has rarely considered the social context in which humor occurs. One such social setting that most of us experience on a daily basis concerns the team context. Building on recent theorizing about the humor-performance link in teams, this study seeks to increase our understanding of the function and effects of humor in team interaction settings. We examined behavioral patterns of humor and laughter in real teams by videotaping and coding humor and laughter during 54 regular organizational team meetings. Performance ratings were obtained immediately following the team meetings as well as at a later time point from the teams' supervisors. At the behavioral unit level within the team interaction process, lag sequential analysis identified humor and laughter patterns occurring above chance (e.g., a joke followed by laughter, followed by another joke). Moreover, humor patterns triggered positive socioemotional communication, procedural structure, and new solutions. At the team level, humor patterns (but not humor or laughter alone) positively related to team performance, both immediately and 2 years later. Team-level job insecurity climate was identified as a boundary condition: In low job insecurity climate conditions, humor patterns were positively related to performance, whereas in high job insecurity climate conditions, humor patterns did not relate to team performance. The role of job insecurity as a boundary condition persisted at both time points. These findings underscore the importance of studying team interactions for understanding the role of humor in organizations and considering team-level boundary conditions over time. (PsycINFO Database Record (c) 2014 APA, all rights reserved).


Development, Reliability, and Validity of the Multiple Errands Test Home Version (MET-Home) in Adults With Stroke.
Our objective was to perform initial psychometric analysis of the Multiple Errands Test Home Version (MET-Home), which was designed to assess the influence of poststroke executive dysfunction on in-home task performance. We examined the reliability and validity of the MET-Home in adults with stroke (n = 23) and individually matched control participants (n = 23). All participants completed a series of assessments during a single in-home visit. Notable differences in MET-Home subscores were discovered between participants with stroke and control participants. Participants with stroke omitted more tasks, broke more rules, passed by tasks more often, and were less efficient than matched control participants. The MET-Home demonstrated evidence of adequate internal consistency, excellent interrater reliability, and significant moderate associations with several tests. This preliminary study suggests that the MET-Home differentiates between adults with stroke and matched control participants. The MET-Home provides evidence of initial reliability and validity among adults with stroke.


Cardiovascular care of patients with stroke and high risk of stroke: The need for interdisciplinary action: A consensus report from the European Society of Cardiology Cardiovascular Round Table.
Comprehensive stroke care is an interdisciplinary challenge. Close collaboration of cardiologists and stroke physicians is critical to ensure optimum utilisation of short- and long-term care and preventive measures in patients with stroke. Risk factor management is an important strategy that requires cardiologic involvement for primary and secondary stroke prevention. Treatment of stroke generally is led by stroke physicians, yet cardiologists need to be integrated care providers in stroke units to address all cardiovascular aspects of acute stroke care, including arrhythmia management, blood pressure control, elevated levels of cardiac troponins, valvular disease/endocarditis, and the general management of cardiovascular comorbidities. Despite substantial progress in stroke research and clinical care has been achieved, relevant gaps in clinical evidence remain and cause uncertainties in best practice for treatment and prevention of stroke. The Cardiovascular Round Table of the European Society of Cardiology together with the European Society of Cardiology Council on Stroke in cooperation with the European Stroke Organisation and partners from related scientific societies, regulatory authorities and industry conveyed a two-day workshop to discuss current and emerging concepts and apparent gaps in stroke care, including risk factor management, acute diagnostics, treatments and complications, and operational/logistic issues for health care systems and integrated networks. Joint initiatives of cardiologists and stroke physicians are needed in research and clinical care to target unresolved interdisciplinary problems and to promote the best possible outcomes for patients with stroke.


