Evaluation of the effects of dietary n-3 fatty acid supplementation on the pharmacokinetics of doxorubicin in dogs with lymphoma.
To determine the effect of dietary n-3 fatty acids on the pharmacokinetics of doxorubicin in dogs with lymphoma. 23 dogs with lymphoma in stages IIIa, IVa, and Va. Dogs receiving doxorubicin chemotherapy were randomly allocated to receive food with a high (test group) or low (control group) content of n-3 fatty acids. Serum doxorubicin and doxorubicinol concentrations were measured via high-performance liquid chromatography before and 6 to 9 weeks after initiation of the diets. Lymph node concentrations of doxorubicin were assessed 6 hours after the initial treatment. Dogs' body composition was assessed by means of dual-energy x-ray absorptiometry scans. No significant differences in doxorubicin pharmacokinetics were detected between treatment groups. Significant differences existed between the first and second sampling times among all dogs for area under the curve, maximum serum concentration, and clearance. Differences in body composition did not affect measured pharmacokinetic variables. The terminal elimination half-life was longer in dogs in which a long-term remission was achieved than in dogs that did not have remission. Dietary supplementation of n-3 fatty acids is common in veterinary patients with neoplasia, but supplementation did not affect doxorubicin pharmacokinetics in this population of dogs. Explanations for the beneficial effects of n-3 fatty acids other than alterations in the pharmacokinetics of chemotherapy drugs should be investigated. Dogs may metabolize drugs differently prior to remission of lymphoma than when in remission. The pharmacokinetics of doxorubicin at the time of the first administration may predict response to treatment.


Effects of signal level and spectral contrast on vowel formant discrimination for normal-hearing and hearing-impaired listeners.
The aim of this study was to determine whether increasing the overall speech level or the individual spectral contrasts of vowel sounds can improve vowel formant discrimination for listeners both with and without normal hearing. Thresholds of vowel formant discrimination were examined for the F2 frequencies of 3 American English vowels for listeners with and without normal hearing. Spectral contrasts of the F2 were enhanced by 3, 6, and 9 dB. Vowel stimuli were presented at 70 and 90 dB SPL. The thresholds of listeners with hearing impairment were reduced significantly after spectral enhancement was implemented, especially at 90 dB SPL, whereas normal-hearing listeners did not benefit from spectral enhancement. These results indicate that a combination of spectral enhancement of F2 and high speech level is most beneficial to improve vowel formant discrimination for listeners with hearing impairment.


Senior GRADE methodologists encounter challenges as part of WHO guideline development panels: an inductive content analysis.
The World Health Organization (WHO) classifies a substantial proportion of their recommendations as strong despite low or very low confidence (certainty) in estimates of effect. Such discordant recommendations are often inconsistent with Grading of Recommendations Assessment, Development and Evaluation (GRADE) guidance. To gain the perspective of senior WHO methodology chairs regarding panels' use of GRADE, particularly regarding discordant recommendations. Senior active GRADE methodologists who had served on at least two WHO panels and were an author on at least one peer-reviewed published article on GRADE methodology. Five eligible methodologists participated in detailed semistructured interviews. Respondents answered questions regarding how they were viewed by other panelists and WHO leadership, and how they handled situations when panelists made discordant recommendations they felt were inappropriate. They also provided information on how the process can be improved. Interviews were recorded and transcribed, and inductive content analysis was used to derive codes, categories, and emergent themes. Three themes emerged from the interviews of five methodologists: (1) The perceived role of methodologists in the process, (2) Contributors to discordant recommendations, and (3) Strategies for improvement. Salient findings included (1) a perceived tension between methodologists and WHO panels as a result of panel members' resistance to adhering to GRADE guidance; (2) both financial and nonfinancial conflicts of interest among panel members as an explanation for discordant recommendations; and (3) the need for greater clarity of, and support for, the role of methodologists as co-chairs of panels. These findings suggest that the role of the GRADE methodologist as a co-chair needs to be clarified by the WHO leadership. They further suggest the need for additional training for panelists, quality monitoring, and feedback to ensure optimal use of GRADE in guideline development at WHO.


The Feasibility of Real-Time Intraoperative Performance Assessment With SIMPL (System for Improving and Measuring Procedural Learning): Early Experience From a Multi-institutional Trial.
Intraoperative performance assessment of residents is of growing interest to trainees, faculty, and accreditors. Current approaches to collect such assessments are limited by low participation rates and long delays between procedure and evaluation. We deployed an innovative, smartphone-based tool, SIMPL (System for Improving and Measuring Procedural Learning), to make real-time intraoperative performance assessment feasible for every case in which surgical trainees participate, and hypothesized that SIMPL could be feasibly integrated into surgical training programs. Between September 1, 2015 and February 29, 2016, 15 U.S. general surgery residency programs were enrolled in an institutional review board-approved trial. SIMPL was made available after 70% of faculty and residents completed a 1-hour training session. Descriptive and univariate statistics analyzed multiple dimensions of feasibility, including training rates, volume of assessments, response rates/times, and dictation rates. The 20 most active residents and attendings were evaluated in greater detail. A total of 90% of eligible users (1267/1412) completed training. Further, 13/15 programs began using SIMPL. Totally, 6024 assessments were completed by 254 categorical general surgery residents (n = 3555 assessments) and 259 attendings (n = 2469 assessments), and 3762 unique operations were assessed. There was significant heterogeneity in participation within and between programs. Mean percentage (range) of users who completed ≥1, 5, and 20 assessments were 62% (21%-96%), 34% (5%-75%), and 10% (0%-32%) across all programs, and 96%, 75%, and 32% in the most active program. Overall, response rate was 70%, dictation rate was 24%, and mean response time was 12 hours. Assessments increased from 357 (September 2015) to 1146 (February 2016). The 20 most active residents each received mean 46 assessments by 10 attendings for 20 different procedures. SIMPL can be feasibly integrated into surgical training programs to enhance the frequency and timeliness of intraoperative performance assessment. We believe SIMPL could help facilitate a national competency-based surgical training system, although local and systemic challenges still need to be addressed.


Trafficked female sex workers awaiting deportation: comparison with brothel workers.
In 2002, we researched the psychosocial characteristics of 55 women working in the commercial brothel-based sex industry in three Israeli cities. This previous social epidemiological study focused exclusively on women working in brothels and the brothel owners consented to their interviews, suggesting that this might be a sample of the most organized brothels with the best social conditions. We therefore decided to study a second sample obtained by different referral methods. The sample consisted of 49 women in a detention center who are awaiting judicial hearings for deportation. This prison sample of sex workers is strikingly similar to the previously studied sample of sex workers working in brothels in terms of demographic features and working conditions. A higher percentage of the prison sample reported depression and somatic symptoms. However, this finding is consistent with a reaction to being arrested and awaiting deportation. Guided by a life course perspective, in the combined sample, we examined whether early exposure to trauma, motherhood and early entry into sex work affected current health and mental health. Those who were mothers were likely to have entered sex work at a later age but no other aspect of their working conditions differed from the non-mothers suggesting that motherhood per se did not appreciably change the experience of these mostly trafficked women sex workers. Early exposure to trauma increased the likelihood for work-related trauma, poor health and mental health outcomes.


Coexistence of mitral valve prolapse in a consecutive group of 528 patients with hypertrophic cardiomyopathy assessed with echocardiography.
Hypertrophic cardiomyopathy and mitral valve prolapse are both conditions that may be genetically transmitted and incur a risk for sudden cardiac death. Although the small left ventricular cavity and distorted geometry characteristic of hypertrophic cardiomyopathy might suggest a predisposition to mitral valve prolapse, the frequency with which these two entities coexist and the potential clinical significance of such an association are not known. To further define the relation of hypertrophic cardiomyopathy and mitral valve prolapse, 528 consecutive patients with hypertrophic cardiomyopathy were studied by echocardiography. Patients ranged in age from 1 to 86 years (mean 45); 335 (63%) were male. Unequivocal echocardiographic evidence of systolic mitral valve prolapse into the left atrium was identified in only 16 (3%) of the 528 patients. The mitral valve excised at operation from three of the patients had morphologic characteristics of a floppy mitral valve, which was judged to be responsible for the echocardiographic findings. Occurrence of clinically evident atrial fibrillation was common in patients with hypertrophic cardiomyopathy and mitral valve prolapse (9 [56%] of 16). Hence, in a large group of patients with hypertrophic cardiomyopathy, the association of echocardiographically documented mitral valve prolapse was uncommon. The coexistence of mitral valve prolapse in patients with hypertrophic cardiomyopathy appears to predispose such patients to atrial fibrillation.


Relationships between lifestyle and dental health behaviors in a rural population in Japan.
The aim of this study was to determine associations of lifestyle with dental health behaviors such as tooth brushing frequency, use of extra cleaning devices, and regular dental visits to a dentist. Data were collected from 1182 dentate residents 18 years of age or older who resided in a typical farming district. The data included data on the demographic factors, dental health behavior, and various aspects of lifestyle, i.e. mental condition, alcohol consumption, smoking habit, physical activity, social activity, dietary habits, and presence of systemic diseases. Multiple logistic regression analysis revealed that subjects in a younger group (18-39 years of age) and subjects who had never smoked brushed their teeth more frequently. Experience of social volunteer work and presence of systemic disease were correlated with use of extra cleaning devices. Associations of female gender with frequency of tooth brushing and use of extra cleaning devices were weakly positive. The subjects who considered dietary combination carefully and those who lived alone were predisposed to visit a dentist regularly. The results indicate that dental health behavior is associated with lifestyle as well as demographic factors.


