Health care costs associated with hepatitis C: a longitudinal cohort study.
Disease-specific estimates of medical costs are important for health policy decision making. To identify predictors of health care costs associated with hepatitis C virus (HCV) seropositivity across disease phases. HCV laboratory tests from the BC Centre for Disease Control were linked to administrative data pertaining to health services and drugs dispensed to estimate costs among case subjects and controls. The case group comprised HCV seropositive individuals (n=20,001), and the control group comprised single-tested, HCV seronegative persons (n=70,752) identified between January 1997 and December 2004. Subject observation time was assigned to the three following disease phases: initial phase (after diagnosis), late phase (late-stage liver disease) and predeath phase (12 months before death). Case subjects and controls were matched for age, sex and a propensity score within each phase to determine the net cost attributable to HCV seropositivity, and were adjusted for demographic and clinical factors. Costs increased with disease progression, with hospitalization being the highest cost component in all phases. Initial and late phase net costs (2005 Canadian dollars) were $1,850 and $6,000 per patient per year, respectively. Costs among case subjects were driven by age, comorbidities, mental illness, illicit drug use and HIV coinfection. While predeath case subject and control costs were virtually the same, costs were high and case subjects died at a younger age.  HCV seropositivity is associated with increased medical costs driven by viral sequelae and medicosocial vulnerabilities (ie, mental illness, illicit drug use and HIV coinfection). Cost mitigation and health outcome improvements will require broad-based prevention programming to reduce vulnerabilities and HCV treatment to prevent disease progression, respectively.


Casting technique and restraint choice influence child safety during transport of body casted children subjected to a simulated frontal MVA.
Hip spica casts (or body casts) are commonly applied to young pediatric trauma and hip dysplasia patients. The greatest hip stability in the cast is achieved via fixed hip flexion or abduction and fixed knee flexion. Unfortunately, this fixed position causes difficulties in restraining children for transport because the child cannot typically accommodate their body to the child car seat geometry. The objectives of the current study were to identify a range of reasonable seating options for casted children. These positions were then studied in frontal crash tests to identify the relative injury exposure for the different positions. A revised casting technique was also investigated in an effort to address head-to-cast contact identified during the course of the study. The current study assessed the ability for different child seats and the vehicle seat belts to accommodate casted 1-year-old and 3-year-old crash test dummies. The restrained dummies were then subjected to frontal 30-mph crash tests with uncasted dummies serving as a control. In general, traditional child seats were able to accommodate both children; however, the child's body shifted anteriorly in the cast when the belts were tightened. This shift produced concerns for pulmonary function and the potential for elevated pressure on the superior mesenteric artery. This anterior shift of the chest was reduced when the dummies were restrained by a special hip spica child seat or solely by the vehicle seat belts. When considering all restraint types, the addition of the cast increased the majority of the injury metric magnitudes. For the 3-year-old dummy these increases were determined to be related to the casting technique; an alternative technique significantly reduced the injury metrics. This study demonstrates that there are anticipated variable effects on basic physiologic function for body-casted children based on the method of restraint. Restraint modalities which place the child forward facing with the face in proximity to the anterosuperior cast overlying the chest should be avoided.


Leaders' perspectives on learning health systems: a qualitative study.
Integrated utilisation of digital health data has the power to transform healthcare to deliver more efficient and effective services, and the learning health system (LHS) is emerging as a model to achieve this. The LHS uses routine data from service delivery and patient care to generate knowledge to continuously improve healthcare. The aim of this project was to explore key features of a successful and sustainable LHS to inform implementation in an Academic Health Science Centre context. We purposively identified and conducted semi-structured qualitative interviews with leaders, experienced in supporting or developing data driven innovations in healthcare. A thematic analysis using NVivo was undertaken. Analysis of 26 interviews revealed five themes thought to be integral in an effective, sustainable LHS: (1) Systematic approaches and iterative, continuous learning with implementation into healthcare contributing to new best-practice care; (2) Broad stakeholder, clinician and academic engagement, with collective vision, leadership, governance and a culture of trust, transparency and co-design; (3) Skilled workforce, capability and capacity building; (4) Resources with sustained investment over time and; (5) Data access, systems and processes being integral to a sustainable LHS. This qualitative study provides insights into the elements of a sustainable LHS across a range of leaders in data-driven healthcare improvement. Fundamentally, an LHS requires continuous learning with implementation of new evidence back into frontline care to improve outcomes. Structure, governance, trust, culture, vision and leadership were all seen as important along with a skilled workforce and sustained investment. Processes and systems to optimise access to quality data were also seen as vital in an effective, sustainable LHS. These findings will inform a co-designed framework for implementing a sustainable LHS within the Australian healthcare and Academic Health Science Centre context. It is anticipated that application of these findings will assist to embed and accelerate the use of routine health data to continuously generate new knowledge and ongoing improvement in healthcare delivery and health outcomes.


How to make exercise counseling more effective: lessons from rural America.
Exercise counseling by primary care physicians has been shown to improve physical activity in patients. However, the prevalence and effectiveness of physician counseling is unknown in rural populations that are at increased risk for chronic diseases. Using a population-based telephone survey at baseline and again at 1-year follow-up, we assessed physical activity behavior among 1141 adults (75% female, 95% white) living within 12 rural communities of Missouri, Tennessee, and Arkansas. We tested the association between physician counseling and patients meeting current physical activity recommendations using logistic regression analysis controlling for demographic variables. Participants who saw a doctor for regular care were 54% more likely to be physically active (adjusted odds ratio [aOR]=1.54; 95% confidence interval [CI], 1.04-2.28). Overweight adults (body mass index [BMI]=25-29.9 kg/m2) who had been advised by their physician to exercise more were nearly 5 times more likely to meet physical activity recommendations if their doctor helped develop an exercise plan (aOR=4.99; 95% CI, 1.69-14.73). Overweight individuals who received additional follow-up with the exercise plan from their doctor had a 51/2-fold increase in likelihood of meeting physical activity recommendations (P<.05). In the overall sample, patients were significantly more likely to initiate (P=.01) and maintain (P=.002) physical activity when the physician prescribed and followed up on an exercise plan. This longitudinal study provides evidence that exercise counseling is most effective when the physician presents the counseling as a plan or prescription and when he or she follows up with the patient on it.


Design of unsymmetrical azo initiators to increase radical generation efficiency in low-density lipoproteins.
Lipid peroxidation studies often employ the use of azo initiators to produce a slow, steady source of free radicals, but the lack of initiators capable of efficiently generating radicals in lipid regions has created persistent problems in these investigations. For example, experiments with symmetrical lipophilic or symmetical hydrophilic azo initiators increasingly suggest that their initiation mechanisms in low-density lipoproteins (LDL) rely upon the presence of alpha-tocopherol to mediate peroxidation. We report here the synthesis and study of the new unsymmetrical azo compounds SA-1, SA-2, C-16, C-12, and C-8 that decompose over a range of convenient temperatures and improve radical generation efficiency and access to lipid compartments. The half-life for decomposition (tau(1/2)) of the unsymmetrical initiators at 37 degrees C in methanol covered a range of 121 hours for SA-1, 77 hours for SA-2, and approximately 25 hours for the series C-16, C-12, and C-8. Agarose gel electrophoresis of LDL incubated with these unsymmetrical initiators supports the conclusion that the initiators associate with lipoprotein without disrupting integrity of the particle. The unsymmetical initiator C-8 when compared to symmetical hydrophilic initiator C-0 is capable of providing increased peroxidation of LDL, as monitored by formation of cholesteryl linoleate oxidation products and consumption of alpha-tocopherol. Efficiency of radical generation in lipophilic and hydrophilic compartments was found to be represented with the use of the radical scavenger combination alpha-tocopherol and uric acid, but not with the use of N,N'-Diphenyl-p-phenylenediamine (DPPD) and uric acid. These unsymmetrical initiators, when compared to the widely used symmetrical azo initiators, provide an advantage of free radical production, lipophilic access, and constant radical generation in the investigation of lipid peroxidation in low-density lipoproteins.


Molecular approaches to probe differential NADH activation of phosphoribulokinase isozymes from Rhodobacter sphaeroides.
The cbbPI and cbbPII genes from Rhodobacter sphaeroides, encoding highly similar phosphoribulokinase (PRK) isozymes, PRK I and PRK II, respectively, exhibited differential allosteric activation by NADH. The two cbbP genes were cloned into expression vectors and homogeneous recombinant protein prepared. PRK II was found to be inherently less stable than PRK I; however, the addition of substrate ATP resulted in the complete protection of both isozymes to a 15-min incubation at 50 degrees C. The relative molecular masses for both octameric isozymes were determined to be approximately 230,000; however, the protective effect of ATP was in accordance with aggregation of monomers to a molecular mass of approximately 750,000. While PRK I exhibited a nearly absolute dependence upon NADH for activity, PRK II retained substantial activity in the absence of NADH. PRK chimeras were thus constructed to facilitate elucidation of the basis for the differential effect of NADH, with advantage taken of the relative sequence identity of about 90% between the two isozymes. Chimeras were constructed either by in vivo homologous recombination, using the sacB gene from Bacillus subtilis as a conditionally lethal marker, or by using convenient restriction sites to combine different parts of the two cbbP genes. The PRK chimeras generated contained either the amino-terminal domain of PRK II and the carboxy-terminal domain of PRK I or the opposite configuration. Subsequent analyses of the chimeras pointed to particular regions and residue(s) as likely being important for NADH activation.