A Randomized Controlled Trial of Caries Prevention in Dental Practice.
We conducted a parallel group randomized controlled trial of children initially aged 2 to 3 y who were caries free, to prevent the children becoming caries active over the subsequent 36 mo. The setting was 22 dental practices in Northern Ireland, and children were randomly assigned by a clinical trials unit (CTU) (using computer-generated random numbers, with allocation concealed from the dental practice until each child was recruited) to the intervention (22,600-ppm fluoride varnish, toothbrush, 50-mL tube of 1,450 ppm fluoride toothpaste, and standardized, evidence-based prevention advice) or advice-only control at 6-monthly intervals. The primary outcome measure was conversion from caries-free to caries-active states. Secondary outcome measures were number of decayed, missing, or filled teeth (dmfs) in caries-active children, number of episodes of pain, and number of extracted teeth. Adverse reactions were recorded. Calibrated external examiners, blinded to the child's study group, assessed the status of the children at baseline and after 3 y. In total, 1,248 children (624 randomized to each group) were recruited, and 1,096 (549 intervention, 547 control) were included in the final analyses. Eighty-seven percent of intervention and 86% of control children attended every 6-mo visit ( P = 0.77). A total of 187 (34%) in the intervention group converted to caries active compared to 213 (39%) in the control group (odds ratio, 0.81; 95% confidence interval, 0.64-1.04; P = 0.11). Mean dmfs of those with caries in the intervention group was 7.2 compared to 9.6 in the control group ( P = 0.007). There was no significant difference in the number of episodes of pain between groups ( P = 0.81) or in the number of teeth extracted in caries-active children ( P = 0.95). Ten children in the intervention group had adverse reactions of a minor nature. This well-conducted trial failed to demonstrate that the intervention kept children caries free, but there was evidence that once children get caries, it slowed down its progression (EudraCT No: 2009-010725-39; ISRCTN: ISRCTN36180119).


Silicosis in Coimbatore district of Tamil Nadu: A passive surveillance study.
SILICOSIS IN COIMBATORE DISTRICT OF TAMIL NADU: A passive surveillance study. This study was done to describe the level of preventive measures and level of awareness among the patients diagnosed with silicosis during a one-year period. Coimbatore Medical College Hospital. This is a passive surveillance study based on patients diagnosed with silicosis in our outpatient facility for a one-year period between January 1, 2012 and December 31, 2012. Seventeen cases of silicosis were diagnosed based on history of exposure to silica and radiological features. The mean age was 55 years with 16 males and one female. The average duration of exposure was 22 years. A protective mask was used by 29% of the patients and one patient had awareness about the risks of exposure to silica. Active tuberculosis was found in 12% and old tuberculosis in 47% of patients; 59% of the patients were smokers. Spirometry showed a restrictive pattern in 59% of the patients. Radiologically nodular opacities with upper-zone predominance was found in majority of the cases. Most patients are exposed to silica in unorganized industries. Majority of the patients lack awareness about the disease and there is a low implementation of preventive and control measures. As this study was a passive surveillance, it represents only the tip of iceberg and an active field-level surveillance could reveal the true prevalence of this disease.


Multiple stressors in amphibian communities: effects of chemical contamination, bullfrogs, and fish.
A leading hypothesis of amphibian population declines is that combinations of multiple stressors contribute to declines. We examined the role that chemical contamination, competition, and predation play singly and in combination in aquatic amphibian communities. We exposed larvae of American toads (Bufo americanus), southern leopard frogs (Rana sphenocephala), and spotted salamanders (Ambystoma maculatum) to overwintered bullfrog tadpoles (R. catesbeiana), bluegill sunfish (Lepomis macrochirus), the insecticide carbaryl, and ammonium nitrate fertilizer in 1000-L mesocosms. Most significantly, our study demonstrated that the presence of multiple factors reduced survival of B. americanus and A. maculatum and lengthened larval periods of R. sphenocephala. The presence of bluegill had the largest impact on the community; it eliminated B. americanus and A. maculatum and reduced the abundance of R. sphenocephala. Chemical contaminants had the second strongest effect on the community with the insecticide, reducing A. maculatum abundance by 50% and increasing the mass of anurans (frogs and toads) at metamorphosis; the fertilizer positively influenced time and mass at metamorphosis for both anurans and A. maculatum. Presence of overwintered bullfrogs reduced mass and increased time to metamorphosis of anurans. While both bluegill and overwintered bullfrog tadpoles had negative effects on the amphibian community, they performed better in the presence of one another and in contaminated habitats. Our results indicate that predicting deleterious combinations from single-factor effects may not be straightforward. Our research supports the hypothesis that combinations of factors can negatively impact some amphibian species and could contribute to population declines.