The impact of social media promotion with infographics and podcasts on research dissemination and readership.
In 2015 and 2016, the Canadian Journal of Emergency Medicine (CJEM) Social Media (SoMe) Team collaborated with established medical websites to promote CJEM articles using podcasts and infographics while tracking dissemination and readership. CJEM publications in the "Original Research" and "State of the Art" sections were selected by the SoMe Team for podcast and infographic promotion based on their perceived interest to emergency physicians. A control group was composed retrospectively of articles from the 2015 and 2016 issues with the highest Altmetric score that received standard Facebook and Twitter promotions. Studies on SoMe topics were excluded. Dissemination was quantified by January 1, 2017 Altmetric scores. Readership was measured by abstract and full-text views over a 3-month period. The number needed to view (NNV) was calculated by dividing abstract views by full-text views. Twenty-nine of 88 articles that met inclusion were included in the podcast (6), infographic (11), and control (12) groups. Descriptive statistics (mean, 95% confidence interval) were calculated for podcast (Altmetric: 61, 42-80; Abstract: 1795, 1135-2455; Full-text: 431, 0-1031), infographic (Altmetric: 31.5, 19-43; Abstract: 590, 361-819; Full-text: 65, 33-98), and control (Altmetric: 12, 8-15; Abstract: 257, 159-354; Full-Text: 73, 38-109) articles. The NNV was 4.2 for podcast, 9.0 for infographic, and 3.5 for control articles. Discussion Limitations included selection bias, the influence of SoMe promotion on the Altmetric scores, and a lack of generalizability to other journals. Collaboration with established SoMe websites using podcasts and infographics was associated with increased Altmetric scores and abstract views but not full-text article views.


Recent advances in the biology of tumour hypoxia with relevance to diagnostic practice and tissue-based research.
In this review article, we examine the importance of low levels of oxygen (hypoxia) in cancer biology. We provide a brief description of how mammalian cells sense oxygen. The hypoxia-inducible factor (HIF) pathway is currently the best characterised oxygen-sensing system, but recent work has revealed that mammals also use an oxygen-sensing system found in plants to regulate the abundance of some proteins and peptides with an amino-terminal cysteine residue. We discuss how the HIF pathway is affected during the growth of solid tumours, which develop in microenvironments with gradients of oxygen availability. We then introduce the concept of 'pseudohypoxia', a state of constitutive, oxygen-independent HIF system activation that occurs due to oncogenic stimulation in a number of specific tumour types that are of immediate relevance to diagnostic histopathologists. We provide an overview of the different methods of quantifying tumour hypoxia, emphasising the importance of pre-analytic factors in interpreting the results of tissue-based studies. Finally, we review recent approaches to targeting hypoxia/HIF system activation for therapeutic benefit, the application of which may require knowledge of which hypoxia signalling components are being utilised by a given tumour. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.


GenBank.
GenBank® (www.ncbi.nlm.nih.gov/genbank/) is a comprehensive database that contains publicly available nucleotide sequences for 370 000 formally described species. These sequences are obtained primarily through submissions from individual laboratories and batch submissions from large-scale sequencing projects, including whole genome shotgun (WGS) and environmental sampling projects. Most submissions are made using the web-based BankIt or the NCBI Submission Portal. GenBank staff assign accession numbers upon data receipt. Daily data exchange with the European Nucleotide Archive (ENA) and the DNA Data Bank of Japan (DDBJ) ensures worldwide coverage. GenBank is accessible through the NCBI Nucleotide database, which links to related information such as taxonomy, genomes, protein sequences and structures, and biomedical journal literature in PubMed. BLAST provides sequence similarity searches of GenBank and other sequence databases. Complete bimonthly releases and daily updates of the GenBank database are available by FTP. Recent updates include changes to policies regarding sequence identifiers, an improved 16S submission wizard, targeted loci studies, the ability to submit methylation and BioNano mapping files, and a database of anti-microbial resistance genes.


Learning under stress: the inverted-U-shape function revisited.
Although the relationship between stress intensity and memory function is generally believed to follow an inverted-U-shaped curve, strikingly this phenomenon has not been demonstrated under the same experimental conditions. We investigated this phenomenon for rats' performance in a hippocampus-dependent learning task, the radial arm water maze (RAWM). Variations in stress intensity were induced using different water temperatures (25°C, 19°C, and 16°C), which elicited increased plasma corticosterone levels. During spatial training over three consecutive days, an inverted-U shape was found, with animals trained at 19°C making fewer errors than animals trained at either higher (16°C) or lower (25°C) stress conditions. Interestingly, this function was already observed by the last trial of day 1 and maintained on the first day trial of day 2. A long-term recall probe test administered under equal temperature conditions (20°C) revealed differences in performance according to the animals' former training conditions; i.e., platform searching for rats trained at 25°C was less accurate than for rats trained at either 16°C or 19°C. In reversal learning, groups trained at both 19°C and 25°C showed better performance than the 16°C group. We also found an interaction between anxiety and exploration traits on how individuals were affected by stressors during spatial learning. In summary, our findings confirm, for the first time, the existence of an inverted-U-shape memory function according to stressor intensity during the early learning and memory phases in a hippocampus-dependent task, and indicate the existence of individual differences related to personality-like profiles for performance at either high or low stress conditions.


Radioactive cesium accumulation in freshwater fishes after the Fukushima nuclear accident.
The Fukushima Daiichi Nuclear Power Plant (F1NPP) accident released large amounts of radioactive substances into the environment and contaminated the terrestrial and marine ecosystems in East Japan. The unpredicted nuclear accident is of global concern for human health and ecosystems. Investigations of radionuclides in the local environments were performed shortly after the accident began; however the temporal and spatial effects and variations in the released radionuclides on the natural environment remain unclear. In the present study, three-year (May 2011 to March 2014) fluctuations and accumulations of total Cs, (134)Cs and (137)Cs in freshwater fishes in Fukushima prefecture after the F1NPP accident were examined. The total Cs, (134)Cs and (137)Cs concentrations decreased gradually during the three-year period that followed the F1NPP accident. However higher levels, i.e., exceeding 100 Bq kg(-1), which is the interim limit of radiocesium level in Japan, were detected in several fish species. Radiocesium accumulation patterns in fishes in Fukushima prefecture varied between regions and corresponded to the environmental radiocesium levels in the Fukushima region. These radionuclides are widely distributed and remain in the natural environment. Moreover, a fresh input of radiocesium substances from the F1NPP site into the terrestrial environment remains.


Fibromyalgia and Chronic Pain Syndromes: A White Paper Detailing Current Challenges in the Field.
This manuscript, developed by a group of chronic pain researchers and clinicians from around the world, aims to address the state of knowledge about fibromyalgia (FM) and identify ongoing challenges in the field of FM and other chronic pain syndromes that may be characterized by pain centralization/amplification/hypersensitivity. There have been many exciting developments in research studies of the pathophysiology and treatment of FM and related syndromes that have the potential to improve the recognition and management of patients with FM and other conditions with FM-like pain. However, much of the new information has not reached all clinicians, especially primary care clinicians, who have the greatest potential to use this new knowledge to positively impact their patients' lives. Furthermore, there are persistent misconceptions about FM and a lack of consensus regarding the diagnosis and treatment of FM. This paper presents a framework for future global efforts to improve the understanding and treatment of FM and other associated chronic pain syndromes, disseminate research findings, identify ways to enhance advocacy for these patients, and improve global efforts to collaborate and reach consensus about key issues related to FM and chronic pain in general.


What interactions can distort the orientational distribution of interfacial water molecules as probed by second harmonic and sum frequency generation?
Aqueous interfaces are omnipresent in nature. Nonlinear optical methods such as second harmonic and sum frequency generation (SHG/SFG) are valuable techniques to access molecular level information from these interfaces. In the interpretation of SHG and SFG data for both scattering and reflection mode experiments, the relation between the second-order hyperpolarizability tensor β(2), a molecular property, and the surface second-order susceptibility χ(2), a surface averaged property, plays a central role. To correctly describe the molecular details of the interface, it needs to be determined how molecules are oriented, and what the influence is of interfacial electrostatic fields and H-bonding on the orientational distribution. Here, we revisit the relations between β(2) and χ(2) and show, by means of a Boltzmann average, that significant energy differences are needed to generate measurable changes in the molecular orientational distribution at the interface. In practice, H-bonding and surface pressure such as applied in a Langmuir trough can be strong enough to alter the shape of the orientational distribution function of water. In contrast, electrostatic fields, such as those present in the Stern layer, will not have a significant impact on the shape of the orientational distribution function of water molecules.


Statins and cancer: A systematic review and meta-analysis.
Systematic reviews on the association between statin therapy and cancer have focused on randomised trials without assessing the quality of evidence. We aimed to review the overall evidence taking study quality into consideration. Publications of original studies on the effect of statin treatment on cancer in adult patients were searched on MEDLINE, EMBASE and CENTRAL databases upto October 2007. Our search yielded 37 eligible original studies out of 3607 references. Five studies were additionally found through manual search. Thus, 42 studies were included in the analyses: 17 randomised controlled trials, 10 cohort studies, and 15 case-control studies. Statins had no effect on the overall incidence of cancer (median risk ratio (RR) 0.96, range 0.72 to 1.2), or on the incidence of lung (median RR 0.92, range 0.83 to 3.0), breast (median RR 1.04, range 0.74 to 19) or prostate cancer (median RR 0.96, range 0.33 to 1.7). They seemed to protect from stomach (median RR 0.59, range 0.40 to 0.88) and liver cancer (median RR 0.62, range 0.33 to 1.2), and from lymphoma (median RR 0.74, range 0.28 to 2.2). They increased the incidence of both melanoma (median RR 1.5, range 1.3 to 1.7) and non-melanoma skin cancer (median RR 1.6, range 1.2 to 2.2). The effect varied, yet inconsistently, by statin type. The median follow-up time was 4 years. The strength of evidence was mostly weak. The evidence suggests that statins do not have short-term effects on cancer risk. The evidence on potentially protective or harmful effects is inconclusive. High quality cohort studies with long follow-up are needed to resolve the issue.