Characteristics of the diet patterns tested in the optimal macronutrient intake trial to prevent heart disease (OmniHeart): options for a heart-healthy diet.
To describe the nutrient and food composition of the diets tested in the Optimal Macronutrient Intake Trial to Prevent Heart Disease (OmniHeart). Two center, randomized, three-period crossover, controlled feeding trial that tested the effects of three healthful diet patterns on blood pressure, serum lipid levels, and estimated cardiovascular risk. One hundred sixty-four participants with prehypertension and hypertension. During the 19 weeks of feeding, participants were required to consume only food prepared as part of the trial. The OmniHeart trial studied three diet patterns that differed in macronutrient composition: a carbohydrate-rich diet similar to the Dietary Approaches to Stop Hypertension diet (58% carbohydrate, 15% protein, and 27% fat), a higher protein diet that had 10% more protein and 10% less carbohydrate (48% carbohydrate, 25% protein, and 27% fat), and a higher unsaturated fat diet that had 10% more unsaturated fat and 10% less carbohydrate (48% carbohydrate, 15% protein, and 37% fat). Each diet contained 6% saturated fat and 100 to 200 mg cholesterol. Sodium was 2,300 mg at the 2,100 kcal energy level and was indexed across energy levels. Calcium, magnesium, and potassium were consistent with recommendations for the Dietary Approaches to Stop Hypertension diet and also indexed to energy levels. Each diet pattern met the major nutrient recommendations set by the Dietary Guidelines for Americans 2005. The 10% protein increase in the higher protein diet emphasized plant protein; however, meat and dairy food sources were also increased somewhat. Olive oil, canola oil, and olive oil spread were used liberally to achieve the unsaturated fat content of the higher unsaturated fat diet. The 10% reduction in carbohydrate in the higher protein diet and the higher unsaturated fat diet was achieved by replacing some fruits with vegetables, reducing sweets, and using smaller portions of grain products. All three diets reduced blood pressure, total and low-density lipoprotein cholesterol levels, and estimated coronary heart disease risk. The OmniHeart diet patterns offer substantial flexibility in macronutrient intake that should make it easier to eat a heart-healthy diet and reduce cardiovascular disease risk.


Incidence of Chronic and Other Knee Pain in Relation to Occupational Risk Factors in a Large Working Population.
The aim of this study was to estimate the incidence of chronic and other knee pain (KP) in relation to occupational and personal risk factors among workers representative of a general working population. Of 3710 workers in a French region included in a surveillance network for musculoskeletal disorders (2002-2005), 2332 completed a follow-up questionnaire in 2007-2009 (Cosali cohort). The questionnaires included questions on musculoskeletal symptoms, and personal and occupational exposure. Incident cases of KP in 2007-2009 (i.e. with KP at follow-up but not at baseline) were dichotomized into chronic KP (>30 days in the previous year) and other KP. Associations between incident KP and personal and occupational factors at baseline were studied separately according to sex using multinomial logistic regression. Of the 1616 respondents without KP at baseline, 122 (7.5%) reported chronic KP and 243 (15.0%) reported other KP. The incidence rate of chronic KP was estimated at 19.6 per 1000 worker-years (95% CI: 16.3-23.5). After adjustment for age and body mass index, significant associations were found between incident chronic KP and handling loads >4kg [odds ratio (OR) 2.1 (1.2-3.6) for men, OR 2.3 (1.1-5.0) for women] and kneeling >2h a day for men [OR 1.8 (1.0-3.0)]. This study highlights the high frequency of chronic KP in the working population and the role of occupational factors in its incidence, in particular those kneeling and handling loads.


CHAracteristics of research studies that iNfluence practice: a GEneral survey of Canadian orthopaedic Surgeons (CHANGES): a pilot survey.
Evidence Based Medicine (EBM) is increasingly being applied to inform clinical decision-making in orthopaedic surgery. Despite the promotion of EBM in Orthopaedic Surgery, the adoption of results from high quality clinical research seems highly unpredictable and does not appear to be driven strictly by randomized trial data. The objective of this study was to pilot a survey to determine if we could identify surgeon opinions on the characteristics of research studies that are perceived as being most likely to influence clinical decision-making among orthopaedic surgeons in Canada. A 28-question electronic survey was distributed to active members of the Canadian Orthopaedic Association (COA) over a period of 11 weeks. The questionnaire sought to analyze the influence of both extrinsic and intrinsic characteristics of research studies and their potential to influence practice patterns. Extrinsic factors included the perceived journal quality and investigator profiles, economic impact, peer/patient/industry influence and individual surgeon residency/fellowship training experiences. Intrinsic factors included study design, sample size, and outcomes reported. Descriptive statistics are provided. Of the 109 members of the COA who opened the survey, 95 (87%) completed the survey in its entirety. The overall response rate was 11% (95/841). Surgeons achieved consensus on the influence of three key designs on their practices: 1) randomized controlled trials 94 (99%), 2) meta-analysis 83 (87%), and 3) systematic reviews 81 (85%). Sixty-seven percent of surgeons agreed that studies with sample sizes of 101-500 or more were more likely to influence clinical practice than smaller studies (n = <100). Factors other than design influencing adoption included 1) reputation of the investigators (99%) and 2) perceived quality of the journal (75%). Although study design and sample size (i.e. minimum of 100 patients) have some influence on clinical decision making, surgeon respondents are equally influenced by investigator reputation and perceived journal quality. At present, continued emphasis on the generation of large, methodologically sound clinical trials remains paramount to translating research findings to clinical practice changes. Specific to this pilot survey, strategies to solicit more widespread responses will be pursued.


Frontolimbic structural changes in borderline personality disorder.
Frontolimbic dysfunction is observed in borderline personality disorder (BPD), with responses to emotional stimuli that are exaggerated in the amygdala and impaired in the anterior cingulate cortex (ACC). This pattern of altered function is consistent with animal models of stress responses and depression, where hypertrophic changes in the amygdala and atrophic changes in the ACC are observed. We tested the hypothesis that BPD patients exhibit gross structural changes that parallel the respective increases in amygdala activation and impairment of rostral/subgenual ACC activation. Twelve unmedicated outpatients with BPD by DSM-IV and 12 normal control (NC) subjects underwent a high-resolution T1-weighted structural MRI scan. Relative gray matter concentration (GMC) in spatially-normalized images was evaluated by standard voxel-based morphometry, with voxel-wise subject group comparisons by t test constrained to amygdala and rostral/subgenual ACC. The BPD group was significantly higher than NC in GMC in the amygdala. In contrast, the BPD group showed significantly lower GMC than the NC group in left rostral/subgenual ACC. This sample of BPD patients exhibits gross structural changes in gray matter in cortical and subcortical limbic regions that parallel the regional distribution of altered functional activation to emotional stimuli among these same subjects. While the histological basis for GMC changes in adult clinical populations is poorly-known at present, the observed pattern is consistent with the direction of change, in animal models of anxiety and depression, of neuronal number and/or morphological complexity in both the amygdala (where it is increased) and ACC (where it is decreased).


Planting Systems Affect Soil Microbial Communities and Enzymes Activities Differentially under Drought and Phosphorus Addition.
The use of phosphorus (P) to alleviate soil nutrient deficiency alters resources in plant and microbial communities, but it remains unknown how mixed and monospecific planting of forest tree species shape soil microbial structure and functions in response to drought and its interplay with phosphorus addition. We investigated the microbial structure and chemical properties of forest soils planted with P. zhennan monoculture, A. cremastogyne monoculture, and their mixed cultures. The three planting systems were exposed to drought (30-35% water reduction) and the combination of drought with P. A well-watered treatment (80-85% water addition) of similar combinations was used as the control. Planting systems shaped the effects of drought on the soil microbial properties leading to an increase in nitrate nitrogen, urease activity, and microbial biomass carbon in the monocultures, but decrease in mixed cultures. In the monoculture of P. zhennan, addition of P to drought-treated soil increased enzyme activities, the concentration of dissolved organic nitrogen, and carbon, leading to increase in the total bacteria, G+ bacteria, and arbuscular mycorrhizal fungi. Except in the drought with P addition treatment, the impact of admixing on total phospholipid fatty acids (PLFAs), bacterial PLFA, and fungi PLFA was synergistic in all treatments. Our findings indicated that in monoculture of P. zhennan and its mixed planting with A. cremastogyne, greater biological activities could be established under drought conditions with the addition of P.


[Dynamic of morphological changes of cerebral hematomas induced by arterial hypertension (analysis of surgical and autopsy materials)].
The pattern of morphological changes in blood clots, brain tissue and vessels of hypertensive hematomas (CH) was studied in 79 surgical and autopsy cases. Brain tissue compression degeneration of cells and fibers, edema were observed during the first 6 hours after the onset of hemorrhage. Necrosis and marked leukocyte infiltration appeared to progress gradually and reach maximum by the disease day 2-3. The degeneration manifested by formation of gliomesodermal capsule surrounding the haemorrhagic lesion from day 3 to 8. Dilatation of small cerebral vessels was followed by an increase in permeability and necrosis of vascular walls predominated within 24-72 hours after initial bleeding. It is suggested that the first 24 hours after CH onset are optimal for surgery.


Identification of stanniocalcin 2 as prognostic marker in renal cell carcinoma.
For an individualized therapy in renal cell carcinoma (RCC), there is a clear need for novel prognostic biomarkers to ensure adequate risk stratification and help with the choice of therapy options. To identify new secreted biomarkers for diagnosis and estimation of prognosis in RCC. A meta-analysis of published microarray data was performed. Stanniocalcin 2 (STC2), a glycoprotein hormone that is involved in regulatory effects on calcium and phosphate transport in the kidney, was found overexpressed in tumors and hence analyzed in detail. Kidney tissue samples derived from 108 patients with RCC undergoing radical nephrectomy between July 2003 and January 2006 were used to validate and estimate the potential of STC2 as a biomarker for RCC. STC2, found upregulated in clear cell RCC, was analyzed in detail using real-time reverse transcription-polymerase chain reaction (RT-PCR), western blotting, and immunohistochemistry. Furthermore, STC2 protein expression determined on a tissue microarray was correlated to clinical pathologic parameters, including patient survival. STC2 was upregulated at the mRNA and protein levels in RCC. In normal renal tissue, STC2 expression was limited to distal tubuli and glomeruli, whereas in tumor a strong cytoplasmic and also membranous staining was detected. STC2 expression was found in clear cell, chromophobe, and papillary RCC. Strong cytoplasmic STC2 expression was significantly associated with shorter patient survival in Kaplan-Meier analyses. In the group of patients without metastases, cytoplasmic STC2 expression was also found as a significant independent risk factor in multivariate analysis. A limitation of the study is the small number of patients. Increased cytoplasmic STC2 expression correlated with conventional indicators of aggressiveness of RCC and shorter overall patient survival times. STC2 could become an adjunct tissue biomarker that may be useful in the postoperative risk stratification of RCC patients.