Effects of Exercise Domain and Intensity on Sleep in Women and Men with Overweight and Obesity.
Inadequate sleep is associated with cardiometabolic risk and adiposity. Exercise has been suggested as an efficient strategy to improve sleep; however, the effects of different types of exercise on sleep in individuals with overweight and obesity are not well understood. We examined effects of active commuting and leisure-time exercise on sleep in individuals with overweight or obesity. 130 physically inactive adults (20-45 years) with overweight or class 1 obesity (body mass index: 25-35 kg/m2) were randomized to 6 months of habitual lifestyle (CON, n = 18), active commuting by bike (BIKE, n = 35), or leisure-time exercise of moderate intensity (MOD, 50% VO2peak-reserve, n = 39) or vigorous intensity (VIG, 70% VO2peak-reserve, n = 38), 5 days/week. Sleep was assessed from 7-day/night accelerometry and questionnaires at baseline, 3 months, and 6 months. 92 participants were included in a per protocol analysis. At 3 months, sleep duration was longer in VIG (29 min/night [3; 55] (mean [95% CI]), p=0.03) but not in BIKE and MOD (p ≥ 0.11) compared with CON and was not different between groups at 6 months (p ≥ 0.36 vs. CON). At 6 months, sleep duration variability was lower in MOD (-31% [-50; -3], p=0.03) and numerically lower in VIG (-28% [-49; 1], p=0.06) relative to CON but was unchanged in BIKE (p=0.17 vs. CON). The effects were, however, primarily attributable to shorter and more irregular sleep in CON over time. Our findings suggest that effects of exercise on sleep in individuals with overweight and obesity may be restricted to leisure-time exercise with a short-term effect on sleep duration after vigorous intensity exercise (3 months) but a more regular sleep pattern after 6 months of moderate and vigorous intensity exercise compared with physically inactive controls. This trial was registered at clinicaltrials.gov with ID NCT01962259.


Feasibility and safety of emergency ERCP and small-caliber pancreatic stenting as a bridging procedure in patients with acute biliary pancreatitis but difficult sphincterotomy.
The aims of the present study were: (1) to assess the feasibility and safety of emergency endoscopic retrograde cholangiopancreatography (ERCP) and pancreatic duct (PD) stenting with small-caliber stents as a bridging procedure in acute biliary pancreatitis (ABP) patients in whom biliary endoscopic sphincterotomy (EST) proved difficult, failed or was contraindicated, and (2) to compare the clinical outcome of those patients having emergency ERCP with and without pancreatic stent. Eighty-seven consecutive patients with ABP were referred for emergency ERCP. In 60 of these ABP patients, ERCP, EST, and stone extraction (if necessary) were performed without PD stenting. In the remaining 27 patients, small-caliber (3-5 F, 4 cm) pancreatic stent insertion was initially applied. All patients were hospitalized for medical therapy and were followed up. The mean ages, the initial symptom-to-ERCP times, the Glasgow severity scores, and the peak amylase and CRP levels at initial presentation were not significantly different in the ERCP + EST with PD stent group versus the ERCP + EST without PD stent group. More importantly, the complication rate was significantly lower in the ERCP + EST with PD stent group versus the ERCP + EST without PD stent group (7.4% vs. 25%); while the mortality rates (0% vs. 6.7%) were comparable, reasonably low, and demonstrated no statistically significant differences. Temporary PD stenting with small-caliber stents is a safe and effective procedure that may afford sufficient PD decompression to reverse the process of ABP and serve as a bridging procedure in severe ABP in patients with failed, complicated, or contraindicated biliary EST.


A controlled trial of sip-feed supplements in elderly orthopaedic patients.
The potential nutritional and clinical benefits of sip-feed supplements were investigated by means of a controlled trial in elderly female patients admitted for orthopaedic surgery. A nutritional risk assessment procedure (Nutritional Risk Questionnaire, NRQ) was used to identify patients who might benefit from supplementation. Patients identified as high risk who did not receive supplements showed significant losses in triceps skinfold thickness (TSF) and mid-upper arm muscle circumference (MUAMC) measurements during hospitalization. Such changes were not observed in high-risk supplemented patients, but significant losses of MUAMC were also recorded in a group of patients who failed to comply with the supplement. No differences in biochemical parameters, muscle function, or clinical outcome were observed between supplemented and unsupplemented and non-compliant patients. The problems of poor compliance to sip-feed supplements and failure to observe clinical benefit in supplemented patients are discussed.


