The effects of human amniotic membrane on silicone related capsule formation in rats.
Silicone breast implants are commonly used materials in plastic surgery for breast augmentation and reconstruction and the most severe complication of silicone implants are capsule contraction which occurs in 40% of patients. The aim of our study is to evaluate how the amniotic membrane alters the capsule formation effects of silicone 24 wistar rats were used in the study. We placed a bare silicone block into the left side (Subgroup A) and single layer amniotic membrane coated silicone block into the right side (Subgroup B) of the rats back. The rats were then separated into three groups and in group 1 rats were euthanized after 3 weeks, in group 2 after 12 weeks and in group 3 after 24 weeks. Then capsule thickness, fibroblast and lymphocyte cell counts were evaluated for each sample. In Group 2 and group 3, the capsule thickness in Subgroup B was detected to be statistically significantly lower than that in Subgroup A. In Group 1, 2, and 3, the lymphocyte count in the capsule tissue taken from Subgroup B was lower than Subgroup A but the difference was not statistically significant. In Group 2 and 3, the fibrocyte count detected in the capsule tissue in Subgroup B was found to be statistically significantly lower than Subgroup A. the amniotic membrane was demonstrated to reduce capsule thickness by the antifibrinolytic effect in our study.


Cellular immunostimulation by CpG-sequence-coated DNA origami structures.
To investigate the potential of DNA origami constructs as programmable and noncytotoxic immunostimulants, we tested the immune responses induced by hollow 30-helix DNA origami tubes covered with up to 62 cytosine-phosphate-guanine (CpG) sequences in freshly isolated spleen cells. Unmethylated CpG sequences that are highly specific for bacterial DNA are recognized by a specialized receptor of the innate immune system localized in the endosome, the Toll-like receptor 9 (TLR9). When incubated with oligonucleotides containing CpGs, immune cells are stimulated through TLR9 to produce and secrete cytokine mediators such as interleukin-6 (IL-6) and interleukin-12p70 (IL-12p70), a process associated with the initiation of an immune response. In our studies, the DNA origami tube built from an 8634 nt long variant of the commonly used single-stranded DNA origami scaffold M13mp18 and 227 staple oligonucleotides decorated with 62 CpG-containing oligonucleotides triggered a strong immune response, characterized by cytokine production and immune cell activation, which was entirely dependent on TLR9 stimulation. Such decorated origami tubes also triggered higher immunostimulation than equal amounts of CpG oligonucleotides associated with a standard carrier system such as Lipofectamine. In the absence of CpG oligonucleotides, cytokine production induced by the origami tubes was low and was not related to TLR9 recognition. Fluorescent microscopy revealed localization of CpG-containing DNA origami structures in the endosome. The DNA constructs showed in contrast to Lipofectamine no detectable toxicity and did not affect the viability of splenocytes. We thus demonstrate that DNA origami constructs represent a delivery system for CpG oligonucleotides that is both efficient and nontoxic.


New primary ipsilateral metachronous breast tumor: a case report.
After breast-conserving treatment, the occurrence of ipsilateral breast tumor relapse raises the concern regarding whether it may represent two distinct types of lesion that it is important to define, a true recurrence (TR) or a new primary tumor (NPT). TR and NPT have different natural histories, prognosis, and in turn different implications for therapeutic management. We report the case of a 35-year-old woman who developed a breast invasive ductal carcinoma, which after receiving breast-conserving treatment with adjuvant chemotherapy, radiotherapy and hormone therapy, developed four years after an inflammatory carcinoma in the same breast, with different expression of immunohistochemical markers than the first breast cancer. The patient was treated with neoadjuvant chemotherapy that allowed the realization of a radical mastectomy with a complete pathological response. We describe the diagnostic and therapeutic approach of ipsilateral breast tumor relapses, along with a review of existing literature.


Be squared: expanding the horizon of squaric acid-mediated conjugations.
Squaric acid diesters can be applied as reagents to couple two amino-functional compounds. Consecutive coupling of two amines allows the synthesis of asymmetric squaric acid bisamides with either low molecular weight compounds but also biomolecules or polymers. The key feature of the squaric acid diester mediated coupling is the reduced reactivity of the resulting ester-amide after the first amidation step of the diester. This allows the sequential amidation and generation of asymmetric squaramides with high selectivity and in high yields. This article gives an overview of the well-established squaric acid diester mediated coupling reactions for glycoconjugates and presents recent advances that aim to expand this very versatile reaction protocol to the modification of peptides and proteins.


The difference between oats and beta-glucan extract intake in the management of HbA1c, fasting glucose and insulin sensitivity: a meta-analysis of randomized controlled trials.
Increasing oats and beta-glucan extract intake has been associated with improved glycemic control, which is associated with the reduction in the development of diabetes. This study aims to assess the different effects between oat (whole and bran) and beta-glucan extract intake on glycemic control and insulin sensitivity. PubMed, Embase, Medline, The Cochrane Library, CINAHL and Web of Science were searched up to February 2014. We included randomized controlled trials with interventions that lasted at least four weeks that compared oats and beta-glucan (extracted from oats or other sources) intake with a control. A total of 1351 articles were screened for eligibility, and relevant data were extracted from 18 studies (n = 1024). Oat product dose ranged from 20 g d(-1) to 136 g d(-1), and beta-glucan extract dose ranged from 3 g d(-1) to 10 g d(-1). Compared with the control, oat intake resulted in a greater decrease in fasting glucose and insulin of subjects (P < 0.05), but beta-glucan extract intake did not. Furthermore, oat intake resulted in a greater decrease in glycosylated hemoglobin (HbA1c) (P < 0.001, I(2) = 0%) and fasting glucose (P < 0.001, I(2) = 68%) after removing one study using a concentrate and a different design and fasting insulin of type 2 diabetes (T2D) (P < 0.001, I(2) = 0%). The intake of oats and beta-glucan extracted from oats were effective in decreasing fasting glucose (P = 0.007, I(2) = 91%) and fasting insulin of T2D (P < 0.001, I(2) = 0%) and tented to lower HbA1c (P = 0.09, I(2) = 92%). Higher consumption of whole oats and oat bran, but not oat or barley beta-glucan extracts, are associated with lower HbA1c, fasting glucose and fasting insulin of T2D, hyperlipidaemic and overweight subjects, especially people with T2D, which supports the need for clinical trials to evaluate the potential role of oats in approaching to the management of glycemic control and insulin sensitivity of diabetes or metabolic syndrome subjects.


Evaluation of knowledge levels amongst village AIDS committees after undergoing HIV educational sessions: results from a pilot study in rural Tanzania.
Village AIDS committees (VAC) were formed by the Tanzanian government in 2003 to provide HIV education to their communities. However, their potential has not been realised due to their limited knowledge and misconceptions surrounding HIV, which could be addressed through training of VAC members. In an attempt to increase HIV knowledge levels and address common misconceptions amongst the VACs, an HIV curriculum was delivered to members in rural north western Tanzania. An evaluation of HIV knowledge was conducted prior to and post-delivery of HIV training sessions, within members of three VACs in Kisesa ward. Quantitative surveys were used with several open-ended questions to identify local misconceptions and evaluate HIV knowledge levels. Short educational training sessions covering HIV transmission, prevention and treatment were conducted, with each VAC using quizzes, role-plays and participatory learning and action tools. Post-training surveys occurred up to seven days after the final training session. Before the training, "good" HIV knowledge was higher amongst men than women (p = 0.041), and among those with previous HIV education (p = 0.002). The trade-centre had a faster turn-over of VAC members, and proximity to the trade-centre was associated with a shorter time on the committee.Training improved HIV knowledge levels with more members achieving a "good" score in the post-training survey compared with the baseline survey (p = < 0.001). The training programme was popular, with 100% of participants requesting further HIV training in the future and 51.7% requesting training at three-monthly intervals. In this setting, a series of HIV training sessions for VACs demonstrated encouraging results, with increased HIV knowledge levels following short educational sessions. Further work is required to assess the success of VAC members in disseminating this HIV education to their communities, as well as up-scaling this pilot study to other regions in Tanzania with different misconceptions.