Quantifying effects of interactions between polyacrylic acid and chlorhexidine in dicalcium phosphate - forming cements.
The aim of this study was to assess how varying the ratio of aqueous 0.8 M citric acid : 6 M polyacrylic acid (PAA) (3 : 0, 1 or 3 by weight) affected setting chemistry, mechanical properties and chlorhexidine di-acetate (CHX) release of dicalcium phosphate - forming bone cements. Cement powder included β-tricalcium phosphate (β-TCP) : monocalcium phosphate monohydrate (MCPM) : CHX at 1 : 1 : (0, 0.08 or 0.16) molar ratio. Powder to liquid ratio was fixed at 3 : 1 by weight. Chemical setting kinetics, reactive intermediate formation and final product homogeneity were assessed by ATR FTIR and Raman mapping. Biaxial flexural strength and modulus were determined after 24 hours setting plus 24 hours in water at 37 °C and analysed using Weibull type equations. CHX release from 1 mm thick set discs was assessed over 4 weeks using UV spectroscopy. FTIR demonstrated that CHX interaction with citric acid inhibited formation of the reactive citrate/dicalcium phosphate intermediate complex that enables delay before snap set. High CHX additionally increased strength variability. Upon partial citric acid substitution with higher levels of PAA, delay before cement set was maintained. Monetite instead of brushite, however, was formed in conjuction with more stable polyacrylate complexes. These formulations had much improved strength but also greater modulus. CHX addition and interaction with PAA encouraged greater brushite instead of monetite formation. These complex interactions enabled formulations with high drug and PAA to have improved strength without increase in modulus. They also had low strength variability and better (slower) controlled release of drug. These properties are beneficial for cement use in a range of orthopaedic and dental applications.


Analysis of "Hybrid Closed Loop Using a Do-It-Yourself Artificial Pancreas System in Adults With Type 1 Diabetes".
In an article in Journal of Diabetes Science and Technology, Nanayakkara and colleagues assessed the glycemic efficacy and safety of AndroidAPS, an open-source automated delivery (AID) system, in a crossover randomized controlled trial. Although the trial included only 20 participants during a relatively short 4-week intervention period, glycemic outcomes attained were similar to commercial AID systems and there were no safety concerns. Validation of open-source AID systems in studies such as this should help address clinician hesitancy regarding these systems, and affirms the role of patient-centered innovation and self-management in diabetes care.


First Lady praises California for work in health care debate.
Hillary Rodham Clinton called California's health care delivery system a model for the nation during a live teleconference at the CAHHS Annual Meeting Oct. 13 in San Diego. In her first-ever address before a state hospital association, the first lady told nearly 1,000 people that California "has its own place of honor in the health care debate" and praised the state for being "years ahead of Washington (D.C.) in recognizing what's right about American health care." What follows is the transcript from her address.


Armored cuticular membranes in Brachycera (Insecta, Diptera).
This study describes and quantifies the ultrastructural design of some cuticular protuberances in the Diptera-Brachycera that appear to have a specialized mechanical function. The microsculpture of membranes in the transitional areas of prothorax-neck, neck-head, head-mouthparts, and in the articulations thorax-coxa and coxa-trochanter was investigated in eight species from six families (Tabanidae, Stratiomyidae, Calliphoridae, Syrphidae, Muscidae and Drosophilidae) by means of scanning electron microscopy. The membrane armatures are single or grouped microtrichia, often located on microplates in the flexible membrane. The different membranes were compared using the following details: microtrichia length, microplate length and width, the shortest distance between microplates, and the number of microtrichia per microplate. Five different types of microstructure were observed: (1) single short papilla-like microtrichia directly arising from the flexible membrane, (2) single elongated microtrichia directly arising from the flexible membrane, (3) single microtrichia located on small areas of the inflexible cuticle, here called microplates, (4) microtrichia groups located on the microplates, and (5) microplates without microtrichia in the flexible membrane. The study reveals the differences in the surface ultrastructure of membranes between different parts of body and between different taxa of flies. The prothorax-neck transition is less specialized in membrane armature as compared with the head-neck articulation, and especially with that of the head-proboscis. The head-proboscis transition has the most complex membrane armature of those species studied. The membrane of the basal joints of the legs has larger plates and a higher number of microtrichia per plate than that of the more distal joints. The complexity of the membrane armature depends on the dimensions of the animal: the smallest species have short ungrouped microtrichia or micropapillae, whereas large species have the highest degree of grouping, the longest microtrichia, and the largest microplates. Three main mechanical functions served by the different armored membranes are suggested, based on the specific characteristics of the microsculptural design: (1) fixation of the folds, (2) prevention of folding, and (3) determination of direction of folding. J. Morphol. 234:213-222, 1997. © 1997 Wiley-Liss, Inc.


Cigarette smoking and albuminuria are associated with impaired arterial smooth muscle function in patients with type 2 diabetes mellitus: a FIELD substudy.
Impaired arterial function has been implicated in diabetes-related atherosclerosis, but its determinants in high-risk adults have not been well characterised. We investigated factors associated with impaired arterial function in adults with type 2 diabetes. Flow-mediated dilatation (a marker of endothelial function) and dilator response to glyceryl trinitrate (to assess smooth muscle function) of the brachial artery were assessed at baseline in 193 patients with type 2 diabetes from the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study. Traditional risk factors were assessed and a multivariable model was constructed to identify factors independently associated with impaired arterial function. Median age was 64 years (interquartile range, 58-69; 61% male) and duration of diabetes was 4 years (interquartile range, 2-9). Flow-mediated dilatation (3.06 ± 0.25%, mean ± SEM) was severely impaired but not significantly associated with other risk factors. Dilator responses to glyceryl trinitrate (10.56 ± 0.52%) were significantly and independently impaired in past and present cigarette smokers (P = 0.005) and in subjects with increased urinary albumin/creatinine ratio (P = 0.01). In adults with type 2 diabetes and known or suspected atherosclerosis, arterial smooth muscle-dependent dilatation was shown to be significantly impaired in cigarette smokers and those with elevated urinary albumin levels.


Photon counting processor for laser velocimetry.
In some of the more difficult applications of laser Doppler velocimetry such as in combustion research, transonic flow, transverse wind, and others, the optical signals are too small for classical detection methods. This paper summarizes the theory, experimental prototype hardware, and test results for a new type of highspeed photon-correlation signal processor which is being developed for weak laser velocimeter signals and other photon-resolved signals. The new system may also be considered to be a statistical digital frequency discriminator. It uses full multiplication with 10-nsec delay time and has the potential for extension to the measurement of the velocity correlations and spectra.


Nanotechnology approaches to improve dental implants.
The requirements imposed by the enormous scale and overall complexity of designing new implants or complete organ regeneration are well beyond the reach of present technology in many dimensions, including nanoscale, as researchers do not yet have the basic knowledge required to achieve these goals. The need for a synthetic implant to address multiple physical and biologic factors imposes tremendous constraints on the choice of suitable materials. There is a strong belief that nanoscale materials will produce a new generation of implant materials with high efficiency, low cost, and high volume. The nanoscale in materials processing is truly a new frontier. Metallic dental implants have been used successfully for decades, but they have serious shortcomings related to their osseointegration and the fact that their mechanical properties do not match those of bone. This paper reviews recent advances in the fabrication of novel coatings and nanopatterning of dental implants. It also provides a general summary of the state of the art in dental implant science and describes possible advantages of nanotechnology for future improvements. The ultimate goal is to produce materials and therapies that will bring state-of-the-art technology to the bedside and improve quality of life and current standards of care.


Performance and microbial community variations of anaerobic digesters under increasing tetracycline concentrations.
The impact of different concentrations of tetracycline on the performance of anaerobic treatment was evaluated. Results revealed that for all of the tested tetracycline concentrations, no major sustained impact on methane production was observed. Instead, a significant increase in propionic acid was observed in the reactor subjected to the highest concentration of tetracycline (20 mg/L). Microbial community analyses suggest that an alternative methanogenic pathway, specifically that of methanol-utilizing methanogens, may be important for ensuring the stability of methane production in the presence of high tetracycline concentrations. In addition, the accumulation of propionate was due to an increase in volatile fatty acids (VFA)-producing bacteria coupled with a reduction in propionate utilizers. An increase in the abundance of tetracycline resistance genes associated with ribosomal protection proteins was observed after 30 days of exposure to high concentrations of tetracycline, while other targeted resistance genes showed no significant changes. These findings suggest that anaerobic treatment processes can robustly treat wastewater with varying concentrations of antibiotics while also deriving value-added products and minimizing the dissemination of associated antibiotic resistance genes.


Applying vibration in early postmenopausal osteoporosis promotes osteogenic differentiation of bone marrow-derived mesenchymal stem cells and suppresses postmenopausal osteoporosis progression.
We aimed to evaluate whether applying low magnitude vibration (LMV) in early postmenopausal osteoporosis (PMO) suppresses its progression, and to investigate underlying mechanisms. Rats were randomly divided into Sham (Sham-operated), Sham+V, OVX (ovariectomized), OVX+E2 (estradiol benzoate), OVX+V (LMV at 12-20 weeks postoperatively), and OVX+Vi (LMV at 1-20 weeks postoperatively) groups. LMV was applied for 20 min once daily for 5 days weekly. V rats were loaded with LMV at 12-20 weeks postoperatively. Vi rats were loaded with LMV at 1-20 weeks postoperatively. Estradiol (E2) rats were intramuscularly injected at 12-20 weeks postoperatively once daily for 3 days. The bone mineral densities (BMDs), biomechanical properties, and histomorphological parameters of tibiae were analyzed. In vitro, rat bone marrow-derived mesenchymal stem cells (rBMSCs) were subjected to LMV for 30 min daily for 5 days, or 17β-E2 with or without 1-day pretreatment of estrogen receptor (ER) inhibitor ICI 182,780 (ICI). The mRNA and protein expresion were performed. Data showed that LMV increased BMD, bone strength, and bone mass of rats, and the effects of Vi were stronger than those of E2. In vitro, LMV up-regulated the mRNA and protein expressions of Runx2, Osx, Col I, and OCN and down-regulated PPARγ, compared with E2. The effects of both LMV and E2 on rBMSCs were inhibited by ICI. Altogether, LMV in early PMO suppresses its progression, which is associated with osteogenic differentiation of rBMSCs via up-regulation of ERα and activation of the canonical Wnt pathway. LMV may therefore be superior to E2 for the suppression of PMO progression.