A Jurassic mammaliaform and the earliest mammalian evolutionary adaptations.
The earliest evolution of mammals and origins of mammalian features can be traced to the mammaliaforms of the Triassic and Jurassic periods that are extinct relatives to living mammals. Here we describe a new fossil from the Middle Jurassic that has a mandibular middle ear, a gradational transition of thoracolumbar vertebrae and primitive ankle features, but highly derived molars with a high crown and multiple roots that are partially fused. The upper molars have longitudinal cusp rows that occlude alternately with those of the lower molars. This specialization for masticating plants indicates that herbivory evolved among mammaliaforms, before the rise of crown mammals. The new species shares the distinctive dental features of the eleutherodontid clade, previously represented only by isolated teeth despite its extensive geographic distribution during the Jurassic. This eleutherodontid was terrestrial and had ambulatory gaits, analogous to extant terrestrial mammals such as armadillos or rock hyrax. Its fur corroborates that mammalian integument had originated well before the common ancestor of living mammals.


Post-Vietnam stress disorder: a metaphor for current and past life events.
Delayed posttraumatic stress reactions are often triggered by events that echo the original trauma. It is not uncommon, however, for these delayed reactions to represent a metaphor for other current or past life events. A case is presented that illustrates the diagnostic and therapeutic significance of understanding these reactions as a metaphor.


A wide range, rapid scanning spectrometer for emission and absorption measurements.
A new, very wide spectral range, fast scanning spectrometer that combines high speed with good resolving power has been developed. The instrument operates with an f number in the vertical and horizontal plane of f/3 and f/17, respectively, and with a useful slit height of 3 cm. The theoretical resolving power in first order is 14,000 using an 1180-lines/mm grating. The optical layout is basically an asymmetrical Czerny-Turner arrangement with the grating at the center of curvature. The scanning element is a six sided, air turbine driven mirror that allows the whole spectrum from zero to 1.2 micro in first order to be scanned in about 70 microsec at mirror speeds of 1500 rps. The wide variation in the spectral response of the instrument presents recording problems, but ways of circumventing or diminishing those problems are suggested. A high intensity, end-on, pulsed flash tube has been used as a source for absorption spectroscopy. Some experiments are described, where the system has been appli d to emission or absorption measurements.


7,12-dimethylbenz[a]anthracene-induced malignancies in a mouse model of menopause.
Ovarian cancer has a high mortality rate because there are few symptoms in early disease development. The incidence of ovarian cancer increases in women after menopause. Understanding early events in this disease can best be achieved by using animal models. Therefore, the objective of this study was to develop and track the onset of ovarian tumorigenesis in mice mimicking characteristics of postmenopausal epithelial cancer in women. Female B6C3F1 mice (age, 28 d) received 4-vinylcyclohexene diepoxide (VCD, 160 mg/kg IV daily for 20 d) to cause ovarian failure. Four months after VCD treatment, via surgical intervention, each mouse received a single injection of 7,12-dimethylbenz[a]anthracene (DMBA) or vehicle control (sesame oil) under the bursa of the right ovary to cause ovarian neoplasms. The experimental groups were untreated controls (Con-Con), DMBA-treatment only (Con-DMBA), VCD treatment only (VCD-Con), and VCD+DMBA-treated (VCD+DMBA) mice. At 3, 5, 7, and 9 mo after DMBA injection, ovaries were collected for histologic and immunohistochemical evaluation. No tumors developed in Con-Con mice. All VCD-treated mice (with or without DMBA) exhibited ovarian failure. Mice that received both VCD and DMBA exhibited tumors at 3 mo (50%), 5 mo (14%), 7 mo (90%), and 9 mo (57%) after DMBA treatment; 31% of the tumors were epithelial in origin. Our findings confirm that inducing ovarian tumors in mice by chemical means is an effective method for studying early stages of tumor development that may be relevant to epithelial ovarian cancers that arise in postmenopausal women.