Phosphofructokinase: structure and control.
Phosphofructokinase from Bacillus stearothermophilus shows cooperative kinetics with respect to the substrate fructose-6-phosphate (F6P), allosteric activation by ADP, and inhibition by phosphoenolpyruvate. The crystal structure of the active conformation of the enzyme has been solved to 2.4 A resolution, and three ligand-binding sites have been located. Two of these form the active site and bind the substrates F6P and ATP. The third site binds both allosteric activator and inhibitor. The complex of the enzyme with F6P and ADP has been partly refined at 2.4 A resolution, and a model of ATP has been built into the active site by using the refined model of ADP and a 6 A resolution map of bound 5'-adenylylimidodiphosphate (AMPPNP). The gamma-phosphate of ATP is close to the 1-hydroxyl of F6P, in a suitable position for in-line phosphoryl transfer. The binding of the phosphate of F6P involves two arginines from a neighbouring subunit in the tetramer, which suggests that a rearrangement of the subunits could explain the cooperativity of substrate binding. The activatory ADP is also bound by residues from two subunits.


National variations in VA mental health care for women veterans.
Although the Veterans Health Administration (VA) has recently adopted new policies encouraging gender-specific mental health (MH) care delivery to women veterans, little is known about the potential difficulties local facilities may face in achieving compliance. We assessed variations in women's mental health care delivery arrangements in VA facilities nationwide. We used results from the VA Survey of Women Veterans Health Programs, a key informant survey of senior women's health clinicians representing all VA facilities serving more than 300 women veterans, to assess the array of gender-sensitive mental health care arrangements (response rate, 86%; n = 195). We also examined organizational and area factors related to availability of women's specialty mental health arrangements using multivariable logistic regression. Nationally, over half (53%) of VA facilities had some form of gender-sensitive mental health care arrangements. Overall, 34% of sites reported having designated women's mental health providers in general outpatient mental health clinics (MHCs). Almost half (48%) had therapy groups for women in their MHCs. VAs with women's primary care clinics also delivered mental health services (24%), and 12% of VAs reported having a separate women's MHC, most of which (88%) offered sexual trauma group counseling. Assignment to same-gender mental health providers is not routine. VAs with comprehensive women's primary care clinics were more likely to integrate mental health care for women as well. Local implementation of gender-sensitive mental health care in VA settings is highly variable. Although this variation may reflect diverse local needs and resources, women veterans may also sometimes face challenges in accessing needed services.


Pandemic serovars (O3:K6 and O4:K68) of Vibrio parahaemolyticus associated with diarrhea in Mozambique: spread of the pandemic into the African continent.
Forty-two episodes of Vibrio parahaemolyticus infections were detected in Beira, Mozambique, from January to May 2004. The majority of the isolates (81%) belonged to the pandemic serovars (O3:K6 and O4:K68) of V. parahaemolyticus. The pandemic serovars were positive by group-specific PCR (GS-PCR) and a PCR specific for open reading frame ORF8 (ORF8-PCR), which are molecular markers of the pandemic clone, and were positive for tdh but negative for trh. The remaining 19% of the strains also possessed the tdh gene but were GS-PCR and ORF8-PCR negative and did not belong to the pandemic serovars. Patients with V. parahaemolyticus infection were older (mean age, 27 years) than patients infected by other diarrheal agents (mean age, 21 years). Ten percent of diarrhea patients from whom no V. parahaemolyticus was cultured were severely dehydrated, but none of the V. parahaemolyticus cases were severely dehydrated. This is the first report of the isolation of pandemic strains of V. parahaemolyticus in sub-Saharan Africa and clearly indicates that the pandemic of V. parahaemolyticus has spread into the African continent.


Pet Ownership and Cancer Risk in the Women's Health Initiative.
Pet ownership and cancer are both highly prevalent in the United States. Evidence suggests that associations may exist between this potentially modifiable factor and cancer prevention, though studies are sparse. The present report examined whether pet ownership (dog, cat, or bird) is associated with lower risk for total cancer and site-specific obesity-related cancers. This was a prospective analysis of 123,560 participants (20,981 dog owners; 19,288 cat owners; 1,338 bird owners; and 81,953 non-pet owners) enrolled in the Women's Health Initiative observational study and clinical trials. Cox proportional hazards models were used to estimate HR and 95% confidence intervals for the association between pet ownership and cancer, adjusted for potential confounders. There were no significant relationships between ownership of a dog, cat, or bird and incidence of cancer overall. When site-specific cancers were examined, no associations were observed after adjustment for multiple comparisons. Pet ownership had no association with overall cancer incidence. This is the first large epidemiologic study to date to explore relationships between pet ownership and cancer risk, as well as associated risks for individual cancer types. This study requires replication in other sizable, diverse cohorts. Cancer Epidemiol Biomarkers Prev; 25(9); 1311-6. ©2016 AACR.


Effects of a standardized pamphlet on insomnia in children with autism spectrum disorders.
Sleep difficulties are common reasons why parents seek medical intervention in children with autism spectrum disorders (ASDs). We determined whether a pamphlet alone could be used by parents to help their child's insomnia. Thirty-six children with ASD, ages 2 to 10 years, were enrolled. All had prolonged sleep latency confirmed by actigraphy showing a mean sleep latency of 30 minutes or more. Parents were randomly assigned to receive the sleep education pamphlet or no intervention. Children wore an actigraphy device to record baseline sleep parameters, with the primary outcome variable being change in sleep latency. Actigraphy data were collected a second time 2 weeks after the parent received the randomization assignment and analyzed by using Student's t test. Parents were also asked a series of questions to gather information about the pamphlet and its usefulness. Although participants randomized to the 2 arms did not differ statistically in age, gender, socioeconomic status, total Children's Sleep Habits Questionnaire score, or actigraphy parameters, some differences may be large enough to affect results. Mean change in sleep-onset latency did not differ between the randomized groups (pamphlet versus no pamphlet). Parents commented that the pamphlet contained good information, but indicated that it would have been more useful to be given specific examples of how to take the information and put it into practice. A sleep education pamphlet did not appear to improve sleep latency in children with ASDs.


Two-dimensional Raman-terahertz spectroscopy of water.
Two-dimensional Raman-terahertz (THz) spectroscopy is presented as a multidimensional spectroscopy directly in the far-IR regime. The method is used to explore the dynamics of the collective intermolecular modes of liquid water at ambient temperatures that emerge from the hydrogen-bond networks water forming. Two-dimensional Raman-THz spectroscopy interrogates these modes twice and as such can elucidate couplings and inhomogeneities of the various degrees of freedoms. An echo in the 2D Raman-THz response is indeed identified, indicating that a heterogeneous distribution of hydrogen-bond networks exists, albeit only on a very short 100-fs timescale. This timescale appears to be too short to be compatible with more extended, persistent structures assumed within a two-state model of water.


The Role of Artificial Intelligence and Machine Learning Amid the COVID-19 Pandemic: What Lessons Are We Learning on 4IR and the Sustainable Development Goals.
The COVID-19 pandemic came with disruptions in every aspect of human existence, with all the sectors of the economies of the world affected greatly. In the health sector, the pandemic halted and reversed progress in health and subsequently shortened life expectancy, especially in developing and underdeveloped nations. On the other hand, machine learning and artificial intelligence contributed a great deal to the handling of the pandemic globally. Therefore, the current study aimed to assess the role played by artificial intelligence and machine learning in addressing the dangers posed by the COVID-19 pandemic, as well as extrapolate the lessons on the fourth industrial revolution and sustainable development goals. Using qualitative content analysis, the results indicated that artificial intelligence and machine learning played an important role in the response to the challenges posed by the COVID-19 pandemic. Artificial intelligence, machine learning, and various digital communication tools through telehealth performed meaningful roles in scaling customer communications, provided a platform for understanding how COVID-19 spreads, and sped up research and treatment of COVID-19, among other notable achievements. The lessons we draw from this is that, despite the disruptions and the rise in the number of unintended consequences of technology in the fourth industrial revolution, the role played by artificial intelligence and machine learning motivates us to conclude that governments must build trust in these technologies, to address health problems going forward, to ensure that the sustainable development goals related to good health and wellbeing are achieved.


Co-infection with two Chlamydophila species in a case of fulminant myocarditis.
The aim of this study is to describe a case of fulminant myocarditis caused by co-infection with Chlamydophila pneumoniae and Chlamydophila psittaci in order to facilitate diagnosis and clinical management of patients suffering from this rare but life-threatening condition. Case report. Intensive care unit of Innsbruck Medical University. A 24-yr-old patient admitted with septicemia and cardiac failure. Cardiopulmonary resuscitation, extracorporal membrane oxygenation, implantation of an extracorporal cardiac assist device, and antibiotic treatment with erythromycin. Cp. pneumoniae and Cp. psittaci were identified by means of polymerase chain reaction and electron microscopy in the patient's myocytes. Successful weaning off the ventricular assist device was performed within 2 wks after commencement of antibiotic therapy. This case report demonstrates co-infection with Cp. pneumoniae and Cp. psittaci to be a hitherto unknown cause of fulminant myocarditis. There is a particular risk of misdiagnosis of viral myocarditis, which must be avoided. Patients should be transferred to a center where extracorporal membrane oxygenation therapy and molecular diagnosis of all members of the family Chlamydiaceae are available.


Unmet information needs of men with breast cancer and health professionals.
Male breast cancer (MBC) is rare. Information about breast cancer is usually designed for female patients. However, in males this disease and some side effects differ from its female counterpart. Therefore, there is a need for male-specific information. The aim was to assess unmet information needs of (a) MBC patients and (b) health professionals. Dutch MBC patients (diagnosed between 2011 and 2016 in 21 hospitals), patient advocates and partners were invited to participate in focus groups and/or complete a paper-based questionnaire on information needs. In addition, an online questionnaire on information needs was sent to health professionals involved in MBC patient care. In three focus groups with MBC patients (N = 12) and partners (N = 2) the following unmet information themes were identified: patients' experiences/photographs, symptoms, (delay of) diagnosis, treatments, side effects, follow-up, psychological impact/coping, genetics and family, research and raising awareness. 77 of 107 MBC patients (72%) completed the questionnaire: most patients lacked information about acute (65%) or late (56%) side effects, particularly sexual side effects. Among health professionals, 110 of 139 (79%) had searched for MBC-related information, specifically: patient information, anti-hormonal therapy, genetic testing, research, and psychosocial issues. Unmet information needs in MBC patients and health professionals were identified. Specific information on MBC should be developed to improve timely diagnosis, quality of life, treatment, and survival. A targeted website is an ideal tool to meet these needs. Therefore, we integrated these results into a user-centered design to develop an informative website, www.mannenmetborstkanker.nl.