DMBT1 inhibition of Pseudomonas aeruginosa twitching motility involves its N-glycosylation and cannot be conferred by the Scavenger Receptor Cysteine-Rich bacteria-binding peptide domain.
The scavenging capacity of glycoprotein DMBT1 helps defend mucosal epithelia against microbes. DMBT1 binding to multiple bacterial species involves its conserved Scavenger Receptor Cysteine-Rich (SRCR) domains, localized to a 16-mer consensus sequence peptide, SRCRP2. Previously, we showed that DMBT1 bound Pseudomonas aeruginosa pili, and inhibited twitching motility, a pilus-mediated movement important for virulence. Here, we determined molecular characteristics required for twitching motility inhibition. Heat-denatured DMBT1 lost capacity to inhibit twitching motility and showed reduced pili binding (~40%). Size-exclusion chromatography of Lys-C-digested native DMBT1 showed that only high-Mw fractions retained activity, suggesting involvement of the N-terminal containing repeated SRCR domains with glycosylated SRCR-Interspersed Domains (SIDs). However, individual or pooled consensus sequence peptides (SRCRPs 1 to 7) showed no activity and did not bind P. aeruginosa pili; nor did recombinant DMBT1 (aa 1-220) or another SRCR-rich glycoprotein, CD163. Enzymatic de-N-glycosylation of DMBT1, but not de-O-glycosylation, reduced its capacity to inhibit twitching motility (~57%), without reducing pili binding. Therefore, DMBT1 inhibition of P. aeruginosa twitching motility involves its N-glycosylation, its pili-binding capacity is insufficient, and it cannot be conferred by the SRCR bacteria-binding peptide domain, either alone or mixed with other unlinked SRCRPs, suggesting an additional mechanism for DMBT1-mediated mucosal defense.


Bacterial composition and succession during storage of North-Atlantic cod (Gadus morhua) at superchilled temperatures.
The bacteriology during storage of the North-Atlantic cod has been investigated for the past decades using conventional cultivation strategies which have generated large amount of information. This paper presents a study where both conventional cultivation and cultivation independent approaches were used to investigate the bacterial succession during storage of cod loins at chilled and superchilled temperatures. Unbrined (0.4% NaCl) and brined (2.5% NaCl) cod loins were stored at chilled (0 degrees C) and superchilled (-2 and -3.6 degrees C) temperatures in air or modified atmosphere (MA, % CO2/O2/N2: 49.0 +/- 0.6/7.4 +/- 0.2/43.7 +/- 0.4). Discrepancy was observed between cultivation enumeration and culture independent methods where the former showed a general dominance of Pseudomonas spp. (up to 59%) while the latter showed a dominance of Photobacterium phosphoreum (up to 100%).Gas chromatography-mass spectrophotometry (GC-MC) showed that trimethylamine was the most abundant volatile in mid- and late storage periods. Terminal restriction polymorphism (t-RFLP) analysis showed that the relative abundance of P. phosphoreum increased with storage time. The present study shows the bacteriological developments on lightly salted or non-salted cod loins during storage at superchilled temperatures. It furthermore confirms the importance of P. phosphoreum as a spoilage organism during storage of cod loins at low temperatures using molecular techniques. The methods used compensate each other, giving more detailed data on bacterial population developments during spoilage.


Potassium buffering in the central nervous system.
Rapid changes in extracellular K+ concentration ([K+](o)) in the mammalian CNS are counteracted by simple passive diffusion as well as by cellular mechanisms of K+ clearance. Buffering of [K+](o) can occur via glial or neuronal uptake of K+ ions through transporters or K+-selective channels. The best studied mechanism for [K+](o) buffering in the brain is called K+ spatial buffering, wherein the glial syncytium disperses local extracellular K+ increases by transferring K+ ions from sites of elevated [K+](o) to those with lower [K+](o). In recent years, K+ spatial buffering has been implicated or directly demonstrated by a variety of experimental approaches including electrophysiological and optical methods. A specialized form of spatial buffering named K+ siphoning takes place in the vertebrate retina, where glial Muller cells express inwardly rectifying K+ channels (Kir channels) positioned in the membrane domains near to the vitreous humor and blood vessels. This highly compartmentalized distribution of Kir channels in retinal glia directs K+ ions from the synaptic layers to the vitreous humor and blood vessels. Here, we review the principal mechanisms of [K+](o) buffering in the CNS and recent molecular studies on the structure and functions of glial Kir channels. We also discuss intriguing new data that suggest a close physical and functional relationship between Kir and water channels in glial cells.


Deliberate self-harm as a cause of persistent discharge from arthroscopic portals.
Persistent discharge and bleeding from arthroscopy portals are rare complications. We report three cases which occurred as a result of deliberate self-harm. To our knowledge the occurrence of self-inflicted injury following arthroscopy has not been reported. Although suspicion of such activity may be delayed we consider it important to be aware of the possibility of this behaviour and to seek specialist help early in order to reduce the likelihood of further permanent physical damage.


Enhancing Kokumi Sensation and Reducing Bitterness in Acid-Hydrolyzed Vegetable Proteins through Lactate and Thermal Processing.
Previous studies have demonstrated that thermal processing in the presence of lactate and amino acids can produce taste-active N-lactoyl amino acids. This study aimed to investigate the impact of lactate and thermal processing on the sensory characteristics of acid-hydrolyzed vegetable proteins (aHVP). The results showed that the processed aHVP exhibited enhanced kokumi, a milder umami taste, and reduced bitterness on treatment with 1% lactate at 110 °C for 3 h or 3% lactate at 120 °C for 2 h compared to the unprocessed samples. Partial or orthogonal least-squares discriminant analysis and variable importance in projection (VIP) analyses revealed the significant contributions of N-,l-Lac-l-hydrophobic AAs [-Met, -Ile, -Leu, -Val, and -Phe (VIP > 1.2)] to the observed differences between the processed and unprocessed samples. Electronic tongue analysis confirmed the sensory findings and indicated a decrease in the aftertaste of bitterness in the processed samples. Furthermore, the study identified the sensory characteristics of N-l-Lac-l-Met, -Ile, and -Leu, highlighting their potential to enhance salty, umami, and kokumi perception in simulated broth. Furthermore, the study incorporated the addition of bitter amino acids (Val, Ile, Leu, Tyr, Phe, Lys, His, and Arg) and the aforementioned N-l-Lac-l-AAs to aHVP, providing further evidence for their contributions to bitterness and aftertaste-B as well as the kokumi differences, respectively. This study provides valuable insights into the sensory effects of lactate and thermal processing on aHVP, facilitating the development of improved taste-enhancing strategies.


Safety, tolerability, and efficacy of raltegravir in a diverse cohort of HIV-infected patients: 48-week results from the REALMRK Study.
The racial diversity and gender distribution of HIV-infected patients make it essential to confirm the safety and efficacy of raltegravir in these populations. A multicenter, open-label, single-arm observational study was conducted in a diverse cohort of HIV-infected patients (goals: ≥25% women; ≥50% blacks in the United States), enrolling treatment-experienced patients failing or intolerant to current antiretroviral therapy (ART) and treatment-naive patients (limited to ≤20%). All patients received raltegravir 400 mg b.i.d. in a combination antiretroviral regimen for up to 48 weeks. A total of 206 patients received study treatment at 34 sites in the United States, Brazil, Dominican Republic, Jamaica, and South Africa: 97 (47%) were female and 153 (74%) were black [116 (56%) in the United States]. Of these, 185 patients were treatment experienced: 97 (47%) were failing and 88 (43%) were intolerant to current therapy; 21 patients (10%) were treatment naive. Among treatment-intolerant patients, 55 (63%) had HIV-1 RNA<50 copies/ml at baseline. Overall, 15% of patients discontinued: 13% of men, 18% of women, 14% of blacks, and 17% of nonblacks. At week 48, HIV RNA was <50 copies/ml in 60/94 (64%) patients failing prior therapy, 61/80 (76%) patients intolerant to prior therapy, and 16/21 (76%) treatment-naive patients. Response rates were similar for men vs. women and black vs. nonblack patients. Drug-related clinical adverse events were reported by 8% of men, 18% of women, 14% of blacks, and 9% of nonblacks. After 48 weeks of treatment in a diverse cohort of HIV-infected patients, raltegravir was generally safe and well tolerated with potent efficacy regardless of gender or race.


Diabetes, fasting glucose, and the risk of glaucoma: a meta-analysis.
We performed a systematic review to summarize the association of diabetes and blood glucose levels with glaucoma, intraocular pressure (IOP), and ocular hypertension in the general population. Diabetes has been proposed as a risk factor for glaucoma, but epidemiologic studies have been inconsistent, and the association is still controversial. Furthermore, no systematic reviews evaluated other metabolic abnormalities, such as the metabolic syndrome, with the risk of glaucoma. We identified the studies by searching the PubMed and EMBASE databases. We used inverse-variance weighted random-effects models to summarize relative risks across studies. We identified 47 studies including 2 981 342 individuals from 16 countries. The quality of evidence generally was higher in the cohort compared with case-control or cross-sectional studies. The pooled relative risk for glaucoma comparing patients with diabetes with those without diabetes was 1.48 (95% confidence interval [CI], 1.29-1.71), with significant heterogeneity across studies (I(2) = 82.3%; P < 0.001). The risk of glaucoma increased by 5% (95% CI, 1%-9%) for each year since diabetes diagnosis. The pooled average difference in IOP comparing patients with diabetes with those without diabetes was 0.18 mmHg (95% CI, 0.09-0.27; I(2) = 73.2%), whereas the pooled average increase in IOP associated with an increase in 10 mg/dl in fasting glucose was 0.09 mmHg (95% CI, 0.05-0.12; I(2) = 34.8%). Diabetes, diabetes duration, and fasting glucose levels were associated with a significantly increased risk of glaucoma, and diabetes and fasting glucose levels were associated with slightly higher IOP.