Intense co-circulation of non-influenza respiratory viruses during the first wave of pandemic influenza pH1N1/2009: a cohort study in Reunion Island.
The aim of the present study was to weigh up, at the community level, the respective roles played by pandemic Influenza (pH1N1) virus and co-circulating human Non-Influenza Respiratory Viruses (NIRVs) during the first wave of the 2009 pH1N1 pandemic. A population-based prospective cohort study was conducted in Reunion Island during the austral winter 2009 (weeks 30-44) that allowed identification of 125 households with at least one member who developed symptoms of Influenza-like illness (ILI). Three consecutive nasal swabs were collected from each household member (443 individuals) on day 0, 3 and 8 post-ILI report and tested for pH1N1 and 15 NIRVs by RT-PCR. Two successive waves of viral infections were identified: a first wave (W33-37) when pH1N1 was dominant and co-circulated with NIRVs, sharply interrupted by a second wave (W38-44), almost exclusively composed of NIRVs, mainly human Rhinoviruses (hRV) and Coronaviruses (hCoV). Data suggest that some interference may occur between NIRVs and pH1N1 when they co-circulate within the same household, where NIRVs were more likely to infect pH1N1 negative individuals than pH1N1 positive peers (relative risk: 3.13, 95% CI: 1.80-5.46, P<0.001). Viral shedding was significantly shorter (P = 0.035) in patients who were co-infected by pH1N1 and NIRV or by two different NIRVs compared to those who were infected with only one virus, whatever this virus was (pH1N1 or NIRVs). Although intense co-circulation of NIRVs (especially hRV) likely brought pH1N1 under the detection threshold, it did not prevent spread of the pandemic Influenza virus within the susceptible population nor induction of an extensive herd immunity to it. Our results suggest that NIRV co-infections during Influenza epidemics may act as cofactors that contribute to shape an outbreak and modulate the attack rate. They further warrant broad spectrum studies to fully understand viral epidemics.


Adjunctive Glucocorticoid Therapy in Patients with Septic Shock.
Whether hydrocortisone reduces mortality among patients with septic shock is unclear. We randomly assigned patients with septic shock who were undergoing mechanical ventilation to receive hydrocortisone (at a dose of 200 mg per day) or placebo for 7 days or until death or discharge from the intensive care unit (ICU), whichever came first. The primary outcome was death from any cause at 90 days. From March 2013 through April 2017, a total of 3800 patients underwent randomization. Status with respect to the primary outcome was ascertained in 3658 patients (1832 of whom had been assigned to the hydrocortisone group and 1826 to the placebo group). At 90 days, 511 patients (27.9%) in the hydrocortisone group and 526 (28.8%) in the placebo group had died (odds ratio, 0.95; 95% confidence interval [CI], 0.82 to 1.10; P=0.50). The effect of the trial regimen was similar in six prespecified subgroups. Patients who had been assigned to receive hydrocortisone had faster resolution of shock than those assigned to the placebo group (median duration, 3 days [interquartile range, 2 to 5] vs. 4 days [interquartile range, 2 to 9]; hazard ratio, 1.32; 95% CI, 1.23 to 1.41; P<0.001). Patients in the hydrocortisone group had a shorter duration of the initial episode of mechanical ventilation than those in the placebo group (median, 6 days [interquartile range, 3 to 18] vs. 7 days [interquartile range, 3 to 24]; hazard ratio, 1.13; 95% CI, 1.05 to 1.22; P<0.001), but taking into account episodes of recurrence of ventilation, there were no significant differences in the number of days alive and free from mechanical ventilation. Fewer patients in the hydrocortisone group than in the placebo group received a blood transfusion (37.0% vs. 41.7%; odds ratio, 0.82; 95% CI, 0.72 to 0.94; P=0.004). There were no significant between-group differences with respect to mortality at 28 days, the rate of recurrence of shock, the number of days alive and out of the ICU, the number of days alive and out of the hospital, the recurrence of mechanical ventilation, the rate of renal-replacement therapy, and the incidence of new-onset bacteremia or fungemia. Among patients with septic shock undergoing mechanical ventilation, a continuous infusion of hydrocortisone did not result in lower 90-day mortality than placebo. (Funded by the National Health and Medical Research Council of Australia and others; ADRENAL ClinicalTrials.gov number, NCT01448109 .).