A question of scent: lavender aroma promotes interpersonal trust.
A previous study has shown that the degree of trust into others might be biased by inducing either a more "inclusive" or a more "exclusive" cognitive-control mode. Here, we investigated whether the degree of interpersonal trust can be biased by environmental factors, such as odors, that are likely to impact cognitive-control states. Arousing olfactory fragrances (e.g., peppermint) are supposed to induce a more exclusive, and calming olfactory fragrances (e.g., lavender) a more inclusive state. Participants performed the Trust Game, which provides an index of interpersonal trust by assessing the money units one participant (the trustor) transfers to another participant (the trustee), while being exposed to either peppermint or lavender aroma. All participants played the role of trustor. As expected, participants transferred significantly more money to the alleged trustee in the lavender as compared to the peppermint and control (no aroma) conditions. This observation might have various serious implications for a broad range of situations in which interpersonal trust is an essential element, such as cooperation (e.g., mixed-motives situations), bargaining and negotiation, consumer behavior, and group performance.


A prospective study of physician-observed concussions during junior ice hockey: implications for incidence rates.
The objective of this study was to measure the incidence of concussion (scaled relative to number of athlete exposures) and recurrent concussion within 2 teams of fourth-tier junior ice hockey players (16-21 years old) during 1 regular season. A prospective cohort study called the Hockey Concussion Education Project was conducted during 1 junior ice hockey regular season (2009-2010) involving 67 male fourth-tier ice hockey players (mean age 18.2 ± 1.2 years, range 16-21 years) from 2 teams. Prior to the start of the season, every player underwent baseline assessments using the Sideline Concussion Assessment Tool 2 (SCAT2) and the Immediate Post-Concussion Assessment and Cognitive Test (ImPACT). The study protocol also required players who entered the study during the season to complete baseline SCAT2 and ImPACT testing. If the protocol was not followed, the postinjury test results of a player without true baseline test results would be compared against previously established age and gender group normative levels. Each regular season game was observed by a qualified physician and at least 1 other neutral nonphysician observer. Players who suffered a suspected concussion were evaluated at the game. If a concussion diagnosis was made, the player was subsequently examined in the physician's office for a full clinical evaluation and the SCAT2 and ImPACT were repeated. Based on these evaluations, players were counseled on the decision of when to return to play. Athlete exposure was defined as 1 game played by 1 athlete. Twenty-one concussions occurred during the 52 physician-observed games (incidence 21.5 concussions per 1000 athlete exposures). Five players experienced repeat concussions. No concussions were reported during practice sessions. A concussion was diagnosed by the physician in 19 (36.5%) of the 52 observed games. One of the 5 individuals who suffered a repeat concussion sustained his initial concussion in a regular season game that was not observed by a physician, and as a result this single case was not included in the total of 21 total concussions. This initial concussion of the player was identified during baseline testing 2 days after the injury and was subsequently medically diagnosed and treated. The incidence of game-related concussions (per 100 [corrected] athlete exposures) in these fourth-tier junior [corrected] ice hockey players was 7 [corrected] times higher than [corrected] previously reported in the literature. This difference may be the result of the use of standardized direct physician observation, diagnosis, and subsequent treatment. The results of this study demonstrate the need for follow-up studies involving larger and more diverse sample groups to reflect generalizability of the findings. These follow-up studies should involve other contact sports (for example football and rugby) and also include the full spectrum of gender, age, and skill levels.


Dabrafenib and Trametinib in Patients With Tumors With BRAFV600E Mutations: Results of the NCI-MATCH Trial Subprotocol H.
BRAFV600 mutations are commonly found in melanoma and thyroid cancers and to a lesser degree in other tumor types. Subprotocol H (EAY131-H) of the NCI-MATCH platform trial sought to investigate the selective BRAF inhibitor dabrafenib and the MEK1/2 inhibitor trametinib in patients with solid tumors, lymphomas, or multiple myeloma whose tumors harbored a BRAFV600 mutation. EAY131-H is an open-label, single-arm study. Patients with melanoma, thyroid, or colorectal cancer were excluded; patients with non-small-cell lung cancer were later excluded in an amendment. Patients received dabrafenib 150 mg twice per day and trametinib 2 mg per day continuously until disease progression or intolerable toxicity. The primary end point was centrally assessed objective response rate (ORR); secondary end points included progression-free survival (PFS), 6-month PFS, and overall survival. Thirty-five patients were enrolled, and 29 were included in the primary efficacy analysis as prespecified in the protocol. Median age was 59 years, and 45% of the patients had received ≥ 3 lines of therapy. The confirmed ORR was 38% (90% CI, 22.9% to 54.9%) with P < .0001 against a null rate of 5%, and PFS was 11.4 months (90% CI, 8.4 to 16.3 months); responses were seen in 7 distinct tumor types. Seven patients had a duration of response of > 12 months, including 4 patients with a duration of response of > 24 months. An additional 8 patients had a PFS > 6 months. The median overall survival was 28.6 months. Reported adverse events were comparable to those noted in previously reported profiles of dabrafenib and trametinib. This study met its primary end point, with an ORR of 38% (P < .0001) in this mixed histology, pretreated cohort. This promising activity warrants additional investigations in BRAFV600-mutated tumors outside of currently approved indications.


The maize W22 genome provides a foundation for functional genomics and transposon biology.
The maize W22 inbred has served as a platform for maize genetics since the mid twentieth century. To streamline maize genome analyses, we have sequenced and de novo assembled a W22 reference genome using short-read sequencing technologies. We show that significant structural heterogeneity exists in comparison to the B73 reference genome at multiple scales, from transposon composition and copy number variation to single-nucleotide polymorphisms. The generation of this reference genome enables accurate placement of thousands of Mutator (Mu) and Dissociation (Ds) transposable element insertions for reverse and forward genetics studies. Annotation of the genome has been achieved using RNA-seq analysis, differential nuclease sensitivity profiling and bisulfite sequencing to map open reading frames, open chromatin sites and DNA methylation profiles, respectively. Collectively, the resources developed here integrate W22 as a community reference genome for functional genomics and provide a foundation for the maize pan-genome.


Modulated Hebb-Oja learning rule--a method for principal subspace analysis.
This paper presents analysis of the recently proposed modulated Hebb-Oja (MHO) method that performs linear mapping to a lower-dimensional subspace. Principal component subspace is the method that will be analyzed. Comparing to some other well-known methods for yielding principal component subspace (e.g., Oja's Subspace Learning Algorithm), the proposed method has one feature that could be seen as desirable from the biological point of view--synaptic efficacy learning rule does not need the explicit information about the value of the other efficacies to make individual efficacy modification. Also, the simplicity of the "neural circuits" that perform global computations and a fact that their number does not depend on the number of input and output neurons, could be seen as good features of the proposed method.