Antigen-specific T cell responses in SARS-CoV-2 mRNA-vaccinated children.
SARS-CoV-2 mRNA vaccines elicit humoral responses in children that are comparable to those in adults. However, early-life T cell responses are distinct from adult ones, and questions remain about the nature and kinetics of mRNA vaccine-induced T cell responses in children. We report that Pfizer BNT162b2 mRNA vaccination elicits a significant antigen-specific CD4+ T cell response in the ≥12-year-old cohort. This response is weaker in magnitude in the 5- to 11-year-old cohort and is not improved by a higher vaccine dose (Moderna mRNA1273, 100 μg), suggesting distinct developmental programming that may underscore early-life T cell immunity. Increased effector phenotypes of antigen-specific T cells in younger children correspond with elevated anti-receptor binding domain antibody levels, albeit at the cost of memory generation. These studies highlight aspects of age-specific adaptive immune responses and the need for careful consideration of priming conditions including vaccine dose and adjuvant in the pediatric population.


TEM-184, a Novel TEM-Derived Extended-Spectrum β-Lactamase with Enhanced Activity against Aztreonam.
TEM-184, a novel TEM-derived extended-spectrum β-lactamase (ESBL), was isolated from an Escherichia coli ST354 clinical strain. Compared to TEM-1, TEM-184 contains the mutations Q6K, E104K, I127V, R164S, and M182T. Kinetic analysis of this enzyme revealed extended-spectrum activity against aztreonam in particular. TEM-184 was also susceptible to inhibitors, including clavulanic acid, tazobactam, and avibactam.


Update of the Xylella spp. host plant database - systematic literature search up to 30 June 2021.
Following a request from the European Commission, EFSA was asked to create and regularly update a database of host plant species of Xylella spp. The mandate now covers the period 2021-2026 and EFSA is requested to release an update of the database twice per year. The aim of the database is to provide information and scientific support to risk assessors, risk managers and researchers dealing with Xylella spp. This report is related to the fifth version of the database published in Zenodo in the EFSA Knowledge Junction community, covering literature published from 1 January 2021 up to 30 June 2021, and recent Europhyt outbreak notifications. Informative data have been extracted from 41 selected publications. Nineteen new host plants were identified and added to the database since the previous update published in June 2021. Those plant species were reported naturally infected by subsp. multiplex or unknown (i.e. not reported in the publication) of X. fastidiosa in the UE (France, Spain and Portugal). No additional data were retrieved for X. taiwanensis. New information on the tolerant/resistant response of plant species to X. fastidiosa infection were added, while no new STs have been identified worldwide compared to the previous update published in May 2021. The overall number of Xylella spp. host plants determined with at least two different detection methods or positive with one method (between: sequencing, pure culture isolation) now reaches 407 plant species, 185 genera and 68 families. Such numbers raise to 655 plant species, 293 genera and 88 families if considered regardless of the detection method applied.


Generation of transmembrane electrical potential during NADH oxidation via the external pathway and the fatty acid uncoupling effect after transient opening of the Ca2+-dependent cyclosporin A-sensitive pore in liver mitochondria.
The effects of transient pore opening on generation of the transmembrane gradient of electrical potential across the inner mitochondrial membrane (DeltaPsi) induced by NADH oxidation through the external pathway as well as on the uncoupling effect of fatty acids were studied. The pore opening was monitored by changes in the DeltaPsi value. The cycle of pore opening/closing was found to have only an insignificant effect on the sensitivity of DeltaPsi to fatty acid uncoupling. Once this cycle is over, NADH oxidation in the presence of exogenous cytochrome c results in generation of DeltaPsi. In the absence of cytochrome c, the generation of DeltaPsi induced by oxidation of exogenous NADH is observed if the incubation medium pH has been decreased from 7.4 to 7.0. The generation of DeltaPsi was inhibited by cyclosporin A. In isotonic salt medium containing 125 mM KCl, the maximum level of DeltaPsi generated by exogenous NADH after the cycle of pore opening/closing was significantly lower than the maximum level of DeltaPsi generated in hypotonic incubation medium. The data obtained in this work suggest that the cycle of pore opening/closing has little if any effect on the energy coupling in liver mitochondria, whereas the external pathway of NADH oxidation activated by this cycle may support the energy-dependent functions of liver mitochondria.


Integrating maternal, infant, and young child nutrition: report on the ten year strategy Infant and Young Child Nutrition (IYCN) Working Group October 2008 workshop.
Members of the Infant and Young Child Nutrition (IYCN) Working Group of the Ten Year Strategy for the Reduction of Vitamin and Mineral Deficiencies and several guests and speakers participated in a workshop in Geneva on 10 October 2008. The workshop had two broad objectives. The first objective was to review the evidence base for maternal and IYCN actions and explore how to integrate action throughout the window of opportunity from the prenatal period through the first 2 years of life. The second objective was to discuss the development of the Maternal, Infant, and Young Child Nutrition (MIYCN) Network in relation to the IYCN Working Group's role and structure. The speakers identified a spectrum of efforts needed to improve maternal, infant, and young child nutrition. The group decided to continue discussion on initiating a structure for an MIYCN Network to enhance collaboration.


Obesity and hypercholesterolemia following heart transplantation.
Successful strategies for avoiding obesity and hypercholesterolemia are difficult to validate because of imprecise problem identification. The purpose of this study was to describe the incidence, severity, and onset of obesity and hypercholesterolemia among heart transplant recipients and identify relationships between demographic variables and weight or cholesterol levels during the first year following transplantation. Data were collected from retrospective chart review. Forty-two patients were randomly selected from 224 patients who were undergoing heart transplantation at the Johns Hopkins Hospital between July 1983 and December 1995. Significant differences were found in weight and cholesterol level during the first 12 months. Patients with ideal body weight less than 110%, compared with greater than 110%, survived longer. Relationships were identified between prednisone dose and weight, cumulative prednisone dose and weight, and weight change and change in total cholesterol level 1 year following transplantation. Multivariate analysis showed cumulative prednisone as an independent predictor of weight. Obesity and hypercholesterolemia were significant problems within 3 months of transplantation. Although prednisone dosage should be adjusted to the lowest possible dose, dietary and lifestyle changes remain the foundation of effective management of these posttransplant complications.


Hypertension linked to Alzheimer's disease via stroke: Mendelian randomization.
This study aimed to investigate the relationship between hypertension and Alzheimer's disease (AD) and demonstrate the key role of stroke in this relationship using mediating Mendelian randomization. AD, a neurodegenerative disease characterized by memory loss, cognitive impairment, and behavioral abnormalities, severely affects the quality of life of patients. Hypertension is an important risk factor for AD. However, the precise mechanism underlying this relationship is unclear. To investigate the relationship between hypertension and AD, we used a mediated Mendelian randomization method and screened for mediating variables between hypertension and AD by setting instrumental variables. The results of the mediated analysis showed that stroke, as a mediating variable, plays an important role in the causal relationship between hypertension and AD. Specifically, the mediated indirect effect value for stroke obtained using multivariate mediated MR analysis was 54.9%. This implies that approximately 55% of the risk of AD owing to hypertension can be attributed to stroke. The results suggest that the increased risk of AD owing to hypertension is mediated through stroke. The finding not only sheds light on the relationship between hypertension and AD but also indicates novel methods for the prevention and treatment of AD. By identifying the critical role of stroke in the link between hypertension and AD, this study provides insights into potential interventions that could mitigate the impact of hypertension on AD. This could help develop personalized treatments and help improve the quality of life of patients with AD who suffer from hypertension.


Composite Classic Hodgkin Lymphoma and Follicular Lymphoma: A Clinicopathologic Study of 22 Cases With Review of 27 Additional Cases in the Literature.
Composite classic Hodgkin lymphoma and follicular lymphoma (CHLFL) is a rare and poorly characterized entity. Herein, we report the clinicopathologic features of 22 cases of CHLFL from 3 institutions and we assess 27 additional cases reported in the literature. In our cohort (n=22), patients with CHLFL had a median age of 61 years and an equal male to female incidence. Most cases (95%) arose de novo with the remaining patients having a history of non-Hodgkin lymphoma. CHLFL always involved lymph nodes (100%) and most cases (95%) revealed 2 distinct areas separately diagnostic for CHL and FL. The CHL component represented a variable proportion of the overall neoplasm (5% to 90%) and was either mixed cellularity (82%) or nodular sclerosis (18%) type. The Hodgkin/Reed-Sternberg cells expressed CD30 (100%), PAX5 (100%), CD15 (62%), BCL6 (47%), BCL2 (29%), and EBER (25%), in a polymorphous inflammatory background typical of CHL. The FL component was low-grade in 55%, grade 3A in 36%, and grade 3B in 9% of cases. All 3 cases investigated by cytogenetic methods for a clonal relationship between the CHL and FL components were clonally related. These clinicopathologic features of our cohort are similar to those of cases reported in the literature. The 5-year overall survival in combined patients with CHLFL (n=49) was 48%, comparable to CHL but worse than FL in the elderly. In summary, CHLFL is a rare entity that most often occurs in older adults, involves lymph nodes, and most commonly presents de novo. In the small number of cases assessed, the CHL and FL components are usually clonally related suggesting that the CHL and FL components may share a common progenitor B-cell, likely a mutated germinal center B-cell.


Neuroprotective role of Sirt1 in mammalian models of Huntington's disease through activation of multiple Sirt1 targets.
Huntington's disease is a fatal neurodegenerative disorder caused by an expanded polyglutamine repeat in huntingtin (HTT) protein. We previously showed that calorie restriction ameliorated Huntington's disease pathogenesis and slowed disease progression in mice that model Huntington's disease (Huntington's disease mice). We now report that overexpression of sirtuin 1 (Sirt1), a mediator of the beneficial metabolic effects of calorie restriction, protects neurons against mutant HTT toxicity, whereas reduction of Sirt1 exacerbates mutant HTT toxicity. Overexpression of Sirt1 improves motor function, reduces brain atrophy and attenuates mutant-HTT-mediated metabolic abnormalities in Huntington's disease mice. Further mechanistic studies suggested that Sirt1 prevents the mutant-HTT-induced decline in brain-derived neurotrophic factor (BDNF) concentrations and the signaling of its receptor, TrkB, and restores dopamine- and cAMP-regulated phosphoprotein, 32 kDa (DARPP32) concentrations in the striatum. Sirt1 deacetylase activity is required for Sirt1-mediated neuroprotection in Huntington's disease cell models. Notably, we show that mutant HTT interacts with Sirt1 and inhibits Sirt1 deacetylase activity, which results in hyperacetylation of Sirt1 substrates such as forkhead box O3A (Foxo3a), thereby inhibiting its pro-survival function. Overexpression of Sirt1 counteracts the mutant-HTT-induced deacetylase deficit, enhances the deacetylation of Foxo3a and facilitates cell survival. These findings show a neuroprotective role for Sirt1 in mammalian Huntington's disease models and open new avenues for the development of neuroprotective strategies in Huntington's disease.