Death following coronary angiography in a young woman with isolated left coronary ostial stenosis.
A 35-year-old woman with angina of five years duration underwent elective cardiac catheterization and coronary angiography which revealed left main stenosis. Immediately afterwards, the patient became distressed, hypotensive and bradycardic. She died despite emergency percutaneous transluminal coronary angioplasty and resuscitative efforts. Autopsy confirmed isolated left coronary ostial stenosis due to the combination of a congenital abnormality of the ostium and initial segment of left main coronary artery, together with a superimposed myointimal flap bridging the ostium. A unique association was an abnormal configuration of the ostia of the branches of the aortic arch.


TMS can reveal contrasting functions of the dorsal and ventral visual processing streams.
In order to investigate the functional specificity of the dorsal and ventral visual processing steams we used transcranial magnetic stimulation (TMS) to briefly disrupt one or the other while subjects performed three tasks, involving discrimination of colour or shape or relative position. TMS was delivered over right posterior parietal cortex (PPC) or right lateral occipital (LO) cortex, regions known to have visuo-spatial and object processing properties respectively. LO but not PPC stimulation had a significant effect on reaction time when subjects were asked to make a discrimination of relative shape. PPC stimulation had a significant effect when subjects were asked to discriminate relative position of the same shapes. Stimulation of LO also lengthened reaction times on the position task. There were no effects of stimulation at either site on colour discrimination. Results are discussed within the framework of how the dorsal stream and ventral stream are dissociated following their damage in neurological patients and possible ways in which they may interact in the normal brain.


Compliance with the City of Chicago's partial ban on menthol cigarette sales.
In the USA, menthol cigarettes are associated with smoking initiation and decreased likelihood of cessation, particularly for low-income and non-White populations. Local ordinances to restrict menthol cigarette sales are an emergent policy option. In July 2016, Chicago, Illinois became the first major US city to ban menthol cigarette sales within 500 feet of schools. This study assessed ban compliance in June 2017. We randomly selected 100 of 154 stores within 500 feet of a high school. Ninety stores were included in the analysis, excluding permanently closed stores or stores that did not sell tobacco prior to the ban. Compliance was determined by whether a menthol cigarette pack was purchased. We also assessed presence of menthol cigarette replacement packs. Multivariable logistic regression modelled compliance by store type, school (distance to high school, school type) and neighbourhood-level factors (poverty level, proportion of non-White residents). Compliance rate was 57% (weighted, n=53) and no replacement packs were observed. Non-compliant stores were more likely to advertise menthol cigarettes, but ads were present in eight compliant stores. Gas stations had 81% lower odds (OR=0.19, 95% CI 0.06 to 0.58) of complying with the menthol cigarette ban compared with larger/chain stores. School-level and neighbourhood factors were not associated with compliance. The poor compliance observed with Chicago's partial menthol cigarette ban highlights the need for comprehensive efforts. Optimising local resources to target enforcement efforts in gas stations could improve compliance. Ordinances that also restrict advertising could potentially enhance ban impact by reducing exposure to product and promotions.


Awareness of colorectal cancer among public in Asir region.
Colorectal cancer (CRC) has different forms of colon cancer or rectal cancer. CRCs are often considered together because they possess many similar features. A severe form of the disease with higher mortality rate increases with increase in age. The most common CRC risk factors include smoking, diabetes, and obesity. This study aims to evaluate the awareness of CRC in a random population of Asir region and to identify the subpopulation that can be recipients of awareness and screening programs. Cross-sectional nonprobable random sampling study using a self-administered questionnaire survey which was employed to include healthy males and females from Asir region. The questionnaire included ten questions in Arabic language and data were categorized according to gender, marital status, age, and level of education to determine whether these demographic groups possess difference in knowledge about CRC. Most of the respondents (51% and 71.6%) knew what is colon and rectum. About 33.8% know the correct function of the colon while 22.5% know the correct incidence and 22.1% know the correct time of screening for CRC. Very few respondents know the symptoms, risks, and screening modalities of CRC. Pearson's Chi-square test was employed to evaluate the differences in responses in four demographic categories of the study population. P <0.05 was considered as statistically significant. Single less educated males lack knowledge of CRC. In addition, there is very low awareness of CRC symptoms, risk factors, and screening modalities among the entire surveyed population.


Photoconductive enhancement of single ZnO nanowire through localized Schottky effects.
We demonstrated the Au nanoparticle (NP) decoration as an effective way to enhance both photocurrent and photoconductive gain of single ZnO nanowire (NW) photodetectors (PDs) through localized Schottky effects. The enhancement is caused by the enhanced space charge effect due to the existence of the localized Schottky junctions under open-circuit conditions at the NW surfaces, leading to a more pronounced electron-hole separation effect. Since the band-bending under illumination varies relatively small for an Au NP-decorated ZnO NW, the decay of gain is less prominent with increased excitation power, demonstrating the feasibility for a PD to maintain a high gain under high-power illumination.


Physical manipulation of the Escherichia coli chromosome reveals its soft nature.
Replicating bacterial chromosomes continuously demix from each other and segregate within a compact volume inside the cell called the nucleoid. Although many proteins involved in this process have been identified, the nature of the global forces that shape and segregate the chromosomes has remained unclear because of limited knowledge of the micromechanical properties of the chromosome. In this work, we demonstrate experimentally the fundamentally soft nature of the bacterial chromosome and the entropic forces that can compact it in a crowded intracellular environment. We developed a unique "micropiston" and measured the force-compression behavior of single Escherichia coli chromosomes in confinement. Our data show that forces on the order of 100 pN and free energies on the order of 10(5) k(B)T are sufficient to compress the chromosome to its in vivo size. For comparison, the pressure required to hold the chromosome at this size is a thousand-fold smaller than the surrounding turgor pressure inside the cell. Furthermore, by manipulation of molecular crowding conditions (entropic forces), we were able to observe in real time fast (approximately 10 s), abrupt, reversible, and repeatable compaction-decompaction cycles of individual chromosomes in confinement. In contrast, we observed much slower dissociation kinetics of a histone-like protein HU from the whole chromosome during its in vivo to in vitro transition. These results for the first time provide quantitative, experimental support for a physical model in which the bacterial chromosome behaves as a loaded entropic spring in vivo.


Rapid Vision Correction by Special Operations Forces.
This report describes a rapid method of vision correction used by Special Operations Medics in multiple operational engagements. Between 2011 and 2015, Special Operations Medics used an algorithm- driven refraction technique. A standard block of instruction was provided to the medics, along with a packaged kit. The technique was used in multiple operational engagements with host nation military and civilians. Data collected for program evaluation were later analyzed to assess the utility of the technique. Glasses were distributed to 230 patients with complaints of either decreased distance or near (reading). Most patients (84%) with distance complaints achieved corrected binocular vision of 20/40 or better, and 97% of patients with near-vision complaints achieved corrected near-binocular vision of 20/40 or better. There was no statistically significant difference between the percentages of patients achieving 20/40 when medics used the technique under direct supervision versus independent use. A basic refraction technique using a designed kit allows for meaningful improvement in distance and/or near vision at austere locations. Special Operations Medics can leverage this approach after specific training with minimal time commitment. It can serve as a rapid, effective intervention with multiple applications in diverse operational environments.


Glyco-conjugates as elicitors or suppressors of plant innate immunity.
Innate immunity is the first line of defense against invading microorganisms in vertebrates and the only line of defense in invertebrates and plants. Bacterial glyco-conjugates, such as lipopolysaccharides (LPS) from the outer membrane of Gram-negative bacteria and peptidoglycan (PGN) from the cell walls of both Gram-positive and Gram-negative bacteria, and fungal and oomycete glycoconjugates such as oligosaccharides derived from the cell wall components beta-glucan, chitin and chitosan, have been found to act as elicitors of plant innate immunity. These conserved indispensable microbe-specific molecules are also referred to as microbe-associated molecular patterns (MAMPs). Other glyco-conjugates such as bacterial extracellular polysaccharides (EPS) and cyclic glucan have been shown to suppress innate immune responses, thus conversely promoting pathogenesis. MAMPs are recognized by the plant innate immune system though the action of pattern recognition receptors (PRRs). A greater insight into the mechanisms of MAMP recognition and the description of PRRs for different microbial glyco-conjugates will have considerable impact on the improvement of plant health and disease resistance. Here we review the current knowledge about the bacterial MAMPs LPS and PGN, the fungal MAMPs beta-glucan, chitin and chitosan oligosaccharides and the bacterial suppressors EPS and cyclic glucan, with particular reference to the chemical structures of these molecules, the PRRs involved in their recognition (where these have been defined), and possible mechanisms underlying suppression.


Current Pharmacological Approach to ARDS: The Place of Bosentan.
Acute respiratory distress syndrome is characterized by dyspnea at presentation, tachypnea on physical examination, findings of bilateral infiltration in chest radiography, refractory hypoxia, and high mortality. Although the main treatment approach is to address the underlying disease, there are also pharmacological and nonpharmacological options for supportive treatment. There is currently no pharmacological agent with proven efficacy in this syndrome, and many drugs are being studied for this purpose. One of these is the endothelin receptor antagonist bosentan.