Ingesting a 6% carbohydrate-electrolyte solution improves endurance capacity, but not sprint performance, during intermittent, high-intensity shuttle running in adolescent team games players aged 12-14 years.
The main aim of this study was to investigate the influence of consuming a 6% carbohydrate-electrolyte (CHO-E) solution on the intermittent, high-intensity endurance performance and capacity of adolescent team games players. Fifteen participants (mean age 12.7 +/- 0.8 years) performed two trials separated by 3-7 days. In each trial, they completed 60 min of exercise composed of four 15-min periods of part A of the Loughborough Intermittent Shuttle Test, followed by an intermittent run to exhaustion (part B). In a double-blind, randomised, counterbalanced fashion participants consumed either the 6% CHO-E solution or a non-carbohydrate (CHO) placebo (5 ml kg(-1) BM) during the 5 min pre-trial and after each 15-min period of part A (2 ml kg(-1) BM). Time to fatigue was increased by 24.4% during part B when CHO was ingested (5.1 +/- 1.8 vs. 4.1 +/- 1.6 min, P < 0.05), with distance covered in part B also significantly greater in the CHO trial (851 +/- 365 vs. 694 +/- 278 m, P < 0.05). No significant between-trials differences were observed for mean 15-m sprint time (P = 0.35), peak sprint time (P = 0.77), or heart rate (P = 0.08) during part A. These results demonstrate, for the first time, that ingestion of a CHO-E solution significantly improves the intermittent, high-intensity endurance running capacity of adolescent team games players during an exercise protocol designed to simulate the physiological demands of team games.


Dysregulation of glucose metabolism is an early event in sporadic Parkinson's disease.
Unlike most other cell types, neurons preferentially metabolize glucose via the pentose phosphate pathway (PPP) to maintain their antioxidant status. Inhibiting the PPP in neuronal cell models causes cell death. In rodents, inhibition of this pathway causes selective dopaminergic cell death leading to motor deficits resembling parkinsonism. Using postmortem human brain tissue, we characterized glucose metabolism via the PPP in sporadic Parkinson's disease (PD), Alzheimer's disease (AD), and controls. AD brains showed increased nicotinamide adenine dinucleotide phosphate (NADPH) production in areas affected by disease. In PD however, increased NADPH production was only seen in the affected areas of late-stage cases. Quantifying PPP NADPH-producing enzymes glucose-6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase by enzyme-linked immunosorbent assay, showed a reduction in the putamen of early-stage PD and interestingly in the cerebellum of early and late-stage PD. Importantly, there was no decrease in enzyme levels in the cortex, putamen, or cerebellum of AD. Our results suggest that down-regulation of PPP enzymes and a failure to increase antioxidant reserve is an early event in the pathogenesis of sporadic PD.


Conflict monitoring versus selection-for-action in anterior cingulate cortex.
The anterior cingulate cortex (ACC), on the medial surface of the frontal lobes of the brain, is widely believed to be involved in the regulation of attention. Beyond this, however, its specific contribution to cognition remains uncertain. One influential theory has interpreted activation within the ACC as reflecting 'selection-for-action', a set of processes that guide the selection of environmental objects as triggers of or targets for action. We have proposed an alternative hypothesis, in which the ACC serves not to exert top-down attentional control but instead to detect and signal the occurrence of conflicts in information processing. Here, to test this theory against the selection-for-action theory, we used functional magnetic resonance imaging to measure brain activation during performance of a task where, for a particular subset of trials, the strength of selection-for-action is inversely related to the degree of response conflict. Activity within the ACC was greater during trials featuring high levels of conflict (and weak selection-for-action) than during trials with low levels of conflict (and strong selection-for-action), providing evidence in favour of the conflict-monitoring account of ACC function.


Factors Associated With Outcomes and Costs After Pediatric Laparoscopic Cholecystectomy.
The prevalence of pediatric cholelithiasis is increasing with the epidemic of childhood obesity. With this rise, the outcomes and costs of pediatric laparoscopic cholecystectomy become an important public health and economic concern. To assess patient and health system factors associated with the outcomes and costs after laparoscopic cholecystectomy among Canadian children. This was a retrospective, population-based study of children 17 years and younger undergoing laparoscopic cholecystectomy from April 1, 2008, until March 31, 2015. The data source was the Canadian Institute for Health Information. The Canadian Institute for Health Information Discharge Abstract Database includes data from all Canadian hospitals. The analysis was limited to inpatient cholecystectomies. All Canadian children undergoing laparoscopic cholecystectomy were included. The exposure in this study was laparoscopic cholecystectomy. The primary outcome was all-cause morbidity, a composite outcome of any complication that prolonged length of stay by 24 hours or required a second, unplanned procedure. The cost of the index admission was also calculated as a secondary outcome. These outcomes of interest were determined before data analysis. Odds ratios and 95% CIs were estimated using multilevel logistic regression models. During the study period, 3519 laparoscopic cholecystectomies were performed; of these, 79.1% (n = 2785) were in girls, and 98.0% (n = 3450) were for gallstone disease. The overall morbidity rate was 3.9% (n = 137). After adjustment, patients with comorbidities were more susceptible to morbidity (odds ratio, 2.68; 95% CI, 1.78-3.86; P < .001). Operations for gallstones were less morbid. High-volume general surgeons had lower morbidity rates compared with low-volume pediatric surgeons (odds ratio, 0.32; 95% CI, 0.12-0.69; P = .005) independent of pediatric volumes. The mean (SD) unadjusted cost of a laparoscopic cholecystectomy was $4115 ($7273). Operative indication, complications, comorbidities, emergency admission, and surgeon volume were associated with cost. The high-volume nature of adult general surgery translated to lower morbidity and cost after pediatric laparoscopic cholecystectomy, suggesting that adult volume is associated with pediatric outcomes. As the rate of pediatric gallstone disease increases, surgeon volume, rather than specialty training, should be considered when pursuing operative management.


Low bone mineral density is a significant risk factor for low-energy distal radius fractures in middle-aged and elderly men: a case-control study.
In general there is a lack of data on osteoporosis and fracture in men; this also includes low-energy distal radius fractures. The objectives of this study were to examine BMD and identify factors associated with distal radius fractures in male patients compared with controls recruited from the background population. In a 2-year period, 44 men 50 years or older were diagnosed with low-energy distal radius fractures, all recruited from one hospital. The 31 men who attended for osteoporosis assessment were age-matched with 35 controls. Demographic and clinical data were collected and BMD at femoral neck, total hip and spine L2-4 was assessed by dual energy X-ray absorptiometry. Apart from weight and living alone, no significant differences were found between patient and controls for demographic variables (e.g. height, smoking) and clinical variables (e.g. co-morbidity, use of glucocorticoids, osteoporosis treatment, falls and previous history of fracture). However, BMD expressed as T-score was significant lower in patients than in controls at all measurement sites (femoral neck: -2.24 vs. -1.15, p < 0.001; Total hip: -1.65 vs. -0.64, p < 0.001; Spine L2-4: -1.26 vs. 0.25, p = 0.002). Among the potential risk factors for fracture evaluated, only reduced BMD was found to be significantly associated with increased risk for low-energy distal radius fractures in men. The results from our study indicate that reduced BMD is an important risk factor for low-energy distal radius fracture in men. This suggests that improvement of BMD by both pharmacological and non-pharmacological initiatives may be a strategy to reduce fracture risk in men.