Lexical-semantic deficits in processing food and non-food items.
The study of category specific deficits in brain-damaged patients has been instrumental in explaining how knowledge about different types of objects is organized in the brain. Much of this research focused on testing putative semantic sensory/functional subsystems that could explain the observed dissociations in performance between living things (e.g., animals and fruits/vegetables) and non-living things (e.g., tools). As neuropsychological patterns that did not fit the original living/non-living distinction were observed, an alternative organization of semantic memory in domains constrained by evolutionary pressure was hypothesized. However, the category of food, that contains both living-natural items, such as an apple, and nonliving-manufactured items as in the case of a hamburger, has never been systematically investigated. As such, food category could turn out to be very useful to test whether the brain organizes the knowledge about food in sensory/functional subsystems, in a specific domain, or whether both approaches might need to be integrated. In the present study we tested the ability of patients with Alzheimer dementia (AD) and with Primary Progressive Aphasias (PPA) as well as healthy controls to perform a confrontation naming task, a categorization task, and a comprehension of edible (natural and manufactured food) and non edible items (tools and non-edible natural things) task (Tasks 1-3). The same photographs of natural and manufactured food were presented together with a description of food's sensory or functional property that could be either congruent or incongruent with that particular food (Task 4). Patients were overall less accurate than healthy individuals, and PPA patients were generally more impaired than AD patients, especially on the naming task. Food tended to be processed better than non-food in two out of three tasks (categorization and comprehension tasks). Patient groups showed no difference in naming food and non-food items, while controls were more accurate with non-food than food (controlling for the linguistic variables and calorie content). AD patients named manufactured food more accurately than natural food (with PPA and controls showing no difference). Recognition of food and, to some extent, of manufactured food seems to be more resilient to brain damage, possibly by virtue of its survival relevance. Furthermore, on Task 4 patients showed an advantage for the sensory-natural pairs over sensory-manufactured combination. Overall, findings do not fit an existing model of semantic memory and suggest that properties intrinsic to the food items (such as the level of transformation and the calorie content) or even to the participants like the Body Mass Index (as shown in another study reviewed here) should be considered.


Booster immunization of children with an acellular pertussis vaccine enhances Th2 cytokine production and serum IgE responses against pertussis toxin but not against common allergens.
Acellular pertussis vaccines (Pa) protect against severe pertussis in children. However, serum antibody responses decline quickly after immunization. Studies in animal models suggest that cell-mediated immunity also contributes to protection against Bordetella pertussis, and it has already been demonstrated that Pa induce T cells that secrete type-1 and type-2 cytokines in children. In this study we examined the persistence of the T cell response and the effect of booster immunization in 4-6-year-old children. Cell-mediated immunity to B. pertussis antigens was detected in a high proportion of children more than 42 months after their last immunization. Peripheral blood mononuclear cells (PBMC) from the majority of children secreted interferon-gamma (IFN-gamma) and a smaller proportion IL-5, in response to specific antigen stimulation in vitro. However, following booster immunization, significantly higher concentrations of IL-5, but not IFN-gamma, were produced by PBMC in response to B. pertussis antigens. Furthermore, plasma IL-4 and IL-5 concentrations were increased, whereas IFN-gamma concentrations were reduced following booster immunization. It has been suggested that childhood immunization with Th2-inducing vaccines may predispose some children to atopic disease. Although we found that pertussis toxin (PT)-specific IgE was significantly increased after booster immunization in both atopic and non-atopic children, the levels of IgE to common allergens and the prevalence of positive skin prick test were unaffected by the booster vaccination. Thus, despite the enhancement of type-2 responses to B. pertussis antigens, booster vaccination with Pa does not appear to be a risk factor for allergy.


How does mindfulness modulate self-regulation in pre-adolescent children? An integrative neurocognitive review.
Pre-adolescence is a key developmental period in which complex intrinsic volitional methods of self-regulation are acquired as a result of rapid maturation within the brain networks underlying the self-regulatory processes of attention control and emotion regulation. Fostering adaptive self-regulation skills during this stage of development has strong implications for physical health, emotional and socio-economic outcomes during adulthood. There is a growing interest in mindfulness-based programmes for pre-adolescents with initial findings suggesting self-regulation improvements, however, neurodevelopmental studies on mindfulness with pre-adolescents are scarce. This analytical review outlines an integrative neuro-developmental approach, which combines self-report and behavioural assessments with event related brain potentials (ERPs) to provide a systemic multilevel understanding of the neurocognitive mechanisms of mindfulness in pre-adolescence. We specifically focus on the N2, error related negativity (ERN), error positivity (Pe), P3a, P3b and late positive potential (LPP) ERP components as indexes of mindfulness related modulations in non-volitional bottom-up self-regulatory processes (salience detection, stimulus driven orienting and mind wandering) and volitional top-down self-regulatory processes (endogenous orienting and executive attention).


Pregnancy as a cardiac stress model.
Cardiac hypertrophy occurs during pregnancy as a consequence of both volume overload and hormonal changes. Both pregnancy- and exercise-induced cardiac hypertrophy are generally thought to be similar and physiological. Despite the fact that there are shared transcriptional responses in both forms of cardiac adaptation, pregnancy results in a distinct signature of gene expression in the heart. In some cases, however, pregnancy can induce adverse cardiac events in previously healthy women without any known cardiovascular disease. Peripartum cardiomyopathy is the leading cause of non-obstetric mortality during pregnancy. To understand how pregnancy can cause heart disease, it is first important to understand cardiac adaptation during normal pregnancy. This review provides an overview of the cardiac consequences of pregnancy, including haemodynamic, functional, structural, and morphological adaptations, as well as molecular phenotypes. In addition, this review describes the signalling pathways responsible for pregnancy-induced cardiac hypertrophy and angiogenesis. We also compare and contrast cardiac adaptation in response to disease, exercise, and pregnancy. The comparisons of these settings of cardiac hypertrophy provide insight into pregnancy-associated cardiac adaptation.


Carbamazepine hypersensitivity syndrome mimicking mycosis fungoides.
We report a case of a patient who experienced a generalized skin rash with systemic involvement 2 months after beginning carbamazepine treatment for trigeminal neuralgia. Skin biopsy specimens suggest mycosis fungoides. Complete remission of the clinical and pathologic changes after drug discontinuation and the positive result of carbamazepine from an epicutaneous test suggest a diagnosis of pseudolymphoma due to carbamazepine.


Structural stability of single-layer PdSe2 with pentagonal puckered morphology and its nanotubes.
Two-dimensional (2D) materials have gained a lot of attention being a new class of materials with unique properties that could influence future technologies. Concomitant computational design and discovery of new two-dimensional materials have therefore become a significant part of modern materials research. The stability of these predicted materials has emerged as the main issue due to drawbacks of the periodic boundary condition approximation that allow one to pass common criteria of stability. Here, based on first-principle calculations, we demonstrate structural stability and instability of several recently proposed 2D materials with pentagonal morphology including the experimentally exfoliated single-layer PdSe2. It is found that an appropriate orientation of the central Pd sublattice with respect to Se2 dimers effectively compensates all mechanical stress and preserves the planar structure of the PdSe2 nanoclusters, while the flakes of all other materials having pentagonal morphology exhibit non-zero curvature induced by excessive interatomic forces. The relative energies of the PdSe2 monolayer and nanotubes per formula unit also confirm that the planar monolayer is a global energy minimum. Like the monolayer, (n,0) PdSe2 tubes are indirect band gap semiconductors with similar band gaps, while (n,n) tubes reveal indirect-direct band gap transitions following the increase of the tube diameter. Small strain energies of large diameter tubes propose their possible experimental realization for various optoelectronic applications.


Transformation of follicular lymphoma to diffuse large-cell lymphoma: alternative patterns with increased or decreased expression of c-myc and its regulated genes.
The natural history of follicular lymphoma (FL) is frequently characterized by transformation to a more aggressive diffuse large B cell lymphoma (DLBCL). We compared the gene-expression profiles between transformed DLBCL and their antecedent FL. No genes were observed to increase or decrease their expression in all of the cases of histological transformation. However, two different gene-expression profiles associated with the transformation process were defined, one in which c-myc and genes regulated by c-myc showed increased expression and one in which these same genes showed decreased expression. Further, there was a striking difference in gene-expression profiles between transformed DLBCL and de novo DLBCL, because the gene-expression profile of transformed DLBCL was more similar to their antecedent FL than to de novo DLBCL. This study demonstrates that transformation from FL to DLBCL can occur by alternative pathways and that transformed DLBCL and de novo DLBCL have very different gene-expression profiles that may underlie the different clinical behaviors of these two types of morphologically similar lymphomas.


Ranking the synthesizability of hypothetical zeolites with the sorting hat.
Zeolites are nanoporous alumino-silicate frameworks widely used as catalysts and adsorbents. Even though millions of siliceous networks can be generated by computer-aided searches, no new hypothetical framework has yet been synthesized. The needle-in-a-haystack problem of finding promising candidates among large databases of predicted structures has intrigued materials scientists for decades; yet, most work to date on the zeolite problem has been limited to intuitive structural descriptors. Here, we tackle this problem through a rigorous data science scheme-the "Zeolite Sorting Hat"-that exploits interatomic correlations to discriminate between real and hypothetical zeolites and to partition real zeolites into compositional classes that guide synthetic strategies for a given hypothetical framework. We find that, regardless of the structural descriptor used by the Zeolite Sorting Hat, there remain hypothetical frameworks that are incorrectly classified as real ones, suggesting that they might be good candidates for synthesis. We seek to minimize the number of such misclassified frameworks by using as complete a structural descriptor as possible, thus focusing on truly viable synthetic targets, while discovering structural features that distinguish real and hypothetical frameworks as an output of the Zeolite Sorting Hat. Further ranking of the candidates can be achieved based on thermodynamic stability and/or their suitability for the desired applications. Based on this workflow, we propose three hypothetical frameworks differing in their molar volume range as the top targets for synthesis, each with a composition suggested by the Zeolite Sorting Hat. Finally, we analyze the behavior of the Zeolite Sorting Hat with a hierarchy of structural descriptors including intuitive descriptors reported in previous studies, finding that intuitive descriptors produce significantly more misclassified hypothetical frameworks, and that more rigorous interatomic correlations point to second-neighbor Si-O distances around 3.2-3.4 Å as the key discriminatory factor.