The Cost-Effectiveness of High-Risk Lung Cancer Screening and Drivers of Program Efficiency.
Lung cancer risk prediction models have the potential to make programs more affordable; however, the economic evidence is limited. Participants in the National Lung Cancer Screening Trial (NLST) were retrospectively identified with the risk prediction tool developed from the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. The high-risk subgroup was assessed for lung cancer incidence and demographic characteristics compared with those in the low-risk subgroup and the Pan-Canadian Early Detection of Lung Cancer Study (PanCan), which is an observational study that was high-risk-selected in Canada. A comparison of high-risk screening versus standard care was made with a decision-analytic model using data from the NLST with Canadian cost data from screening and treatment in the PanCan study. Probabilistic and deterministic sensitivity analyses were undertaken to assess uncertainty and identify drivers of program efficiency. Use of the risk prediction tool developed from the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial with a threshold set at 2% over 6 years would have reduced the number of individuals who needed to be screened in the NLST by 81%. High-risk screening participants in the NLST had more adverse demographic characteristics than their counterparts in the PanCan study. High-risk screening would cost $20,724 (in 2015 Canadian dollars) per quality-adjusted life-year gained and would be considered cost-effective at a willingness-to-pay threshold of $100,000 in Canadian dollars per quality-adjusted life-year gained with a probability of 0.62. Cost-effectiveness was driven primarily by non-lung cancer outcomes. Higher noncurative drug costs or current costs for immunotherapy and targeted therapies in the United States would render lung cancer screening a cost-saving intervention. Non-lung cancer outcomes drive screening efficiency in diverse, tobacco-exposed populations. Use of risk selection can reduce the budget impact, and screening may even offer cost savings if noncurative treatment costs continue to rise.


Changes in plasma concentrations of aromatic and branched-chain amino acids during sustained exercise in man and their possible role in fatigue.
The plasma concentrations of branched-chain and aromatic amino acids have been measured in two different types of sustained dynamic exercise. Twenty-two subjects participated in the 1986 Stockholm Marathon and eight subjects took part in an army training programme of approximately 1.5-h duration. Both types of exercise caused a significant decrease in the plasma concentration of branched-chain amino acids, while there was no change in the concentration of total (free plus bound to albumin) tryptophan. The plasma concentration of free tryptophan, which was measured in the marathon runners, was found to increase 2.4-fold during the race. This increase is probably caused by a pronounced elevation in the concentration of plasma free fatty acids during exercise, since these are known to displace tryptophan from albumin. The observed increase in plasma free tryptophan concentration, together with the decrease in plasma concentration of branched-chain amino acids, gives rise to a marked increase in the plasma concentration ratio of free tryptophan/branched-chain amino acids. This should lead to an increase in the rate of transport of tryptophan across the blood-brain barrier and hence to an increase in the rate of synthesis of 5-hydroxytryptamine (5-HT) in the brain. An elevated concentration of 5-HT in specific areas of the brain may be responsible, at least in part, for the development of physical, and/or mental fatigue during prolonged exercise.


Gamma-Normal-Gamma mixture model for detecting differentially methylated loci in three breast cancer cell lines.
With state-of-the-art microarray technologies now available for whole genome CpG island (CGI) methylation profiling, there is a need to develop statistical models that are specifically geared toward the analysis of such data. In this article, we propose a Gamma-Normal-Gamma (GNG) mixture model for describing three groups of CGI loci: hypomethylated, undifferentiated, and hypermethylated, from a single methylation microarray. This model was applied to study the methylation signatures of three breast cancer cell lines: MCF7, T47D, and MDAMB361. Biologically interesting and interpretable results are obtained, which highlights the heterogeneity nature of the three cell lines. This underlies the premise for the need of analyzing each of the microarray slides individually as opposed to pooling them together for a single analysis. Our comparisons with the fitted densities from the Normal-Uniform (NU) mixture model in the literature proposed for gene expression analysis show an improved goodness of fit of the GNG model over the NU model. Although the GNG model was proposed in the context of single-slide methylation analysis, it can be readily adapted to analyze multi-slide methylation data as well as other types of microarray data.


Quantitative ultrasound assessment of acute bone loss following spinal cord injury: a longitudinal pilot study.
Spinal cord injury (SCI) results in substantial and rapid osteoporosis. Given its rapid onset, assessment of bone changes in the early stages (first 6 months) following SCI is important. This is particularly pertinent if intervention is to be implemented. Quantitative ultrasound (QUS) represents a potential assessment tool for the evaluation of skeletal changes in the early stages following SCI. This longitudinal pilot study assessed changes in QUS measures of calcaneal broadband ultrasound attenuation (BUA) and speed of sound (SOS) in 15 male subjects (age 23.9+/-7.3 years) over a 6-week period. Their mean time since SCI was 110.3+/-34.5 days. Also assessed were bone mineral density of the calcaneus (BMDc) and proximal tibia (BMDt) using dual-energy X-ray absorptiometry (DXA). Confirming the rapid onset of bone loss following SCI, BMDc and BMDt decreased by 7.5+/-3.0% ( p<0.001) and 5.3+/-4.2% ( p<0.001), respectively. QUS was sensitive to these changes. BUA decreased by 8.5+/-6.9% ( p<0.001), whilst SOS decreased by 1.5+/- 1.3% ( p<0.001). Suggesting an influence of the material properties of bone on BUA, BUA was correlated with BMDc at both the initial ( r = 0.68, p<0.01) and final ( r = 0.62, p<0.01) assessments. There were no significant correlations in the magnitude of change over the 6-week assessment period between any of the skeletal measures (all p>0.05). This suggests that skeletal qualities other than material properties also influence QUS measures. Overall, this study confirmed the rapid onset of bone loss following SCI and showed QUS to be a useful portable measure of acute bone changes. This may allow assessment of bone loss and the efficacy of intervention on this loss in the early stages following injury, a period where traditional axial DXA assessment is limited by practical constraints.


Alloy formation and chemisorption at Zn/Pt(111) bimetallic surfaces using alkali ISS, XPD, and TPD.
Alloy formation and chemisorption at bimetallic surfaces formed by vapor-depositing Zn on a Pt(111) single crystal were investigated primarily by using X-ray photoelectron diffraction (XPD), X-ray photoelectron spectroscopy (XPS), low-energy alkali ion scattering spectroscopy (ALISS), low electron energy diffraction (LEED), and temperature programmed desorption (TPD). A wide range of conditions were investigated to explore whether deposition and annealing of Zn films could produce well-defined, ordered alloy surfaces, similar to those encountered for Sn/Pt(111) surface alloys. These attempts were unsuccessful, although weak, diffuse (2 × 2) spots were observed under special conditions. The particular PtZn bimetallic alloy created by annealing one monolayer of Zn on Pt(111) at 600 K, which has a Zn composition in the surface layer of about 5 at. %, was investigated in detail by using XPD and ALISS. Only a diffuse (1 × 1) pattern was observed from this surface by LEED, suggesting that no long-range, ordered alloy structure was formed. Zn atoms were substitutionally incorporated into the Pt(111) crystal to form a near-surface alloy in which Zn atoms were found to reside primarily in the topmost and second layers. The alloyed Zn atoms in the topmost layer are coplanar with the Pt atoms in the surface layer, without any "buckling" of Zn, that is, displacement in the vertical direction. This result is expected because of the similar size of Pt and Zn, based on previous studies of bimetallic Pt alloys. Zn atoms desorb upon heating rather than diffusing deep into the bulk of the Pt crystal. Temperature programmed desorption (TPD) measurements show that both CO and NO have lower desorption energies on the PtZn alloy surface compared to that on the clean Pt(111) surface.


Plant-expressed virus-like particles reveal the intricate maturation process of a eukaryotic virus.
Many virus capsids undergo exquisitely choreographed maturation processes in their host cells to produce infectious virions, and these remain poorly understood. As a tool for studying virus maturation, we transiently expressed the capsid protein of the insect virus Nudaurelia capensis omega virus (NωV) in Nicotiana benthamiana and were able to purify both immature procapsids and mature capsids from infiltrated leaves by varying the expression time. Cryo-EM analysis of the plant-produced procapsids and mature capsids to 6.6 Å and 2.7 Å resolution, respectively, reveals that in addition to large scale rigid body motions, internal regions of the subunits are extensively remodelled during maturation, creating the active site required for autocatalytic cleavage and infectivity. The mature particles are biologically active in terms of their ability to lyse membranes and have a structure that is essentially identical to authentic virus. The ability to faithfully recapitulate and visualize a complex maturation process in plants, including the autocatalytic cleavage of the capsid protein, has revealed a ~30 Å translation-rotation of the subunits during maturation as well as conformational rearrangements in the N and C-terminal helical regions of each subunit.


Spectral simplicity of apparent complexity. I. The nondiagonalizable metadynamics of prediction.
Virtually all questions that one can ask about the behavioral and structural complexity of a stochastic process reduce to a linear algebraic framing of a time evolution governed by an appropriate hidden-Markov process generator. Each type of question-correlation, predictability, predictive cost, observer synchronization, and the like-induces a distinct generator class. Answers are then functions of the class-appropriate transition dynamic. Unfortunately, these dynamics are generically nonnormal, nondiagonalizable, singular, and so on. Tractably analyzing these dynamics relies on adapting the recently introduced meromorphic functional calculus, which specifies the spectral decomposition of functions of nondiagonalizable linear operators, even when the function poles and zeros coincide with the operator's spectrum. Along the way, we establish special properties of the spectral projection operators that demonstrate how they capture the organization of subprocesses within a complex system. Circumventing the spurious infinities of alternative calculi, this leads in the sequel, Part II [P. M. Riechers and J. P. Crutchfield, Chaos 28, 033116 (2018)], to the first closed-form expressions for complexity measures, couched either in terms of the Drazin inverse (negative-one power of a singular operator) or the eigenvalues and projection operators of the appropriate transition dynamic.