Early student (dis)engagement: Contributions of household chaos, parenting, and self-regulatory skills.
Previous studies suggest that the roots of school dropout (a) can be established early in life, (b) are likely to involve multilevel factors (home, child, classroom) operating prior to and during the elementary school years, and (c) can be identified by 3rd grade. The decision to drop out of school is thus a dynamic developmental process that can begin with disengagement in elementary school. Yet few studies have examined the multilevel factors that might contribute to children's early disengagement from school. In the present study, we examined associations between household chaos (i.e., disorganization and instability) from birth to age 5 and student (dis)engagement in third grade. We also examined positive parenting in early childhood (6-60 months) and child self-regulatory skills at kindergarten as potential mediators in this pathway. Participants were 1,097 children who participated in the Family Life Project, a longitudinal study of the development of children living in underresourced high poverty rural areas. Study questions were addressed using structural equation models. Results indicated that, even after taking into account a considerable number of covariates, early positive parenting and children's self-regulatory skills were viable process mechanisms through which early household disorganization, but not instability, was linked to student (dis)engagement in third grade. Findings are discussed with respect to the multilevel proximal forces at play in children's risk for early disengagement from school. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


1,003 reference genomes of bacterial and archaeal isolates expand coverage of the tree of life.
We present 1,003 reference genomes that were sequenced as part of the Genomic Encyclopedia of Bacteria and Archaea (GEBA) initiative, selected to maximize sequence coverage of phylogenetic space. These genomes double the number of existing type strains and expand their overall phylogenetic diversity by 25%. Comparative analyses with previously available finished and draft genomes reveal a 10.5% increase in novel protein families as a function of phylogenetic diversity. The GEBA genomes recruit 25 million previously unassigned metagenomic proteins from 4,650 samples, improving their phylogenetic and functional interpretation. We identify numerous biosynthetic clusters and experimentally validate a divergent phenazine cluster with potential new chemical structure and antimicrobial activity. This Resource is the largest single release of reference genomes to date. Bacterial and archaeal isolate sequence space is still far from saturated, and future endeavors in this direction will continue to be a valuable resource for scientific discovery.


AST/ALT ratio is not useful in predicting the degree of fibrosis in chronic viral hepatitis patients.
Noninvasive tests are primarily used for staging hepatic fibrosis in patients with chronic liver disease. In clinical practice, serum aminotransferase levels, coagulation parameters, and platelet count have been used to predict whether or not a patient has cirrhosis. In addition, several studies have evaluated the accuracy of combinations (or ratios) of these measures. The present study aimed to investigate the relationship between five noninvasive models [AST/ALT ratio (AAR), aspartate aminotransferase to platelet ratio index (APRI), Bonacini cirrhosis discriminant score (CDS), age-platelet index (APind), and King's score] and the degree of hepatic fibrosis as determined by biopsy in patients with chronic hepatitis B and C. A total of 380 patients with viral hepatitis (237 with chronic hepatitis B and 143 with chronic hepatitis C) who were seen at our clinic between January 2005 and January 2011 were retrospectively analyzed. The degree of fibrosis was determined using the Ishak score. Patients with a fibrosis score of 0-2 were considered to have low fibrosis and those with a score between 3 and 6 were considered to have high fibrosis. Five noninvasive models were compared between the groups with low and high fibrosis. There were statistically significant differences between the hepatitis B and C patients with high and low fibrosis with respect to APind (4.49±2.35 vs. 2.41±1.84; P<0.001 in hepatitis B and 4.83±2.25 vs. 2.92±1.88; P<0.001 in hepatitis C), APRI (1.00±1.17 vs. 0.47±0.39; P<0.001 in hepatitis B and 1.01±1.01 vs. 0.41±0.29; P<0.001 in hepatitis C), CDS (4.53±1.90 vs. 3.58±1.30; P<0.001 in hepatitis B and 4.71±2.03 vs. 3.42±1.49; P<0.05 in hepatitis C), and King's score (24.31±3.14 vs. 7.65±6.70; P<0.001 in hepatitis B and 24.82±2.55 vs. 8.33±7.29; P<0.001 in hepatitis C). There were no significant differences in the AAR between the hepatitis B and C patients with high and low fibrosis (0.78±0.31 vs. 0.74±0.34; P=0.082 in hepatitis B and 0.91±0.40 vs. 0.85±0.27; P=0.25 in hepatitis C). The area under the receiver-operating characteristic curve of the APind, APRI, CDS, and King's score in the hepatitis B group were 0.767, 0.710, 0.646, and 0.770, respectively; these values were 0.732, 0.763, 0.677, and 0.783, respectively, in the hepatitis C group. In conclusion, our data suggest that four of the five noninvasive methods evaluated in this study can be used to predict advanced fibrosis in patients with hepatitis B and C. However, there was no significant relationship between the degree of hepatic fibrosis and the AAR score, indicating that AAR is not useful in estimating the fibrosis stage in hepatitis B and C patients.


Patient-reported outcomes, patient-reported information: from randomized controlled trials to the social web and beyond.
Internet communication is developing. Social networking sites enable patients to publish and receive communications very easily. Many stakeholders, including patients, are using these media to find new ways to make sense of diseases, to find and discuss treatments, and to give support to patients and their caregivers. We argue for a new definition of patient-reported information (PRI), which differs from the usual patient-reported outcomes (PRO). These new emergent data from the social web have important implications for decision making, at both an individual and a population level. We discuss new emergent technologies that will help aggregate this information and discuss how this will be assessed alongside the use of PROs in randomized controlled trials and how these new emergent data will be one facet of changing the relationship between the various stakeholders in achieving better co-created health.


Norepinephrine and dopamine as learning signals.
The present review focuses on the hypothesis that norepinephrine (NE) and dopamine (DA) act as learning signals. Both NE and DA are broadly distributed in areas concerned with the representation of the world and with the conjunction of sensory inputs and motor outputs. Both are released at times of novelty and uncertainty, providing plausible signal events for updating representations and associations. These catecholamines activate intracellular machinery postulated to serve as a memory-formation cascade. Yet, despite the plausibility of an NE and DA role in vertebrate learning and memory, most evidence that they provide a learning signal is circumstantial. The major weakness of the data available is the lack of a specific description of how the neural circuit modulated by NE or DA participates in the learning being analyzed. Identifying a conditioned stimuli (CS) representation would facilitate the identification of a learning signal role for NE or DA. Describing how the CS representation comes to relate to learned behavior, either through sensory-sensory associations, in which the CS acquires the motivational significance of reward or punishment, thus driving appropriate behavior, or through direct sensory-motor associations is necessary to identify how NE and DA participate in memory creation. As described here, evidence consistent with a direct learning signal role for NE and DA is seen in the changing of sensory circuits in odor preference learning (NE), defensive conditioning (NE), and auditory cortex remodeling in adult rats (DA). Evidence that NE and DA contribute to normal learning through unspecified mechanisms is extensive, but the details of that support role are lacking.


High Burden of Human Papillomavirus (HPV) Infection among Young Women in KwaZulu-Natal, South Africa.
HPV infection causes cervical cancer, yet information on prevalence and risk factors for HPV in Africa remain sparse. This study describes the prevalence of HPV genotypes and risk factors associated with HPV among young women ≤ 30 years of age in KwaZulu-Natal (KZN), South Africa. Cervicovaginal lavage samples were tested for HPV genotypes in 224 women enrolled in a prospective cohort study. Clinical, behavioural and demographic data were collected. We measured prevalence of HPV genotypes and using logistic regression, examined for factors associated with HPV. Median age of participants was 21 years [interquartile range (IQR):18-23]. The overall prevalence of HPV was 76.3% (171/224) with multiple and single genotypes prevalent in 56.3% and 20.1% of women respectively. Proportion of women with high-risk genotypes (16, 18, 31, 33, 35, 39, 45, 51, 52, 56 and 58) was 54.5%. Women not living with their partner [adjusted odds ratio (aOR)] = 3.42 95% CI1.22-9.60; p = 0.019), was significantly associated with HPV infection and high-risk HPV genotype infection. The high burden of HPV and associated risk behaviours highlight the need to intensify behavioural interventions to prevent HPV acquisition in young women. The large scale delivery of HPV vaccine should be prioritised to prevent HPV acquisition and reduce HPV-related morbidity.