First Report of Phytophthora × pelgrandis Causing Root Rot and Lower Stem Necrosis of Common Box, Lavender and Port-Orford-Cedar in Hungary.
In 2008 and 2009, necrotic bark lesions at the root collar and lower stem associated with root rot, reduced growth, and wilting were observed on container-grown common box (Buxus sempervirens L.), lavender (Lavandula angustifolia Mill. 'Hidcote'), and Port-Orford-cedar (Chamaecyparis lawsoniana (A. Murray) Parl. 'Columnaris') in three ornamental nurseries in western Hungary. Number of affected plants ranged from approximately 100 (Port-Orford-cedar) to 250 (lavender). Isolations from necrotic root collars of each host plant species yielded four Phytophthora isolates developing uniform colonies on carrot agar with a maximum growth temperature of 35 to 36°C. The isolates were homothallic with smooth-walled oogonia (32.2 ± 2.3 to 35.9 ± 3.5 μm), aplerotic oospores (27.5 ± 1.8 to 32.1 ± 3.1 μm) and both amphigynous and paragynous antheridia, and produced chlamydospores (25.8 ± 3.9 to 29.1 ± 5.2 μm) and papillate sporangia (35.2 ± 2.5 to 43.5 ± 5.6 μm long and 27.6 ± 2.2 to 32.0 ± 3.8 μm wide), mostly obpyriform to nearly spherical or rarely distorted with two or three apices. In spring water, sporangia were both caducous with short pedicel and non-caducous. Multiplex ITS-PCR assay of DNA from all isolates, using primers specific for P. nicotianae (NICF1 and NICR2.1) and P. cactorum (CACTF1 and CACTR1) (1), amplified DNA fragments of the expected size for each Phytophthora species. In addition, isoenzyme analysis revealed a characteristic banding pattern of one heterodimer and two homodimer bands at both loci of the dimeric enzyme malate dehydrogenase. These bands comigrated with those of P. × pelgrandis (Gerlach et al.) (CBS 123385) and isolate PD 93/1339 (courtesy of W. A. Man in 't Veld), two natural hybrid strains of P. nicotianae and P. cactorum (2,3), proving that our four isolates can be referred to as this interspecific hybrid. Pathogenicity was tested on 1- or 3-year-old plants of the original host species and cultivars (for common box, cv. Faulkner was used). Cultures were grown for 4 to 6 weeks at 20°C on autoclaved millet grains moistened with V8 broth. Infested and uninfested grains were mixed with autoclaved soil in a ratio of 6% (w/v), and the mixes were used as potting media for transplanting five treated and five control plants per isolate, respectively. Plants were kept in a growth chamber (20°C, 70% RH, 12-h photoperiod). Pots were flooded for 24 h on the 1st and 21st day after transplanting. All plants in infested potting mix showed symptoms of wilt associated with basal stem and root necrosis, similar to those observed on the plants from the field, within 2 and 3 months on lavender and both common box or Port-Orford-cedar, respectively. Additionally, a reduction of root weight ranging from 35 to 68% compared to the control was recorded. Growth reduction was significant at P ≤ 0.019 according to Mann Whitney test. Control plants remained healthy. The same Phytophthora hybrid was reisolated solely from inoculated plants. In Europe, hybrid isolates of P. nicotianae × P. cactorum have been reported on several ornamental plants, including lavender, in the Netherlands and Germany (2,3). However, to our knowledge, this is the first report of this hybrid in Hungary and as a pathogen of common box and Port-Orford-cedar in the world. References: (1) P. J. M. Bonants et al. Phytopathology 90:867, 2000. (2) W. A. Man in 't Veld et al. Phytopathology 88:922, 1998. (3) H. I. Nirenberg et al. Mycologia 101:220, 2009.


Meal size is a critical driver of weight gain in early childhood.
Larger serving sizes and more frequent eating episodes have been implicated in the rising prevalence of obesity at a population level. This study examines the relative contributions of meal size and frequency to weight gain in a large sample of British children. Using 3-day diet diaries from 1939 children aged 21 months from the Gemini twin cohort, we assessed prospective associations between meal size, meal frequency and weight gain from two to five years. Separate longitudinal analyses demonstrated that every 10 kcal increase in meal size was associated with 1.5 g/wk or 4% (p = 0.005) faster growth rate, while meal frequency was not independently associated with growth (β = 0.3 g/wk p = 0.20). Including both meal parameters in the model strengthened associations (meal size: β = 2.6 g/wk, p < 0.001; meal frequency: β = 1.0 g/wk, p = 0.001). Taken together, the implication is that meal size promotes faster growth regardless of frequency, but meal frequency has a significant effect only if meal size is assumed to be held constant. Clearer advice on meal size and frequency, especially advice on appropriate meal size, may help prevent excess weight gain.