Longitudinal relationships among visual acuity, daily functional status, and mortality: the Salisbury Eye Evaluation Study.
Determination of the mechanisms by which visual loss increases mortality risk is important for developing interventional strategies. To evaluate the direct and indirect effects of loss of visual acuity (VA) on mortality risk through functional status changes among aging adults. Prospective longitudinal study of a population-based sample of 2520 noninstitutionalized adults aged 65 to 84 years from September 16, 1993, through July 26, 2003, in the greater Salisbury area of Maryland. Participants underwent reassessment 2, 6, and 8 years after baseline. Mortality status was ascertained from linkage with the National Death Index through 2009. Results of VA testing and self-reported functional status based on activities of daily living (ADL) and instrumental ADL (IADL). Mortality. Worse VA levels at baseline were associated with an increased the risk for mortality (hazard ratio [HR], 1.16 [95% CI, 1.04-1.28]; P < .01) through their effect on lower IADL levels at baseline. Declines in VA over time were associated with increased mortality risk (HR, 1.78 [95% CI, 1.27-2.51]; P < .001) by way of decreasing IADL levels over time. Participants experiencing the mean linear decline in VA of 1 letter on the Early Treatment Diabetic Retinopathy Study acuity chart per year are expected to have a 16% increase in mortality risk during the 8-year study exclusively through associated declines in IADL levels. In this longitudinal study of older adults, VA loss adversely affected IADL levels, which subsequently increased the risk for mortality. Prevention of disabling ocular conditions, treatment of correctable visual impairment, and interventions designed to prevent the effect of visual impairment on IADL declines may all reduce mortality risk in aging adults.


Congenital transmission of Toxoplasma gondii in deer mice (Peromyscus maniculatus) after oral oocyst infection.
To investigate how different routes of Toxoplasma gondii transmission influence the antibody response and infection status of deer mice (Peromyscus maniculatus), 80 mice were orally infected with 1, 5, 10, or 100 T. gondii oocysts. Ten weeks postinfection, 15 T. gondii -seropositive female mice were bred and allowed to produce 2 litters. Evidence of persistent T .gondii infection in orally infected mice was detected by serology and DNA amplification in mice from all 4 oocyst treatment groups, including those that received only a single T. gondii oocyst. Congenital transmission of T. gondii was detected by polymerase chain reaction (PCR) in 7/8 first and 4/7 second litters. Toxoplasma gondii was also detected by PCR in 9/30 congenitally infected offspring 16 wk after birth, despite the fact that detectable serological titers had waned. These findings raise questions about the applicability of serological testing to assess the prevalence of T. gondii infection in deer mice and other rodents in the wild. Additionally, the detection of frequent congenital transmission suggests that deer mice could help maintain T. gondii in the environment even in the absence of definitive feline hosts.


Resveratrol Co-Treatment Attenuates the Effects of HIV Protease Inhibitors on Rat Body Weight and Enhances Cardiac Mitochondrial Respiration.
Since the early 1990s human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) emerged as a global health pandemic, with sub-Saharan Africa the hardest hit. While the successful roll-out of antiretroviral (ARV) therapy provided significant relief to HIV-positive individuals, such treatment can also elicit damaging side-effects. Here especially HIV protease inhibitors (PIs) are implicated in the onset of cardio-metabolic complications such as type-2 diabetes and coronary heart disease. As there is a paucity of data regarding suitable co-treatments within this context, this preclinical study investigated whether resveratrol (RSV), aspirin (ASP) or vitamin C (VitC) co-treatment is able to blunt side-effects in a rat model of chronic PI exposure (Lopinavir/Ritonavir treatment for 4 months). Body weights and weight gain, blood metabolite levels (total cholesterol, HDL, LDL, triglycerides), echocardiography and cardiac mitochondrial respiration were assessed in PI-treated rats ± various co-treatments. Our data reveal that PI treatment significantly lowered body weight and cardiac respiratory function while no significant changes were found for heart function and blood metabolite levels. Moreover, all co-treatments ameliorated the PI-induced decrease in body weight after 4 months of PI treatment, while RSV co-treatment enhanced cardiac mitochondrial respiratory capacity in PI-treated rats. This pilot study therefore provides novel hypotheses regarding RSV co-treatment that should be further assessed in greater detail.


Red-Osier Dogwood Extracts Prevent Inflammatory Responses in Caco-2 Cells and a Caco-2 BBe1/EA.hy926 Cell Co-Culture Model.
Red-osier dogwood extracts (RDE) contain high levels of phenolic compounds which have been recognized as natural antioxidants. In this study, the potential of RDE to prevent cardiovascular diseases (CVDs) was evaluated using Caco-2 cells and a co-culture model of Caco-2 BBe1/EA.hy926 cells in Transwell® plates. The results showed that RDE supplementation significantly prevented interleukin-8 (IL-8) production and suppressed the gene expression of IL-8, tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and cyclooxygenase 2 (COX-2) in the TNF-α inflamed Caco-2 cells. Meanwhile, the polyphenols (quercetin-3-glucoside, quercetin-glucuronide, rutin, quercetin-3-O-malonylglucoside, and kaempferol-glucoside) in the RDE were validated to be absorbed by Caco-2 BBe1 cells and transported to the basal chamber where EA.hy926 cells were located during 12 h incubation. The transported polyphenols were able to prevent IL-8 production and suppress the gene expression of proinflammatory mediators (TNF-α, ICAM-1, VCAM-1, and COX-2) in the TNF-α or oxidized low-density lipoprotein (ox-LDL) treated EA.hy926 cells. These novel findings demonstrated that phenolic compounds in RDE can be transported to the cardiovascular system by intestinal absorption and mitigate the inflammatory responses of vascular endothelial cells, indicating that RDE could be a natural resource of polyphenols to prevent inflammation cytokine or oxidized lipid-induced CVDs.


Mitral valved stent implantation.
To date, transfemoral and trans-apical valved stent implantation techniques are limited to the replacement of pulmonary and aortic valves in a strictly selected group of patients. The current study was designed to assess the short-term follow-up using a mitral valved stent in off-pump technique. A self-expanding, repositionable mitral valved stent was created for trans-apical implantation. Five pigs underwent successful trans-catheter implantation. Data were gathered to assess the animals' haemodynamical stability after stent implantation (n=5), 6h (n=5) and 1 week (n=4). The valved stent function was assessed by trans-oesophageal echocardiography and ventriculogram. Cardiac computed tomography (CT) was used to evaluate positioning of the new implant. Precise valved stent deployment and accurate subsequent adjustment of its intra-annular position allowed for reduction of paravalvular leakage in all animals. The deployment time ranged from 122 to 271 s and blood loss from 65 to 245 cc. Accurate positioning was established in all but one animal. The average mean transvalvular gradient and mean gradient across left ventricular outflow tract (LVOT) recorded immediately after deployment, 6 h and 1 week were 1.9 + or - 0.9 mmHg, 3.5 + or - 1.6 mmHg, 4.1 + or - 02.3 mmHg and 1.4 + or - 01.3 mmHg, 1.5 + or - 0.7 mmHg 1.9 + or - 0.7 mmHg, respectively. Mild regurgitation was present after valved stent deployment in one out of five animals after 1h, one out of five animals at 6h, and two out of four animals at 1 week. All animals exhibited normal haemodynamics after mitral valved stent implantation and maintained stability for the period of monitoring (6h). One animal died of unrecognised imperfect valved stent positioning after 1 day. In the subsequent animals, valved stent migration, embolisation, systolic anterior movement or LVOT obstruction was not observed after 1 week follow-up. The new mitral valved stent can be deployed in a reproducible manner to achieve reliable stent stability, minimal gradients across the LVOT and adequate valved stent function in short-term follow-up.


Changes in patch features may exacerbate or compensate for the effect of habitat loss on forest bird populations.
One and a half centuries after Darwin visited Chiloe Island, what he described as "…an island covered by one great forest…" has lost two-thirds of its forested areas. At this biodiversity hotspot, forest surface is becoming increasingly fragmented due to unregulated logging, clearing for pastures and replacement by exotic tree plantations. Decrease in patch size, increased isolation and "edge effects" can influence the persistence of forest species in remnant fragments. We assessed how these variables affect local density for six forest birds, chosen to include the most important seed dispersers (four species) and bird pollinators (two species, one of which acts also as seed disperser), plus the most common insectivore (Aphrastura spinicauda). Based on cue-count point surveys (8 points per fragment), we estimated bird densities for each species in 22 forest fragments of varying size, shape, isolation and internal-habitat structure (e.g. tree size and epiphyte cover). Bird densities varied with fragment connectivity (three species) and shape (three species), but none of the species was significantly affected by patch size. Satellite image analyses revealed that, from 1985 to 2008, forested area decreased by 8.8% and the remaining forest fragments became 16% smaller, 58-73% more isolated and 11-50% more regular. During that period, bird density estimates for the northern part of Chiloé (covering an area of 1214.75 km(2)) decreased for one species (elaenia), increased for another two (chucao and hummingbird) and did not vary for three (rayadito, thrust and blackbird). For the first three species, changes in patch features respectively exacerbated, balanced and overcame the effects of forest loss on bird population size (landscape-level abundance). Hence, changes in patch features can modulate the effect of habitat fragmentation on forest birds, suggesting that spatial planning (guided by spatially-explicit models) can be an effective tool to facilitate their conservation.


Human auditory cortical activation during self-vocalization.
During speaking, auditory feedback is used to adjust vocalizations. The brain systems mediating this integrative ability have been investigated using a wide range of experimental strategies. In this report we examined how vocalization alters speech-sound processing within auditory cortex by directly recording evoked responses to vocalizations and playback stimuli using intracranial electrodes implanted in neurosurgery patients. Several new findings resulted from these high-resolution invasive recordings in human subjects. Suppressive effects of vocalization were found to occur only within circumscribed areas of auditory cortex. In addition, at a smaller number of sites, the opposite pattern was seen; cortical responses were enhanced during vocalization. This increase in activity was reflected in high gamma power changes, but was not evident in the averaged evoked potential waveforms. These new findings support forward models for vocal control in which efference copies of premotor cortex activity modulate sub-regions of auditory cortex.