Identification of an H2-Kb or H2-Db restricted and glypican-3-derived cytotoxic T-lymphocyte epitope peptide.
Glypican-3 (GPC3) is overexpressed in human hepatocellular carcinoma (HCC) but not expressed in normal tissues except for placenta and fetal liver and therefore is an ideal target for cancer immunotherapy. In this study, we identified an H2-Kb or H2-Db restricted and murine GPC3 (mGPC3)-derived cytotoxic T-lymphocyte (CTL) epitope peptide in C57BL/6 (B6) mice, which can be used in the design of preclinical studies of various therapies with GPC3-target immunotherapy in vivo. First, 11 types of 9- to 10-mer peptides predicted to bind with H2-Kb or H2-Db were selected from the mGPC3 amino acid sequence based on the binding score as calculated by the BIMAS software. We evaluated the peptide-binding affinity and confirmed that all peptides were able to bind to H2-Kb or H2-Db by in vitro cellular binding assay. Subsequently, a mixed peptide vaccine and single peptide vaccine were given to B6 mice to evaluate immunogenic potential of the 11 selected peptides. Using the splenocytes from peptide-vaccinated mice, interferon (IFN)-γ enzyme-linked immunospot (ELISPOT) assays showed that mGPC3-1127-136 (AMFKNNYPSL) peptide was the most efficient for inducing CTLs among the 11 peptides. Next, we demonstrated that the mGPC3-1 peptide-specific CTL line could recognize mGPC3-expressing cancer cells, suggesting that mGPC3-1 peptide was an endogenously presented peptide. In conclusion, we identified mGPC3-1 as an H2-Kb or H2-Db restricted, mGPC3-derived CTL epitope peptide.


Why It's Inappropriate Not to Treat Incarcerated Patients with Opioid Agonist Therapy.
Due to the criminalization of drug use and addiction, opioid use disorder is overrepresented in incarcerated populations. Decades of evidence supports opioid agonist therapy as a highly effective treatment that improves clinical outcomes and reduces illicit opioid use, overdose death, and cost. Opioid agonist therapy has been both studied within correctional facilities and initiated prerelease. It has been found to be beneficial, yet few incarcerated persons receive this evidence-based treatment. In addition to not offering treatment initiation for those who need it, most correctional facilities forcibly withdraw stable patients from opioid agonist therapy upon their entry into the criminal justice system. This approach limits their access to evidence-based health care and results in negative outcomes for individuals, communities, and society.


Multiplexed Spectral Imaging of 120 Different Fluorescent Labels.
The number of fluorescent labels that can unambiguously be distinguished in a single image when acquired through band pass filters is severely limited by the spectral overlap of available fluorophores. The recent development of spectral microscopy and the application of linear unmixing algorithms to spectrally recorded image data have allowed simultaneous imaging of fluorophores with highly overlapping spectra. However, the number of distinguishable fluorophores is still limited by the unavoidable decrease in signal to noise ratio when fluorescence signals are fractionated over multiple wavelength bins. Here we present a spectral image analysis algorithm to greatly expand the number of distinguishable objects labeled with binary combinations of fluorophores. Our algorithm utilizes a priori knowledge about labeled specimens and imposes a binary label constraint on the unmixing solution. We have applied our labeling and analysis strategy to identify microbes labeled by fluorescence in situ hybridization and here demonstrate the ability to distinguish 120 differently labeled microbes in a single image.


Factors affecting effective communication between registered nurses and adult cancer patients in an inpatient setting: a systematic review.
To establish the best available evidence regarding the factors affecting effective communication between registered nurses and inpatient cancer adults. Electronic databases (CINAHL, Ovid, PubMed, ScienceDirect, Scopus and Wiley InterScience) were searched using a three-step search strategy to identify the relevant quantitative and qualitative studies published in English. The grey literature was not included in the review. The identified studies were evaluated using the guidelines from the Joanna Briggs Institute System for the Unified Management, Assessment and Review of Information. A total of three studies were included in the quantitative component of the review, and the data were presented in a narrative summary. Five studies were included in the qualitative component of the review, and the findings were categorised in a meta-synthesis which generated four synthesised findings. The factors that were found to influence effective communication were identified in the characteristics of nurses, patients and the environment. The promoting factors in nurses included genuineness, competency and effective communication skills. The role of post-basic training in improving nurse-patient communication remained inconclusive. Conversely, nurses who were task-orientated, who feared death and who had low self-awareness of their own verbal behaviours inhibited communication. Nurses were also observed to communicate less effectively when delivering psychosocial aspects of care and in emotionally charged situations. On the other hand, patients who participated actively in their own care and exhibited information-seeking behaviour promoted communication with the nurses. However, patients' unwillingness to discuss their disease/feelings, their preference to seek emotional support from their family/friends and their use of implicit cues were some of the factors that were found to inhibit communication. A supportive ward environment increased facilitative behaviour in nurses, whereas conflict among the staff led to increased use of blocking behaviours. Cultural norms within the Chinese society were also found to inhibit nurse-patient communication. Within the constraints of the study and the few quality papers available, it appeared that personal characteristics of patients and nurses are the key factors that influence effective nurse-patient communication within the oncology setting. Very little evidence exists to explain the role of environment in effective nurse-patient communication, particularly within an Asian setting. Training can be implemented to inform nurses about the communication challenges, to equip them with effective communication skills and improve their receptivity to patient cues. Information-sharing can be used as a non-threatening approach to initiate rapport-building and open communication. Nurses should consider patients' psychological readiness to communicate and respect their preference as to whom they wish to share their thoughts/emotions with. Hospitals/institutions also need to ensure a supportive ward culture and appropriate workload that will enable nurses to provide holistic care to patients. Further research on the effect of the Asian culture on effective communication within the oncology setting is required to expand the knowledge in this area. Studies to ascertain the effect of the patient's age and place within the oncology treatment cycle are also warranted. The lack of evidence on the effectiveness of post-basic communication education also requires further investigation.


Pentavalent phosphorus as a unique phosphorus donor in POCl3 homodimer and POCl3-H2O heterodimer: matrix isolation infrared spectroscopic and computational studies.
Phosphorus, an important element among the pnicogen group, opens up avenues for experimental and computational explorations of its interaction in a variety of compounds. Although experimental proof of trivalent phosphorus bonding is limited and is growing with time, phosphorus bonding with pentavalent phosphorus has been a long sought after interaction both computationally and experimentally. In the present work, for the first time, we have provided unambiguous experimental evidence for the pentavalent phosphorus bonding interaction by exploiting a phosphoryl chloride (POCl3) prototype under isolated conditions at low temperatures. The POCl3 dimer and higher aggregates can be set as a unique example possessing pentavalent phosphorus bonding with a competing halogen bonding interaction. The POCl3-H2O heterodimer is another interesting system, stabilized through multiple phosphorus and hydrogen bonded interactions. Using matrix isolation infrared spectroscopy, the POCl3 homodimer and POCl3-H2O heterodimer were characterized and the structures were elucidated by employing ab initio and DFT methods. The multifaceted interactions in the POCl3 paradigm were investigated by using Natural Bond Orbital, Energy Decomposition and Electrostatic Potential Mapping analyses.


Genomic trajectories to fluoroquinolone resistance in Francisella tularensis subsp. holarctica live vaccine strain.
Fluoroquinolone (FQ)-resistant mutants were previously selected from the live vaccine strain (LVS) of Francisella tularensis (F. tularensis) subsp. holarctica. This study further characterised all genetic changes that occurred in these mutants during the evolutionary trajectory toward high-level FQ resistance, and their potential impact on F. tularensis antibiotic resistance and intracellular fitness. The whole genomes of FQ-resistant mutants were determined and compared with those of their parental strain. All detected mutations were evaluated for their potential impact on FQ resistance and intracellular multiplication of F. tularensis. As compared with the parental LVS genome, 28 mutations were found in the derived FQ-resistant mutants. These mutations involved all genes encoding type II topoisomerases (i.e. gyrA, gyrB, parC, and parE). Interestingly, some of them were not previously associated with FQ resistance, warranting further characterisation. Mutations associated with FQ resistance were also found in other genes, including three encoding proteins involved in transport processes. Most of the detected mutations did not alter multiplication of the corresponding mutants in J774 cells. In contrast, all mutations at locus FTL_0439 encoding FupA/B, a membrane protein involved in iron transport, were associated with FQ resistance and fitness loss. FQ resistance in F. tularensis is complex and may involve single or combined mutations in genes encoding type II topoisomerases, transport systems and FupA/B. In vivo studies are now required to assess the potential role of these mutations in FQ treatment failures.