Applications of linking PBPK and PD models to predict the impact of genotypic variability, formulation differences, differences in target binding capacity and target site drug concentrations on drug responses and variability.
This study aimed to demonstrate the added value of integrating prior in vitro data and knowledge-rich physiologically based pharmacokinetic (PBPK) models with pharmacodynamics (PDs) models. Four distinct applications that were developed and tested are presented here. PBPK models were developed for metoprolol using different CYP2D6 genotypes based on in vitro data. Application of the models for prediction of phenotypic differences in the pharmacokinetics (PKs) and PD compared favorably with clinical data, demonstrating that these differences can be predicted prior to the availability of such data from clinical trials. In the second case, PK and PD data for an immediate release formulation of nifedipine together with in vitro dissolution data for a controlled release (CR) formulation were used to predict the PK and PD of the CR. This approach can be useful to pharmaceutical scientists during formulation development. The operational model of agonism was used in the third application to describe the hypnotic effects of triazolam, and this was successfully extrapolated to zolpidem by changing only the drug related parameters from in vitro experiments. This PBPK modeling approach can be useful to developmental scientists who which to compare several drug candidates in the same therapeutic class. Finally, differences in QTc prolongation due to quinidine in Caucasian and Korean females were successfully predicted by the model using free heart concentrations as an input to the PD models. This PBPK linked PD model was used to demonstrate a higher sensitivity to free heart concentrations of quinidine in Caucasian females, thereby providing a mechanistic understanding of a clinical observation. In general, permutations of certain conditions which potentially change PK and hence PD may not be amenable to the conduct of clinical studies but linking PBPK with PD provides an alternative method of investigating the potential impact of PK changes on PD.


Cost-effectiveness analyses in multiple sclerosis: a review of modelling approaches.
The growing number of disease-modifying treatments (DMTs) for patients with multiple sclerosis (MS) and the high acquisition costs of these DMTs are likely to increase the demand for information on their cost effectiveness. To improve the comparability and applicability of the findings from future cost-effectiveness analyses, it would be useful to have a clear understanding of the methodological challenges of modelling the cost effectiveness of DMTs in MS and the different approaches taken by such studies to date. In contrast to previous review studies, this review focuses on long-term time horizon (≥10 years) simulation-based cost-effectiveness analyses with homogeneous contexts of analysis (i.e. those with similar study objectives, comparators, and target populations) published over the past decade. By doing so, it provides a clearer picture of how modelling approaches taken in the existing studies truly differ across studies, and reveals major areas for improvement in conducting future cost-effectiveness analyses of DMTs for patients with MS.


Observation-centered approach to ASD assessment in Tanzania.
Abstract In many lower-income countries, there is a paucity of assessment services for autism spectrum disorders (ASD)., Guidelines will be provided for conducting cross-cultural assessments in the context of limited validated resources in Tanzania. By examining behavioral, social, and adaptive differences we were able to provide differential diagnostic evaluations aligning with best practice standards for 41 children in Tanzania age 2-21 years. We describe the utility of a flexible, behavioral observation instrument, the Childhood Autism Rating Scales, Second Edition (CARS2), to gather diagnostic information in a culturally sensitive manner. We observed that the ASD group was characterized by significantly higher scores on the CARS2, F = 21.09, p < .001, η(2) = .37, than the general delay comparison group. Additional recommendations are provided for making cultural adaptations to current assessment instruments for use in a country without normed instruments, such as Tanzania.


Real-world outcomes for neoadjuvant capecitabine versus infusional 5-fluorouracil in the treatment of locally advanced rectal cancer.
Neoadjuvant chemoradiation therapy is standard-of-care treatment for locally advanced rectal cancer (LARC). A pathological complete response (pCR) following chemoradiation therapy is an early indicator of treatment benefit and associated with excellent survival outcomes, with capecitabine largely replacing infusional 5-fluorouracil as the choice in routine care of LARC. To analyse the uptake of capecitabine usage over time, and on the back of clinical trial data demonstrating equivalence between fluoropyrimidines, confirm that efficacy is maintained in the real-world setting. We analysed data from a prospectively maintained colorectal cancer database at three Australian hospitals including patients diagnosed from January 2009 to December 2018. Pathological response was determined as either complete or incomplete and compared for patients receiving 5-FU or capecitabine. A total of 657 patients was analysed, 498 receiving infusional 5-FU and 159 capecitabine. Capecitabine use has markedly increased from approval in 2014 in Australia, now being used in more than 80% of patients. Patient characteristics were similar by treatment, including age, tumour location and pre-treatment stage. pCR was reported in 22/159 (13.8%) of capecitabine-treated patients and 118/380 (23.7%) that received 5-FU (P ≤ 0.01). More capecitabine-treated patients received post-operative oxaliplatin (44.2% vs 6.3%, P < 0.01). Two-year progression-free survival was similar (84.9% vs 88.0%, P = 0.34). Capecitabine is now the dominantly used neoadjuvant chemotherapy in LARC. Capecitabine use was associated with a lower rate of pCR versus infusional 5-FU, a difference not explained by examined patient or tumour characteristics. Poor treatment compliance with oral therapy in the real-world setting is one possible explanation.