Multiparametric classification links tumor microenvironments with tumor cell phenotype.
While it has been established that a number of microenvironment components can affect the likelihood of metastasis, the link between microenvironment and tumor cell phenotypes is poorly understood. Here we have examined microenvironment control over two different tumor cell motility phenotypes required for metastasis. By high-resolution multiphoton microscopy of mammary carcinoma in mice, we detected two phenotypes of motile tumor cells, different in locomotion speed. Only slower tumor cells exhibited protrusions with molecular, morphological, and functional characteristics associated with invadopodia. Each region in the primary tumor exhibited either fast- or slow-locomotion. To understand how the tumor microenvironment controls invadopodium formation and tumor cell locomotion, we systematically analyzed components of the microenvironment previously associated with cell invasion and migration. No single microenvironmental property was able to predict the locations of tumor cell phenotypes in the tumor if used in isolation or combined linearly. To solve this, we utilized the support vector machine (SVM) algorithm to classify phenotypes in a nonlinear fashion. This approach identified conditions that promoted either motility phenotype. We then demonstrated that varying one of the conditions may change tumor cell behavior only in a context-dependent manner. In addition, to establish the link between phenotypes and cell fates, we photoconverted and monitored the fate of tumor cells in different microenvironments, finding that only tumor cells in the invadopodium-rich microenvironments degraded extracellular matrix (ECM) and disseminated. The number of invadopodia positively correlated with degradation, while the inhibiting metalloproteases eliminated degradation and lung metastasis, consistent with a direct link among invadopodia, ECM degradation, and metastasis. We have detected and characterized two phenotypes of motile tumor cells in vivo, which occurred in spatially distinct microenvironments of primary tumors. We show how machine-learning analysis can classify heterogeneous microenvironments in vivo to enable prediction of motility phenotypes and tumor cell fate. The ability to predict the locations of tumor cell behavior leading to metastasis in breast cancer models may lead towards understanding the heterogeneity of response to treatment.


Postulated Adjuvant Therapeutic Strategies for COVID-19.
The number of COVID-19 patients is still growing exponentially worldwide due to the high transmissibility of the SARS-CoV-2 virus. Therapeutic agents currently under investigation are antiviral drugs, vaccines, and other adjuvants that could relieve symptoms or improve the healing process. In this review, twelve therapeutic agents that could play a role in prophylaxis or improvement of the COVID-19-associated symptoms (as add-on substances) are discussed. Agents were identified based on their known pharmacologic mechanism of action in viral and/or nonviral fields and are postulated to interact with one or more of the seven known mechanisms associated with the SARS-CoV-2 virus: (i) regulation of the immune system; (ii) virus entrance in the cell; (iii) virus replication; (iv) hyperinflammation; (v) oxidative stress; (vi) thrombosis; and (vii) endotheliitis. Selected agents were immune transfer factor (oligo- and polypeptides from porcine spleen, ultrafiltered at <10 kDa; Imuno TF®), anti-inflammatory natural blend (Uncaria tomentosa, Endopleura uchi and Haematoccocus pluvialis; Miodesin®), zinc, selenium, ascorbic acid, cholecalciferol, ferulic acid, spirulina, N-acetylcysteine, glucosamine sulfate potassium hydrochloride, trans-resveratrol, and maltodextrin-stabilized orthosilicic acid (SiliciuMax®). This review gives the scientific background on the hypothesis that these therapeutic agents can act in synergy in the prevention and improvement of COVID-19-associated symptoms.


Assessment and documentation of non-healing, chronic wounds in inpatient health care facilities in the Czech Republic: an evaluation study.
The foundation of health care management of patients with non-healing, chronic wounds needs accurate evaluation followed by the selection of an appropriate therapeutic strategy. Assessment of non-healing, chronic wounds in clinical practice in the Czech Republic is not standardised. The aim of this study was to analyse the methods being used to assess non-healing, chronic wounds in inpatient facilities in the Czech Republic. The research was carried out at 77 inpatient medical facilities (8 university/faculty hospitals, 63 hospitals and 6 long- term hospitals) across all regions of the Czech Republic. A mixed model was used for the research (participatory observation including creation of field notes and content analysis of documents for documentation and analysis of qualitative and quantitative data). The results of this research have corroborated the suspicion of inconsistencies in procedures used by general nurses for assessment of non-healing, chronic wounds. However, the situation was found to be more positive with regard to evaluation of basic/fundamental parameters of a wound (e.g. size, depth and location of a wound) compared with the evaluation of more specific parameters (e.g. exudate or signs of infection). This included not only the number of observed variables, but also the action taken. Both were significantly improved when a consultant for wound healing was present (P = 0·047). The same applied to facilities possessing a certificate of quality issued by the Czech Wound Management Association (P = 0·010). In conclusion, an effective strategy for wound management depends on the method and scope of the assessment of non-healing, chronic wounds in place in clinical practice in observed facilities; improvement may be expected following the general introduction of a 'non-healing, chronic wound assessment' algorithm.


ADAM17 is essential for ectodomain shedding of the EGF-receptor ligand amphiregulin.
The epidermal growth factor (EGF)-receptor ligand amphiregulin (AREG) is a potent growth factor implicated in proliferative skin diseases and in primary and metastatic epithelial cancers. AREG, synthesized as a propeptide, requires conversion to an active peptide by metalloproteases by a process known as ectodomain shedding. Although (ADAM17) a disintegrin and metalloprotease 17 is a key sheddase of AREG, ADAM8-, ADAM15-, and batimastat (broad metalloprotease inhibitor)-sensitive metalloproteases have also been implicated in AREG shedding. In the present study, using a curly bare (Rhbdf2cub ) mouse model that shows loss-of-hair, enlarged sebaceous gland, and rapid cutaneous wound-healing phenotypes mediated by enhanced Areg mRNA and protein levels, we sought to identify the principal ectodomain sheddase of AREG. To this end, we generated Rhbdf2cub mice lacking ADAM17 specifically in the skin and examined the above phenotypes of Rhbdf2cub mice. We find that ADAM17 deficiency in the skin of Rhbdf2cub mice restores a full hair coat, prevents sebaceous gland enlargement, and impairs the rapid wound-healing phenotype observed in Rhbdf2cub mice. Furthermore, in vitro, stimulated shedding of AREG is abolished in Rhbdf2cub mouse embryonic keratinocytes lacking ADAM17. Thus, our data support previous findings demonstrating that ADAM17 is the major ectodomain sheddase of AREG.


Parathyroid hormone and growth hormone have additive or synergetic effect when used as intervention treatment in ovariectomized rats with established osteopenia.
The severely osteoporotic human skeleton is characterized by thin cortices and a very fragile cancellous framework. To increase the biomechanical competence of such a skeleton, powerful anabolic agents are needed. The aim of the present study was to compare the effect of parathyroid hormone (PTH), growth hormone (GH) and combination treatment with PTH and GH in an aged, rat model with established osteopenia. Furthermore, envelope- and site-specific effects of the two agents are described. Twelve-month-old virgin F344 rats were divided into six groups with 11 animals per group: (1) baseline; (2) sham-operated + solvent vehicle (s.v.) (sham); (3) ovariectomized + s.v. (ovx); (4) ovx + GH 2.5 mg/kg body weight per day; (5) ovx + PTH 80 microg/kg body weight per day; and (6) ovx + GH and PTH treatment. Group 1 were killed to establish baseline values. Groups 2 (sham) and 3 (ovx) were killed after 24 weeks. Groups 4, 5, and 6 were allowed to develop osteopenia for 16 weeks before treatment was initiated. Treatment was given for a period of 8 weeks. The effects of GH, PTH, and GH + PTH cotherapy were measured by biomechanical testing at four different skeletal sites: lumbar vertebra; femoral diaphysis; femoral neck; and distal femoral metaphysis. In addition, static histomorphometry was performed at the middiaphyseal region. Ovx induced a loss of bone strength at all sites, but this was significant only at the femoral diaphysis and distal metaphysis. GH could reverse the loss of strength at the diaphysis, but not at the metaphysis. PTH, on the other hand, reversed the loss of strength to values significantly over ovx at all four sites. At the metaphysis, PTH monotherapy increased strength to above sham levels. However, GH + PTH cotherapy showed additive or synergistic effects at the four tested sites, leading to strength values significantly over sham at all these sites. Static histomorphometry showed that GH exerted its main effect on the periosteal envelope and PTH on the endocortical envelope; for this reason, the GH + PTH combination treatment had an additive or synergistic effect. We conclude that GH and PTH have a very pronounced anabolic effect when given in cotherapy. Therefore, this treatment regime seems promising in the clinical situation for management of patients with severe, established osteoporosis.


Comparison of the lower extremity function of patients with foot problems according to the level of kinesiophobia.
The presence of kinesiophobia was identified in patients with foot problems. There was no finding of foot functionality according to the level of kinesiophobia in lower extremity problems. The aim of this study was to compare the lower extremity functional status in foot problems with a low or high level of kinesiophobia. Evaluated herein were 37 patients with foot problems (plantar fasciitis, hallux valgus, flat foot). Physical and demographic characteristics were recorded. Patients were divided into two groups based on if they had a high or low level of kinesiophobia using the Tampa kinesiophobia scale. Ankle plantar flexor and knee flexor muscles tightness were recorded. The foot posture was evaluated using the Foot Posture Index. Foot-related pain was measured using the Visual Analog Scale Foot & Ankle. The Foot Function Index and the American Orthopaedics Foot and Ankle Foundation Ankle-Hindfoot Scale and Hallux Metatarsophalangeal-Interphalangeal Scale were used to assess the foot function. The general functional status of the lower extremities was evaluated using the Lower Extremity Functional Scale. Foot function was better in patients with a low level of kinesiophobia (p < 0.05). Pain was higher in patients with high level of kinesiophobia than in patients with a low level of kinesiophobia (p < 0.05). There was no difference between the groups in terms of foot posture index and muscle tightness (p > 0.05). The general lower extremity function was more negatively affected in patients with a high level of kinesiophobia (p < 0.05). Patients with a high level of kinesiophobia presented with more functional problems in the foot and whole lower extremity; hence, function-based rehabilitation and pain coping strategies should be a crucial part of the rehabilitation program at the earliest opportunity.