Properties of the major component of a peptic digest of rabbit antibody.
The molecular weight of the active, major component isolated from a peptic digest of rabbit antibody was found to be 106,000. After treatment with a disulfide-splitting reagent, the molecular weight was 56,000, and the products migrated as a single peak in the ultracentrifuge. he univalent fragments thus formed can be partially recombined by passage through IR-120 cation-exchange resin at room temperature or by treatment with a difunctional organic mercurial. Some splitting of the pepsin-treated antibody molecule occurs on carboxymethylcellulose at pH 5.4.


A small heat shock protein of Ostertagia ostertagi: stage-specific expression, heat inducibility, and protection trial.
In this study, we isolated and analyzed a small heat shock protein (HSP) of Ostertagia ostertagi (Oo-HSP18). Oo-hsp18 is encoded by a single-copy gene and the full-length cDNA represents an 18-kDa protein. The expression of Oo-hsp18 is highly stage specific and restricted to the adult stage. The protein is synthesized in a tissue-specific manner and localized in the body muscle layer. The levels of Oo-hsp18 mRNAs are sharply induced by heat shock but not by other stressors such as levamisole and H2O2. A vaccination trial with recombinant Oo-HSP18 failed to protect calves against a challenge infection.


Exploring the International Food Safety Authorities Network as a Community of Practice: Results from a Global Survey of Network Members.
The International Food Safety Authorities Network (INFOSAN) is a global network of national food safety authorities from 190 countries, managed jointly by the Food and Agriculture Organization of the United Nations and the World Health Organization, which facilitates the rapid exchange of information during food safety incidents. Until now, INFOSAN has not been characterized or examined as a functional community of practice, and its value, as understood from the perspective of its members, has not been determined in a systematic or rigorous way. The purpose of this study was to explore and describe the experiences and opinions of INFOSAN members to better understand the role of the network in improving food safety and mitigating the burden of foodborne illness globally. There were four main research questions: (i) How is the INFOSAN Community Website being used to support network activities? (ii) What are the barriers to active participation in INFOSAN? (iii) Do INFOSAN members believe that participation in the network prevents foodborne illness and saves lives? and (iv) Does participation in INFOSAN create value for members, and if so, through what mechanisms does this occur? To answer these questions, an online questionnaire was developed and adapted from English into French and Spanish before being disseminated to INFOSAN members. Responses were received from 239 INFOSAN members in 137 countries over a 10-week period between August and October 2019. This study represents the first to explore and describe the experiences of INFOSAN members with respect to their participation in network activities to improve global food safety and prevent foodborne diseases and to describe the characteristics of INFOSAN as a community of practice. The results suggest that INFOSAN is a valued tool, used globally to reduce the burden of foodborne illness and save lives. The INFOSAN Secretariat could use the results to prioritize future activities to further strengthen the network and support participation of members.


Simultaneous determination of dacarbazine, its photolytic degradation product, 2-azahypoxanthine, and the metabolite 5-aminoimidazole-4-carboxamide in plasma and urine by high-pressure liquid chromatography.
A high-pressure liquid chromatographic method has been developed that allows for the simultaneous analysis of dacarbazine (DTIC), 5-aminoimidazole-4-carboxamide (AIC), and 2-azahypoxanthine (2-AZA) in plasma or urine. Plasma samples were prepared by ultrafiltration, whereas urine samples were filtered and diluted for analysis. Chromatography was done with a C18 mu Bondapak column along with gradient elution of the drugs. The mobile phase consisted of 100% 0.5 M sodium acetate (pH 7.0) and 25% acetonitrile in 0.05 M sodium acetate (pH 5.5) with detection at 280 nm. Linearity was observed up to 500 micrograms/ml for DTIC and up to 53 micrograms/ml for AIC and 2-AZA. The assay methodology was reproducible, with a lower limit of detection of 5.0, 0.5, and 0.5 micrograms/ml for DTIC, AIC, and 2-AZA, respectively. Interday and intraday coefficients of variation ranged between 4 to 14% and 2 to 16%, respectively. The analytical method was applied to the analysis of plasma and urine samples resulting from the isolation perfusion chemotherapy of an extremity with 57 mg of DTIC per kg in a patient with melanoma.


Talbot plane patterns: grating images or interference effects?
It has been widely said that with the Talbot effect a grating makes images of itself unaided. However, the effect as produced by simple amplitude gratings was recently redefined in terms of interference-pattern visibility or contrast instead of self-imaging. Then, by starting with a pair of slits instead of the usual infinite grating, a new and more general description of the effect was developed. Now numerical methods and tools from physical optics are used further to characterize the influences of the grating, light parameters, and the position of the plane of observation on pattern form, fine structure, band positions, and phases. It is found that none of the patterns in the Talbot planes actually approximates grating images in terms of all of these properties. Hence the Talbot effect should be defined in terms of interference effects, not grating images.


Casein kinase II is a selective target of HIV-1 transcriptional inhibitors.
The identification of cellular factors that are required to complete various steps of the HIV-1 life cycle may lead to the development of new therapeutics. One key step, transcription from the integrated provirus, is inhibited by members of two distinct classes of compounds, the flavonoids and the benzothiophenes, via an unknown mechanism, possibly involving a cellular factor. A marked specificity toward inhibiting HIV-1 transcription is evidenced by the ability of drug-treated cells to retain their proliferative and differentiation capabilities. In addition, the compounds do not impede the activation and function of the transcriptional factor NF-kappaB. Here we report on the identification of several cellular proteins that mediate the HIV-1 transcriptional inhibitory property of the flavonoid chrysin. Chemical and immunologic analyses identified these cellular proteins as the individual subunits of casein kinase II (CKII). Though structurally unrelated to chrysin, an HIV-1 inhibitory benzothiophene also bound selectively to CKII. Both chrysin and the benzothiophenes inhibited human recombinant CKII enzymatic activity and showed competitive kinetics with respect to ATP, analogous to the classic CKII inhibitor 5, 6-dichloro-1-beta-D-ribofuranosylbenzimidazole (DRB). Moreover, DRB potently inhibited HIV-1 expression in chronically infected cells. CKII may regulate HIV-1 transcription by phosphorylating cellular proteins involved in HIV-1 transactivation that contain multiple CKII phosphorylation consensus sequences.


Differences between early and late onset Alzheimer's disease.
Previous studies comparing early-onset Alzheimer's disease (EOAD) and late-onset AD (LOAD) have been limited by cross-sectional design and a focus on isolated clinical variables. This study aims to explore differentials in clinical features between EOAD and LOAD and to examine longitudinally trends in cognitive function. Data from 3,747 subjects with AD from C-Path Online Data Repository was used to compare demographics, body mass index (BMI), mean arterial pressure (MAP), biochemistry and cognitive assessments, including mini-mental state examination (MMSE) and Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-Cog), between EOAD and LOAD. The baseline differences were examined by binominal proportion test and t-test. The trends of cognitive functions, evaluating by MMSE and ADAS-Cog, were examined by the mixed model, controlling for the effect of repeated measures of the same person. No significant difference was found in BMI and MAP. C-reactive protein, creatinine and blood urea nitrogen (BUN) (p<0.05) were significantly higher in LOAD. The APOE ε4 alleles was more likely to be found among LOAD compared to APOE ε2 or APOE ε3. EOAD had significantly lower MMSE at baseline and this difference significantly increased over time. Despite an insignificant differential in ADAS-Cog between EOAD and LOAD at baseline, the differential was enlarged gradually and became more significant with time. Our findings suggest that elevated inflammatory markers, impaired renal function and APOE ε4 alleles are overrepresented in LOAD, possibly indicating that different factors determine the development of EOAD and its more rapid cognitive deterioration.


[Arthrogryposis, renal tubular dysfunction, cholestasis (ARC) syndrome: case report and review of the literature].
The ARC-syndrome is a rare disease with the obligatory symptoms arthrogryposis, renal tubular dysfunction and cholestasis. Optional further symptoms like ichthyosis, diarrhea, central nervous system defects and recurrent infections have been reported. The ARC-syndrome was first reported by Lutz-Richner and Landolt in 1973. The pathophysiology is still unknown, an autosomal recessive inheritance is postulated. Patients rarely exceed an age of six month. We report a boy of consanguineous Turkish parents who suffered from congenital deformities of the lower extremities, a metabolic acidosis and failure to thrive. In the sequel he developed a renal Fanconi syndrome and cholestasis. Histology of liver and muscle biopsy specimen showed the typical findings of the disease with giant cell hepatitis and neurogenous muscle atrophy. His condition could be stabilized and he increased in weight by substituting fluid, electrolytes, buffer and parenteral nutrition. Total enteral nutrition of the 280 ml/kg/d he required failed even by nasogastric tube and percutaneous endoscopic gastrostomy. Additional fluid substitution by central venous catheter remained necessary. At the age of 7 month he died.


Dietary patterns reflecting healthy food choices are associated with lower serum LPS activity.
Gram-negative bacteria-derived lipopolysaccharides (LPS) are associated with various negative health effects. Whether diet is associated with LPS, is an understudied phenomenon. We investigated the association between diet and serum LPS activity in 668 individuals with type 1 diabetes in the FinnDiane Study. Serum LPS activity was determined using the Limulus Amoebocyte Lysate assay. Diet was assessed with a food frequency questionnaire (FFQ) section of a diet questionnaire and a food record. The food record was used to calculate energy, macronutrient, and fibre intake. In a multivariable model, energy, macronutrient, or fibre intake was not associated with the LPS activity. Using factor analysis, we identified seven dietary patterns from the FFQ data ("Sweet", "Cheese", "Fish", "Healthy snack", "Vegetable", "Traditional", and "Modern"). In a multivariable model, higher factor scores of the Fish, Healthy snack, and Modern patterns predicted lower LPS activity. The validity of the diet questionnaire was also investigated. The questionnaire showed reasonable relative validity against a 6-day food record. The two methods classified participants into the dietary patterns better than expected by chance. In conclusion, healthy dietary choices, such as consumption of fish, fresh vegetables, and fruits and berries may be associated with positive health outcomes by reducing systemic endotoxaemia.