Changes in mean concentration, phase shifts, and dissipation in a forced oscillatory reaction.
Experiments are presented that confirm earlier predictions that the mode of supply of reactants to a nonlinear (bio)chemical reaction determines or controls concentrations at steady states far from equilibrium. The oxidation of nicotinamide adenine dinucleotide (NADH) catalyzed by the enzyme horseradish peroxidase with continuous input of oxygen was studied; NAD+ is continuously recycled to NADH through a glucose-6-phosphate dehydrogenase system. A comparison of steady-state concentrations is made with an oscillatory oxygen input and a constant input at the same average oxygen input for both modes. By varying the frequency and amplitude of the perturbation (O2 influx), the following may be changed: the average concentration of NADH; the Gibbs free energy difference delta G of the reactants and products at steady state; the average rate of the reaction; the phase relation between the oscillatory rate and delta G; and the dissipation. These results confirm the possibility of an "alternating current chemistry," of control and optimization of thermodynamic efficiency and dissipation by means of external variation of constraints in classes of nonlinear reactions and biological pumps, and of improvements of the yield in such reactions (heterogeneous catalysis, for example).


Abundant occurrence of basal radial glia in the subventricular zone of embryonic neocortex of a lissencephalic primate, the common marmoset Callithrix jacchus.
Subventricular zone (SVZ) progenitors are a hallmark of the developing neocortex. Recent studies described a novel type of SVZ progenitor that retains a basal process at mitosis, sustains expression of radial glial markers, and is capable of self-renewal. These progenitors, referred to here as basal radial glia (bRG), occur at high relative abundance in the SVZ of gyrencephalic primates (human) and nonprimates (ferret) but not lissencephalic rodents (mouse). Here, we analyzed the occurrence of bRG cells in the embryonic neocortex of the common marmoset Callithrix jacchus, a near-lissencephalic primate. bRG cells, expressing Pax6, Sox2 (but not Tbr2), glutamate aspartate transporter, and glial fibrillary acidic protein and retaining a basal process at mitosis, occur at similar relative abundance in the marmoset SVZ as in human and ferret. The proportion of progenitors in M-phase was lower in embryonic marmoset than developing ferret neocortex, raising the possibility of a longer cell cycle. Fitting the gyrification indices of 26 anthropoid species to an evolutionary model suggested that the marmoset evolved from a gyrencephalic ancestor. Our results suggest that a high relative abundance of bRG cells may be necessary, but is not sufficient, for gyrencephaly and that the marmoset's lissencephaly evolved secondarily by changing progenitor parameters other than progenitor type.


Feelings of loneliness, but not social isolation, predict dementia onset: results from the Amsterdam Study of the Elderly (AMSTEL).
Known risk factors for Alzheimer's disease and other dementias include medical conditions, genetic vulnerability, depression, demographic factors and mild cognitive impairment. The role of feelings of loneliness and social isolation in dementia is less well understood, and prospective studies including these risk factors are scarce. We tested the association between social isolation (living alone, unmarried, without social support), feelings of loneliness and incident dementia in a cohort study among 2173 non-demented community-living older persons. Participants were followed for 3 years when a diagnosis of dementia was assessed (Geriatric Mental State (GMS) Automated Geriatric Examination for Computer Assisted Taxonomy (AGECAT)). Logistic regression analysis was used to examine the association between social isolation and feelings of loneliness and the risk of dementia, controlling for sociodemographic factors, medical conditions, depression, cognitive functioning and functional status. After adjustment for other risk factors, older persons with feelings of loneliness were more likely to develop dementia (OR 1.64, 95% CI 1.05 to 2.56) than people without such feelings. Social isolation was not associated with a higher dementia risk in multivariate analysis. Feeling lonely rather than being alone is associated with an increased risk of clinical dementia in later life and can be considered a major risk factor that, independently of vascular disease, depression and other confounding factors, deserves clinical attention. Feelings of loneliness may signal a prodromal stage of dementia. A better understanding of the background of feeling lonely may help us to identify vulnerable persons and develop interventions to improve outcome in older persons at risk of dementia.