A Low-Intensity Mobile Health Intervention With and Without Health Counseling for Persons With Type 2 Diabetes, Part 1: Baseline and Short-Term Results From a Randomized Controlled Trial in the Norwegian Part of RENEWING HEALTH.
Self-management support for people with type 2 diabetes is essential in diabetes care. Thus, mobile health technology with or without low-intensity theory-based health counseling could become an important tool for promoting self-management. The aim was to evaluate whether the introduction of technology-supported self-management using the Few Touch Application (FTA) diabetes diary with or without health counseling improved glycated hemoglobin (HbA1c) levels, self-management, behavioral change, and health-related quality of life, and to describe the sociodemographic, clinical, and lifestyle characteristics of the participants after 4 months. A 3-armed randomized controlled trial was conducted in Norway during 2011-2013. In the 2 intervention groups, participants were given a mobile phone for 1 year, which provided access to the FTA diary, a self-help tool that recorded 5 elements: blood glucose, food habits, physical activity, personal goal setting, and a look-up system for diabetes information. One of the intervention groups was also offered theory-based health counseling with a specialist diabetes nurse by telephone for 4 months from baseline. Both intervention groups and the control group were provided usual care according to the national guidelines. Adults with type 2 diabetes and HbA1c ≥7.1% were included (N=151). There were 3 assessment points: baseline, 4 months, and 1 year. We report the short-term findings after 4 months. HbA1c was the primary outcome and the secondary outcomes were self-management (Health Education Impact Questionnaire, heiQ), behavioral change (diet and physical activity), and health-related quality of life (SF-36 questionnaire). The data were analyzed using univariate methods (ANOVA), multivariate linear, and logistic regression. Data were analyzed from 124 individuals (attrition rate was 18%). The groups were well balanced at baseline. There were no differences in HbA1c between groups after 4 months, but there was a decline in all groups. There were changes in self-management measured using the health service navigation item in the heiQ, with improvements in the FTA group compared to the control group (P=.01) and in the FTA with health counseling group compared with both other groups (P=.04). This may indicate an improvement in the ability of patients to communicate health needs to their health care providers. Furthermore, the FTA group reported higher scores for skill and technique acquisition at relieving symptoms compared to the control group (P=.02). There were no significant changes in any of the domains of the SF-36. The primary outcome, HbA1c, did not differ between groups after 4 months. Both of the intervention groups had significantly better scores than the control group for health service navigation and the FTA group also exhibited improved skill and technique acquisition.


BK Polyomavirus Diversity After Hematopoietic Stem Cell Transplantation.
BK polyomavirus (BKPyV) infection is common after hematopoietic stem cell transplantation (HSCT) and is associated with the development of hemorrhagic cystitis (HC). The role that BKPyV plays in the pathogenesis of HC is not well characterized. We investigated the impact of BKPyV diversity on the development of HC using a previously established cohort of pediatric HSCT patients. There were 147 urine samples with quantifiable BKPyV at month 1 after HSCT; 137 (93.2%) were amplified using our in-house polymerase chain reaction approach and sent for next-generation sequencing. Subtype Ia was most frequent (61.3%), followed by subtype Ib1 (31.4%). The median viral load of subtype Ia samples was higher than for subtype Ib1 at month 1. Across the protein coding regions, APOBEC-induced mutations and signature patterns associated with HC were identified. This is the largest sequencing study of a single cohort of HSCT patients, providing a vast resource of sequence data for future analyses.


Increased mitochondrial respiratory chain enzyme activities correlate with minor extent of liver damage in mice suffering from erythropoietic protoporphyria.
Mitochondrial dysfunction might play a role in the pathogenesis of liver damage in erythropoietic protoporphyria (EPP). Changes in mitochondrial respiratory chain activities were evaluated in the Fech(m1pas)/Fech(m1pas) mouse model for EPP. Mice from different strains congenic for the same ferrochelatase germline mutation manifest variable degrees of hepatobiliary injury. Protoporphyric animals bred into the C57BL/6J background showed a higher degree of hepatomegaly and liver damage as well as higher protoporphyrin (PP) accumulation than those bred into the SJL/J and BALB/cJ backgrounds. Whereas mitochondrial respiratory chain activities remained unchanged in the liver of protoporphyric mice C57BL/6J, they were increased in protoporphyric mice from both SJL/J and BALB/cJ backgrounds, when compared to wild-type animals. Mitochondrial respiratory chain activities were increased in Hep G2 cell line after accumulation of PP following addition of aminolevulinic acid. As a direct effect of these elevated mitochondrial activities, in both hepatic cells from mutant mouse strains and Hep G2 cells, adenosine 5'-triphosphate (ATP) levels significantly increased as the intracellular PP concentration was reduced. These results indicate that PP modifies intracellular ATP requirements as well as hepatic mitochondrial respiratory chain enzymatic activities and further suggest that an increase of these activities may provide a certain degree of protection against liver damage in protoporphyric mice.


Brain Networks Sensitive to Object Novelty, Value, and Their Combination.
Novel and valuable objects are motivationally attractive for animals including primates. However, little is known about how novelty and value processing is organized across the brain. We used fMRI in macaques to map brain responses to visual fractal patterns varying in either novelty or value dimensions and compared the results with the structure of functionally connected brain networks determined at rest. The results show that different brain networks possess unique combinations of novelty and value coding. One network identified in the ventral temporal cortex preferentially encoded object novelty, whereas another in the parietal cortex encoded the learned value. A third network, broadly composed of temporal and prefrontal areas (TP network), along with functionally connected portions of the striatum, amygdala, and claustrum, encoded both dimensions with similar activation dynamics. Our results support the emergence of a common currency signal in the TP network that may underlie the common attitudes toward novel and valuable objects.


Improved tRNA prediction in the American house dust mite reveals widespread occurrence of extremely short minimal tRNAs in acariform mites.
Atypical tRNAs are functional minimal tRNAs, lacking either the D- or T-arm. They are significantly shorter than typical cloverleaf tRNAs. Widespread occurrence of atypical tRNAs was first demonstrated for secernentean nematodes and later in various arachnids. Evidence started to accumulate that tRNAs of certain acariform mites are even shorter than the minimal tRNAs of nematodes, raising the possibility that tRNAs lacking both D- and T-arms might exist in these organisms. The presence of cloverleaf tRNAs in acariform mites, particularly in the house dust mite genus Dermatophagoides, is still disputed. Mitochondrial tRNAs of Dermatophagoides farinae are minimal, atypical tRNAs lacking either the T- or D-arm. The size (49-62, 54.4 +/- 2.86 nt) is significantly (p = 0.019) smaller than in Caenorhabditis elegans (53-63, 56.3 +/- 2.30 nt), a model minimal tRNA taxon. The shortest tRNA (49 nt) in Dermatophagoides is approaching the length of the shortest known tRNAs (45-49 nt) described in other acariform mites. The D-arm is absent in these tRNAs, and the inferred T-stem is small (2-3 bp) and thermodynamically unstable, suggesting that it may not exist in reality. The discriminator nucleotide is probably not encoded and is added postranscriptionally in many Dermatophagoides tRNAs. Mitochondrial tRNAs of acariform mites are largely atypical, non-cloverleaf tRNAs. Among them, the shortest known tRNAs with no D-arm and a short and unstable T-arm can be inferred. While our study confirmed seven tRNAs in Dermatophagoides by limited EST data, further experimental evidence is needed to demonstrate extremely small and unusual tRNAs in acariform mites.