Targeting dysregulated lipid metabolism in the tumor microenvironment.
The reprogramming of lipid metabolism and its association with oncogenic signaling pathways within the tumor microenvironment (TME) have emerged as significant hallmarks of cancer. Lipid metabolism is defined as a complex set of molecular processes including lipid uptake, synthesis, transport, and degradation. The dysregulation of lipid metabolism is affected by enzymes and signaling molecules directly or indirectly involved in the lipid metabolic process. Regulation of lipid metabolizing enzymes has been shown to modulate cancer development and to avoid resistance to anticancer drugs in tumors and the TME. Because of this, understanding the metabolic reprogramming associated with oncogenic progression is important to develop strategies for cancer treatment. Recent advances provide insight into fundamental mechanisms and the connections between altered lipid metabolism and tumorigenesis. In this review, we explore alterations to lipid metabolism and the pivotal factors driving lipid metabolic reprogramming, which exacerbate cancer progression. We also shed light on the latest insights and current therapeutic approaches based on small molecular inhibitors and phytochemicals targeting lipid metabolism for cancer treatment. Further investigations are worthwhile to fully understand the underlying mechanisms and the correlation between altered lipid metabolism and carcinogenesis.


Suicide and mental disorders: A discourse of politics, power, and vested interests.
One of the most well-established truths in suicidology is that mental disorders play a significant role in at least 90% of suicides, and a causal relationship between the two is often implied. In this article, the authors argue that the evidence base for this truth is weak and that there is much research questioning the 90% statistic. Based on numerous examples, they also argue that ideology, politics, power, and vested interests among influential professionals in the field obstruct argument-based discussion of this issue. The authors also discuss unfortunate consequences of the constant reiteration of the 90% statistic.


Efficacy and tolerance of vinpocetine in ambulant patients suffering from mild to moderate organic psychosyndromes.
The efficacy and tolerance of orally administered vinpocetine was investigated in patients suffering from mild to moderate organic psychosyndromes including primary dementia. Two hundred and three patients were included in a placebo-controlled, randomized double-blind, multicentre trial and received every day for 16 weeks either: 3 x 10 mg doses of vinpocetine, 3 x 20 mg doses of vinpocetine, or 3 x placebo. Patients were assessed on ratings of clinical global impression, cognitive performance and on measures of the quality of life including depressive illness. There were no clinically relevant side-effects reported and the frequencies of adverse events between patients treated with vinpocetine (30 mg or 60 mg) and placebo were comparable. Statistically significant improvements were found in favour of both active treatment groups compared to placebo in both confirmatory evaluations of efficacy of treatment: the "Global Improvement" (on the CGI scale) and cognitive performance (SKT). Vinpocetine was also superior to placebo in ratings of the "severity of illness". This study demonstrates the usefulness and efficacy of vinpocetine in the management of patients with moderate organic psychosyndromes. An apparently greater therapeutic efficacy of 3 x 10 mg vinpocetine compared with the higher vinpocetine dosage is statistically not significant.


TLD array for precise dose measurements in stereotactic radiation techniques.
We developed a new TLD array for precise dose measurement and verification of the spatial dose distribution in small radiation targets. It consists of a hemicylindrical, tissue-equivalent rod made of polystyrene with 17 parallel moulds for an exact positioning of each TLD. The spatial resolution of the TLD array was evaluated using the Leskell spherical phantom. Dose planning was performed with KULA 4.4 under stereotactic conditions on axial CT images. In the Leksell gamma unit the TLD array was irradiated with a maximal dose of 10 Gy with an unplugged 14 mm collimator. The doses delivered to the TLDs were rechecked by diode detector and film dosimetry and compared to the computer-generated dose profile. We found excellent agreement of our measured values, even at the critical penumbra decline. For the 14 mm and 18 mm collimator and for the 11 mm collimator combination we compared the measured and calculated data at full width at half maximum. This TLD array may be useful for phantom or tissue model studies on the spatial dose distribution in confined radiation targets as used in stereotactic radiotherapy.


Localization of full-length recombinant human proteoglycan-4 in commercial contact lenses using confocal microscopy.
The aim of this study was to determine the sorption location of full-length recombinant human proteoglycan 4 (rhPRG4) tagged with fluorescein isothiocyanate (FITC) to four silicone hydrogel contact lenses [balafilcon A (PureVision, Bausch + Lomb), senofilcon A (Acuvue Oasys, Johnson & Johnson), comfilcon A (Biofinity, CooperVision), lotrafilcon B (Air Optix, Alcon)] and one conventional hydrogel lens [etafilcon A (Acuvue 2, Johnson & Johnson)], using confocal laser scanning microscopy (CLSM). Lenses (n = 3 each) were incubated under two conditions: (1) FITC-rhPRG4 solution at 300 μg/mL and (2) phosphate-buffered saline, for 1 h at 37 °C in darkness with gentle shaking. The central 4 mm of each lens was removed and viewed with the Zeiss 510 CLSM using an argon laser at 488 nm (FITC excitation 495 nm, emission 521 nm). Depth scans were taken at 1 μm intervals to a maximum depth of 100 μm. All lens materials demonstrated sorption of rhPRG4. Both senofilcon A and balafilcon A revealed FITC-rhPRG4 penetration into the bulk of the lens, generally favoring the surface. rhPRG4 was observed exclusively on the surface of lotrafilcon B, with no presence within the bulk of the lens. rhPRG4 was evenly distributed throughout the bulk of the lens, as well as on the surface, for comfilcon A and etafilcon A. The sorption profile of FITC-rhPRG4 was successfully visualized using CLSM in various contact lens materials. The polymer composition, surface treatment and pore size of the material can influence the sorption of rhPRG4.


Reaching the end of the line: Operational issues with implementing phone-based unannounced pill counts in resource-limited settings.
Accurate measurement of adherence is necessary to ensure that therapeutic outcomes can be attributed to the recommended treatment. Phone-based unannounced pill counts were shown to be feasible and reliable measures of adherence in developed settings; and have been further used as part of medication adherence interventions. However, it is not clear whether this method can be implemented successfully in resource-limited settings, where cellular network and mobile phone coverage may be low. Our objective is to describe operational issues surrounding the use of phone-based unannounced pill counts in Lesotho and Ethiopia. Phone-based monthly unannounced pill counts, using an adaptation of a standardized protocol from previous US-based studies, were utilized to measure anti-TB and antiretroviral medication adherence in two implementation science studies in resource-limited settings, START (Lesotho) and ENRICH (Ethiopia). In START, 19.6% of calls were completed, with 71.9% of participants reached at least once; majority of failed call attempts were due to phones not being available (54.8%) or because participants were away from the pills (32.7%). In ENRICH, 33.5% of calls were completed, with 86.7% of participants reached at least once; the main reasons for failed call attempts were phones being switched off (31.5%), participants not answering (27.3%), participants' discomfort speaking on the phone (15.4%), and network problems (13.2%). Structural, facility-level, participant-level, and data collection challenges were encountered in these settings. Phone-based unannounced pill counts were found to be challenging, and response rates suboptimal. While some of these challenges were specific to local contexts, most of them are generalizable to resource-limited settings. In a research study context, a possible solution to ease operational challenges may be to focus phone-based unannounced pill count efforts on a randomly selected sample from participants who are provided with study phones and rigorously ensure that call attempts are made for these participants.


The multidimensional nature of HIV stigma: evidence from Mozambique.
HIV stigma continues to be a major challenge to addressing HIV/AIDS in various countries in sub-Saharan Africa, including Mozambique. This paper explores the multidimensional nature of HIV stigma through the thematic analysis of five qualitative studies conducted in high HIV prevalence provinces in Mozambique between 2009 and 2012. These studies included 23 interviews with people living with HIV (PLHIV) (10 women and 13 men); 6 focus groups with 32 peer educators (24 women and 8 men) working for community-based organisations (CBOs) providing services to PLHIV; 17 focus groups with community members (72 men and 70 women); 6 interviews (4 women and 2 men) with people who had family members living with HIV/AIDS; 24 focus groups (12 with men and 12 with women) and 6 interviews with couples. Our findings indicate that HIV stigma is a barrier to HIV testing and counselling, status disclosure, partner notification, and antiretroviral therapy (ART) access and adherence, and that moral stigma seems to be more common than physical stigma. Additionally, the findings highlight that HIV stigma is a dynamic social process that is conceptualised as being tied to personal responsibility. To effectively diminish HIV stigma in Mozambique, future interventions should address moral stigma and re-conceptualise HIV as a chronic disease.


Bioavailability, disposition, and dose-response effects of soy isoflavones when consumed by healthy women at physiologically typical dietary intakes.
The pharmacokinetics of isoflavones in 10 healthy women were determined from serum appearance/disappearance concentration profiles and urinary excretions after single-bolus ingestion of 10, 20 or 40 g of soy nuts delivering increasing amounts of the conjugated forms of daidzein (6.6, 13.2 and 26.4 mg) and genistein (9.8, 19.6 and 39.2 mg). Peak serum daidzein and genistein concentrations were attained after 4-8 h, and elimination half-lives were 8.0 and 10.1 h, respectively. There were no differences in the pharmacokinetics of daidzein and genistein between pre- and postmenopausal women, indicating absorption and disposition of isoflavones to be independent of age or menopausal status. A curvilinear relationship was observed between the bioavailability of daidzein and genistein, apparent from the area under the curve to infinity (AUC(inf)) of the serum concentration-time profiles and the amount of isoflavones ingested. The mean fraction of the isoflavones excreted in urine decreased with increasing intake when expressed as a percentage of the administered dose (63.2 +/- 8.0, 54.4 +/- 8.1 and 44.0 +/- 4.3%, respectively, for daidzein, and correspondingly, 25.2 +/- 5.3, 13.4 +/- 2.1 and 15.8 +/- 2.7% for genistein), underscoring the trend toward nonlinear pharmacokinetics. Equol was identified as a metabolite in 30% of women; it was present consistently in urine and blood from the same subjects. Its delayed appearance was consistent with colonic synthesis. On the basis of the pharmacokinetics, optimum steady-state serum isoflavone concentrations would be expected from modest intakes of soy foods consumed regularly throughout the day rather than from a single highly enriched product.