Properties of oscillatory afterpotentials in young embryonic chick hearts.
Oscillatory afterpotentials in cardiac tissues are believed to result from an activation of calcium-operated cation channels of mixed selectivity (sodium, potassium), or perturbation of an electrogenic sodium-calcium exchange carrier, by an oscillatory release of calcium from sarcoplasmic reticulum. In the present experiments, the presence and properties of ouabain-induced oscillatory afterpotentials were examined in young (3-day-old) embryonic chick hearts, both fresh and organ cultured for 6-14 days. The hearts did not differentiate in organ culture, and the cells retained slowly rising spontaneous action potentials. To induce the oscillatory afterpotentials, automaticity was suppressed by elevating extracellular K+ ion concentration from 4 mM to 6 mM, and the preparations were electrically stimulated at a rate of 0.5 Hz. Stable oscillatory afterpotentials were induced with 1.3-7.5 microM ouabain. The oscillatory afterpotential amplitude was increased when the stimulation rate was increased to 3 and 4 Hz. The oscillatory afterpotentials were potentiated when extracellular Ca++ ion concentration was increased to 3.6 mM or by the addition of barium (0.1 mM). Low extracellular Na+ ion concentration (40-121 mM), strontium (4 mM), magnesium (2-4 mM), and manganese (1-4 mM) significantly depressed the oscillatory afterpotentials. These properties of the oscillatory afterpotentials are similar to those described for adult mammalian ventricular muscles and Purkinje fibers. Our results suggest that young embryonic chick hearts (which lack fast sodium channels and, instead, have slow sodium channels) possess the calcium-operated mixed cation channels at a very early developmental stage if the oscillatory afterpotentials result from the activation of the mixed cation channels by intracellular calcium.


Transgenic elimination of high-affinity antidepressant and cocaine sensitivity in the presynaptic serotonin transporter.
Serotonin [i.e., 5-hydroxytryptamine (5-HT)]-targeted antidepressants are in wide use for the treatment of mood disorders, although many patients do not show a response or experience unpleasant side effects. Psychostimulants, such as cocaine and 3,4-methylenedioxymethamphetamine (i.e., "ecstasy"), also impact 5-HT signaling. To help dissect the contribution of 5-HT signaling to the actions of these and other agents, we developed transgenic mice in which high-affinity recognition of multiple antidepressants and cocaine is eliminated. Our animals possess a modified copy of the 5-HT transporter (i.e., SERT, slc6a4) that bears a single amino acid substitution, I172M, proximal to the 5-HT binding site. Although the M172 substitution does not impact the recognition of 5-HT, this mutation disrupts high-affinity binding of many competitive antagonists in transfected cells. Here, we demonstrate that, in M172 knock-in mice, basal SERT protein levels, 5-HT transport rates, and 5-HT levels are normal. However, SERT M172 mice display a substantial loss of sensitivity to the selective 5-HT reuptake inhibitors fluoxetine and citalopram, as well as to cocaine. Through a series of biochemical, electrophysiological, and behavioral assays, we demonstrate the unique properties of this model and establish directly that SERT is the sole protein responsible for selective 5-HT reuptake inhibitor-mediated alterations in 5-HT clearance, in 5-HT1A autoreceptor modulation of raphe neuron firing, and in behaviors used to predict the utility of antidepressants.


Dietary emulsifiers impact the mouse gut microbiota promoting colitis and metabolic syndrome.
The intestinal tract is inhabited by a large and diverse community of microbes collectively referred to as the gut microbiota. While the gut microbiota provides important benefits to its host, especially in metabolism and immune development, disturbance of the microbiota-host relationship is associated with numerous chronic inflammatory diseases, including inflammatory bowel disease and the group of obesity-associated diseases collectively referred to as metabolic syndrome. A primary means by which the intestine is protected from its microbiota is via multi-layered mucus structures that cover the intestinal surface, thereby allowing the vast majority of gut bacteria to be kept at a safe distance from epithelial cells that line the intestine. Thus, agents that disrupt mucus-bacterial interactions might have the potential to promote diseases associated with gut inflammation. Consequently, it has been hypothesized that emulsifiers, detergent-like molecules that are a ubiquitous component of processed foods and that can increase bacterial translocation across epithelia in vitro, might be promoting the increase in inflammatory bowel disease observed since the mid-twentieth century. Here we report that, in mice, relatively low concentrations of two commonly used emulsifiers, namely carboxymethylcellulose and polysorbate-80, induced low-grade inflammation and obesity/metabolic syndrome in wild-type hosts and promoted robust colitis in mice predisposed to this disorder. Emulsifier-induced metabolic syndrome was associated with microbiota encroachment, altered species composition and increased pro-inflammatory potential. Use of germ-free mice and faecal transplants indicated that such changes in microbiota were necessary and sufficient for both low-grade inflammation and metabolic syndrome. These results support the emerging concept that perturbed host-microbiota interactions resulting in low-grade inflammation can promote adiposity and its associated metabolic effects. Moreover, they suggest that the broad use of emulsifying agents might be contributing to an increased societal incidence of obesity/metabolic syndrome and other chronic inflammatory diseases.


Influenzanet: Citizens Among 10 Countries Collaborating to Monitor Influenza in Europe.
The wide availability of the Internet and the growth of digital communication technologies have become an important tool for epidemiological studies and health surveillance. Influenzanet is a participatory surveillance system monitoring the incidence of influenza-like illness (ILI) in Europe since 2003. It is based on data provided by volunteers who self-report their symptoms via the Internet throughout the influenza season and currently involves 10 countries. In this paper, we describe the Influenzanet system and provide an overview of results from several analyses that have been performed with the collected data, which include participant representativeness analyses, data validation (comparing ILI incidence rates between Influenzanet and sentinel medical practice networks), identification of ILI risk factors, and influenza vaccine effectiveness (VE) studies previously published. Additionally, we present new VE analyses for the Netherlands, stratified by age and chronic illness and offer suggestions for further work and considerations on the continuity and sustainability of the participatory system. Influenzanet comprises country-specific websites where residents can register to become volunteers to support influenza surveillance and have access to influenza-related information. Participants are recruited through different communication channels. Following registration, volunteers submit an intake questionnaire with their postal code and sociodemographic and medical characteristics, after which they are invited to report their symptoms via a weekly electronic newsletter reminder. Several thousands of participants have been engaged yearly in Influenzanet, with over 36,000 volunteers in the 2015-16 season alone. In summary, for some traits and in some countries (eg, influenza vaccination rates in the Netherlands), Influenzanet participants were representative of the general population. However, for other traits, they were not (eg, participants underrepresent the youngest and oldest age groups in 7 countries). The incidence of ILI in Influenzanet was found to be closely correlated although quantitatively higher than that obtained by the sentinel medical practice networks. Various risk factors for acquiring an ILI infection were identified. The VE studies performed with Influenzanet data suggest that this surveillance system could develop into a complementary tool to measure the effectiveness of the influenza vaccine, eventually in real time. Results from these analyses illustrate that Influenzanet has developed into a fast and flexible monitoring system that can complement the traditional influenza surveillance performed by sentinel medical practices. The uniformity of Influenzanet allows for direct comparison of ILI rates between countries. It also has the important advantage of yielding individual data, which can be used to identify risk factors. The way in which the Influenzanet system is constructed allows the collection of data that could be extended beyond those of ILI cases to monitor pandemic influenza and other common or emerging diseases.


Charging and aggregation of positively charged latex particles in the presence of anionic polyelectrolytes.
Charging behavior and colloidal stability of amidine latex particles are studied in the presence of poly(sodium styrene sulfonate) (PSS) and KCl. Detailed measurements of electrophoretic mobility, adsorbed layer thickness, and aggregation (or coagulation) rate constant on varying the polymer dose, molecular mass of the polymer, and ionic strength are reported. Polyelectrolyte adsorption leads to the characteristic charge reversal (or overcharging) of the colloidal particles at the isoelectric point (IEP). In accordance with classical Derjaguin-Landau-Verwey-Overbeek (DLVO) theory, uncharged particles tend to aggregate because of van der Waals attraction, whereas charged particles are stabilized by electrical double layer repulsion. Attractive patch-charge interactions originating from the laterally inhomogeneous structure of the adsorbed polymer substantially decrease the suspension stability or even accelerate the aggregation rate beyond diffusion control. These electrostatic non-DLVO forces become progressively important with increasing molecular mass of the polymer and the ionic strength of the solution. At higher polymer dose of typically 10 times the IEP, one observes the formation of a saturated layer of the adsorbed polymer with a thickness of several nanometers. Its thickness increases with increasing molecular mass, whereby the layer becomes increasingly porous. This layer does not seem to be involved in the suspension stabilization, since at such high polymer doses the double layer repulsion has attained sufficient strength to stabilize the suspension.


Consumption of a fermented dairy product containing the probiotic Lactobacillus casei DN-114001 reduces the duration of respiratory infections in the elderly in a randomised controlled trial.
Common infectious diseases (CID) of the airways and the gastrointestinal tract are still a considerable cause of morbidity and mortality in elderly. The present study examined the beneficial effect of a dairy product containing the probiotic strain Lactobacillus casei DN-114 001 (fermented product) on the resistance of free-living elderly to CID. The study was multicentric, double blind and controlled, involving 1072 volunteers (median age = 76.0 years) randomised for consumption of either 200 g/d of fermented (n 537) or control (non-fermented) dairy product (n 535) for 3 months, followed by an additional 1 month's follow-up. The results showed that, when considering all CID, the fermented product significantly reduced the average duration per episode of CID (6.5 v. 8 d in control group; P = 0.008) and the cumulative duration of CID (7 v. 8 d in control group; P = 0.009). Reduction in both episode and cumulative durations was also significant for all upper respiratory tract infections (URTI; P < 0.001) and for rhinopharyngitis (P < 0.001). This was accompanied with an increase of L. casei species in stools throughout the fermented product consumption (2-3.8 x 107 equivalents of colony-forming unit/g of stools, P < 0.001). The cumulative number of CID (primary outcome) was not different between groups nor was the CID severity, fever, pathogens' occurrence, medication, immune blood parameters and quality of life. The fermented product was safe and well tolerated. In conclusion, consumption of a fermented dairy product containing the probiotic strain L. casei DN-114 001 in elderly was associated with a decreased duration of CID in comparison with the control group, especially for URTI such as rhinopharyngitis.