The interplay between apparent viscosity and wettability in nanoconfined water.
Understanding and manipulating fluids at the nanoscale is a matter of growing scientific and technological interest. Here we show that the viscous shear forces in nanoconfined water can be orders of magnitudes larger than in bulk water if the confining surfaces are hydrophilic, whereas they greatly decrease when the surfaces are increasingly hydrophobic. This decrease of viscous forces is quantitatively explained with a simple model that includes the slip velocity at the water surface interface. The same effect is observed in the energy dissipated by a tip vibrating in water perpendicularly to a surface. Comparison of the experimental data with the model shows that interfacial viscous forces and compressive dissipation in nanoconfined water can decrease up to two orders of magnitude due to slippage. These results offer a new understanding of interfacial fluids, which can be used to control flow at the nanoscale.


Rickettsia felis: molecular characterization of a new member of the spotted fever group.
In this report, placement of Rickettsia felis in the spotted fever group (SFG) rather than the typhus group (TG) of Rickettsia is proposed. The organism, which was first observed in cat fleas (Ctenocephalides felis) by electron microscopy, has not yet been reported to have been cultivated reproducibly, thereby limiting the standard rickettsial typing by serological means. To overcome this challenge, several genes were selected as targets to be utilized for the classification of R. felis. DNA from cat fleas naturally infected with R. felis was amplified by PCR utilizing primer sets specific for the 190 kDa surface antigen (rOmpA) and 17 kDa antigen genes. The entire 5,513 bp rompA gene was sequenced, characterized and found to have several unique features when compared to the rompA genes of other Rickettsia. Phylogenetic analysis of the partial sequence of the 17 kDa antigen gene indicated that R. felis is less divergent from the SFG rickettsiae than from the TG rickettsiae. The data corroborate results from previous reports that analysed the citrate synthase, 16S rRNA, rompB (135 kDa surface antigen), metK, ftsY, polA and dnaE genes that placed R. felis as a member of the SFG. The organism is passed trans-stadially and transovarially, and infection in the cat flea has been observed in the midgut, tracheal matrix, muscle, hypodermis, ovaries and testes.


Role of Pten in leukemia stem cells.
Chronic myeloid leukemia (CML) is initiated from the BCR-ABL-expressing leukemia stem cells (LSCs). These LSCs are highly resistant to BCR-ABL kinase inhibitors, imatinib, dasantinib and nilotinib, and methods for eradication of LSCs are still not available. It is critical to identify genes that play roles in survival and proliferation of LSCs. We recently discovered that the tumor suppressor gene Pten is downregulated in LSCs of CML mice. By genetic deletion or overexpression of Pten, we confirmed that Pten functions as a tumor suppressor in LSCs of CML, consistent with the role of Pten in LSCs of acute myeloid leukemia (AML) and progenitor cells of T-ALL progenitors. Functional enhancement of the Pten pathway provides a therapeutic strategy for targeting LSCs.


The composition of phobos: evidence for carbonaceous chondrite surface from spectral analysis.
A reflectance spectrum of Phobos (from 200 to 1100 nanometers) has been compiled from the Mariner 9 ultraviolet spectrometer, Viking lander imaging, and ground-based photometric data. The reflectance of the martian satellite is approximately constant at 5 percent from 1100 to 400 nanometers but drops sharply below 400 nanometers, reaching a value of 1 percent at 200 nanometers. The spectral albedo of Phobos bears a striking resemblance to that of asteroids (1) Ceres and (2) Pallas. Comparison of the reflectance spectra of asteroids with those of meteorites has shown that the spectral signature of Ceres is indicative of a carbonaceous chondritic composition. A physical explanation of how the compositional information is imposed on the reflectance spectrum is given. On the basis of a good match between the reflectance spectra of Phobos and Ceres and the extensive research that has been done to infer the composition of Ceres, it seems reasonable to believe that the surface composition of Phobos is similar to that of carbonaceous chondrites. This suggestion is consistent with the recently determined low density of Mars's inner satellite. Our result and recent Viking noble gas measurements suggest different modes of origin for Mars and Phobos.


Head and neck squamous cell carcinoma.
Most head and neck cancers are derived from the mucosal epithelium in the oral cavity, pharynx and larynx and are known collectively as head and neck squamous cell carcinoma (HNSCC). Oral cavity and larynx cancers are generally associated with tobacco consumption, alcohol abuse or both, whereas pharynx cancers are increasingly attributed to infection with human papillomavirus (HPV), primarily HPV-16. Thus, HNSCC can be separated into HPV-negative and HPV-positive HNSCC. Despite evidence of histological progression from cellular atypia through various degrees of dysplasia, ultimately leading to invasive HNSCC, most patients are diagnosed with late-stage HNSCC without a clinically evident antecedent pre-malignant lesion. Traditional staging of HNSCC using the tumour-node-metastasis system has been supplemented by the 2017 AJCC/UICC staging system, which incorporates additional information relevant to HPV-positive disease. Treatment is generally multimodal, consisting of surgery followed by chemoradiotherapy (CRT) for oral cavity cancers and primary CRT for pharynx and larynx cancers. The EGFR monoclonal antibody cetuximab is generally used in combination with radiation in HPV-negative HNSCC where comorbidities prevent the use of cytotoxic chemotherapy. The FDA approved the immune checkpoint inhibitors pembrolizumab and nivolumab for treatment of recurrent or metastatic HNSCC and pembrolizumab as primary treatment for unresectable disease. Elucidation of the molecular genetic landscape of HNSCC over the past decade has revealed new opportunities for therapeutic intervention. Ongoing efforts aim to integrate our understanding of HNSCC biology and immunobiology to identify predictive biomarkers that will enable delivery of the most effective, least-toxic therapies.


Nationwide cohort study of risk of ischemic heart disease in patients with celiac disease.
Studies on ischemic heart disease (IHD) incidence in individuals with celiac disease (CD) are contradictory and do not take small intestinal pathology into account. In this Swedish population-based cohort study, we examined the risk of IHD in patients with CD based on small intestinal histopathology. We defined IHD as death or incident disease in myocardial infarction or angina pectoris in Swedish national registers. In 2006 to 2008, we collected duodenal/jejunal biopsy data on CD (equal to villous atrophy; Marsh 3; n=28 190 unique individuals) and inflammation without villous atrophy (Marsh 1 to 2; n=12 598) from all 28 pathology departments in Sweden. A third cohort consisted of 3658 individuals with normal mucosa but positive CD serology (Marsh 0, latent CD). We found an increased risk of incident IHD in patients undergoing small intestinal biopsy that was independent of small intestinal histopathology (CD: hazard ratio [HR], 1.19; 95% confidence interval [CI], 1.11 to 1.28; 991 events; inflammation: HR, 1.28; 95% CI, 1.19 to 1.39; 809 events; and latent CD: HR, 1.14; 95% CI, 0.87 to 1.50; 62 events). Celiac disease (HR, 1.22; 95% CI, 1.06 to 1.40) and inflammation (HR, 1.32; 95% CI, 1.14 to 1.52) were both associated with death resulting from IHD, whereas latent CD was not (HR, 0.71; 95% CI, 0.34 to 1.50). Individuals with CD or small intestinal inflammation are at increased risk of incident IHD. We were unable to show a positive association between latent CD and incident IHD.


Local elasticity in nonlinear rheology of interacting colloidal glasses revealed by neutron scattering and rheometry.
The flow of colloidal suspensions is ubiquitous in nature and industry. Colloidal suspensions exhibit a wide range of rheological behavior, which should be closely related to the microscopic structure of the systems. With in situ small-angle neutron scattering complemented by rheological measurements, we investigated the deformation behavior of a charge-stabilized colloidal glass at particle level undergoing steady shear. A short-lived, localized elastic response at particle level, termed as the transient elasticity zone (TEZ), was identified from the neutron spectra. The existence of the TEZ, which could be promoted by the electrostatic interparticle potential, is a signature of deformation heterogeneity: the body of fluids under shear behaves like an elastic solid within the spatial range of the TEZ but like fluid outside the TEZ. The size of the TEZ shrinks as the shear rate increases in the shear thinning region, which shows that the shear thinning is accompanied by a diminishing deformation heterogeneity. More interestingly, the TEZ is found to be the structural unit that provides the resistance to the imposed shear, as evidenced by the quantitative agreement between the local elastic stress sustained by the TEZ and the macroscopic stress from rheological measurements at low and moderate shear rates. Our findings provide an understanding on the nonlinear rheology of interacting colloidal glasses from a micro-mechanical view.


Sodium and Lithium Storage Properties of Spray-Dried Molybdenum Disulfide-Graphene Hierarchical Microspheres.
Developing nano/micro-structures which can effectively upgrade the intriguing properties of electrode materials for energy storage devices is always a key research topic. Ultrathin nanosheets were proved to be one of the potential nanostructures due to their high specific surface area, good active contact areas and porous channels. Herein, we report a unique hierarchical micro-spherical morphology of well-stacked and completely miscible molybdenum disulfide (MoS2) nanosheets and graphene sheets, were successfully synthesized via a simple and industrial scale spray-drying technique to take the advantages of both MoS2 and graphene in terms of their high practical capacity values and high electronic conductivity, respectively. Computational studies were performed to understand the interfacial behaviour of MoS2 and graphene, which proves high stability of the composite with high interfacial binding energy (-2.02 eV) among them. Further, the lithium and sodium storage properties have been tested and reveal excellent cyclic stability over 250 and 500 cycles, respectively, with the highest initial capacity values of 1300 mAh g(-1) and 640 mAh g(-1) at 0.1 A g(-1).


Bringing ethical thinking to social change initiatives: Why it matters.
Norms-shifting interventions (NSI) seek to improve people's well-being by facilitating the transformation of harmful social norms, the shared rules of acceptable actions in a group that prop up harmful health behaviours. Community-based NSI aim for incremental normative change and complement other social and behaviour change strategies, addressing gender, other inequalities, and the power structures that hold inequalities in place. Consequently, they demand that designers and implementers-many who are outsiders-grapple with power, history, and community agency operating in complicated social contexts. Ethical questions include whose voices and values, at which levels, should inform intervention design; who should be accountable for managing resistance that arises during implementation? As interest and funding for NSI increases in lower and middle-income countries, their potential to yield sustained change is balanced by unintentionally reinforcing inequities that violate human rights and social justice pillars guiding health promotion efforts. A review of 125 articles on ethical considerations in public health, social justice, and human rights-where NSI actions intersect-indicated little guidance on practice. To begin to address this gap, we propose ten ethical values and practical ways to engage ethically with the social complexities of NSI and the social change they seek, and a way forward.


Estrous influence on surgical cure of a mouse breast cancer.
We have studied the effect of estrous stage, as reflected by vaginal cellularity, at the time of surgical resection of an estrogen receptor-bearing mammary adenocarcinoma upon the metastatic potential of that tumor in the C3HeB/FeJ mouse. Presence of the tumor prolonged the length of the estrous cycle by approximately 25% and removal of the tumor returned the cycle to its usual duration. Neither estrous stage at tumor implant nor size of tumor at resection (within a small range) had significant independent effects upon differences observed in the incidence of subsequent pulmonary metastases. However, estrous stage at time of surgical removal of the tumor, as reflected by cell types in vaginal smear, markedly affected whether or not metastases ultimately appeared. Because the estrous cycle in mice, comparable to the human menstrual cycle, reflects high-amplitude, rhythmic changes in hormone concentrations, it may be that the hormonal status of a women at the time of tumor resection is an important determinant of whether or not that breast cancer ultimately metastasizes.


Testing for measurement invariance and latent mean differences across methods: interesting incremental information from multitrait-multimethod studies.
Models of confirmatory factor analysis (CFA) are frequently applied to examine the convergent validity of scores obtained from multiple raters or methods in so-called multitrait-multimethod (MTMM) investigations. We show that interesting incremental information about method effects can be gained from including mean structures and tests of MI across methods in MTMM models. We present a modeling framework for testing MI in the first step of a CFA-MTMM analysis. We also discuss the relevance of MI in the context of four more complex CFA-MTMM models with method factors. We focus on three recently developed multiple-indicator CFA-MTMM models for structurally different methods [the correlated traits-correlated (methods - 1), latent difference, and latent means models; Geiser et al., 2014a; Pohl and Steyer, 2010; Pohl et al., 2008] and one model for interchangeable methods (Eid et al., 2008). We demonstrate that some of these models require or imply MI by definition for a proper interpretation of trait or method factors, whereas others do not, and explain why MI may or may not be required in each model. We show that in the model for interchangeable methods, testing for MI is critical for determining whether methods can truly be seen as interchangeable. We illustrate the theoretical issues in an empirical application to an MTMM study of attention deficit and hyperactivity disorder (ADHD) with mother, father, and teacher ratings as methods.


Lumbar extraforaminal ligaments act as a traction relief and prevent spinal nerve compression.
In a previous study, ligaments that connect the extraforaminal lumbar spinal nerves with the fibrous capsule of the facet joints and the dorsolateral side of the intervertebral disc were described. This anatomical configuration suggests a mechanical role in transferring extraforaminal spinal nerve traction. One embalmed human lumbar spine was dissected from the twelfth thoracic vertebra to the first sacral vertebra to isolate the twelfth thoracic to the fourth lumbar spinal nerves. The spinal nerves from L1 to L4 were pulled at different angles with respect to the axis of the spine. Forces of 1-6N were applied. The displacements of reflective markers glued to the proximal and distal ends of the adjoining ligaments were recorded with a video system. The spinal nerve proximal of the extraforaminal ligaments stays centred in the intervertebral foramen when pulling at an angle. At levels L1-L4 strain reduction by the extraforaminal ligaments was largest when pulling at a wider angle to the spinal axis in the sagittal plane. Proximal to the extraforaminal ligaments less displacement was seen compared to the displacement distal of the extraforaminal ligaments when pulling in longitudinal direction. A graded decrease in the displacement proximal to the extraforaminal ligaments was seen from the levels L1-L4. Extraforaminal ligaments play an important role in the prevention of damage due to spinal nerve traction. The proximal attachments secure a spinal nerve position central in the intervertebral foramen and also reduce longitudinal tension.


Vertical arrays of nanofluidic channels fabricated without nanolithography.
Vertical arrays of sealed nanofluidic channels, in which both cross-sectional dimensions are controllable down to 10 nm, were fabricated by selective side etching of a SiGe heterostructure comprised of layers of alternating Ge fractions. Capillary filling of these nanochannel arrays with fluorescent dye solutions was investigated using a confocal microscope. The feasibility of using nanochannels for size-based separation of biomolecules was demonstrated by imaging aggregates of tagged amyloid-beta peptide. The ability to integrate a large number of nanochannels shows promise for high throughput applications involving lab-on-a-chip systems.


Salt intake in children and its consequences on blood pressure.
Sodium is the most abundant extracellular cation and therefore pivotal in determining fluid balance. At the beginning of life, a positive sodium balance is needed to grow. Newborns and preterm infants tend to lose sodium via their kidneys and therefore need adequate sodium intake. Among older children and adults, however, excessive salt intake leads to volume expansion and arterial hypertension. Children who are overweight, born preterm, or small for gestational age and African American children are at increased risk of developing high blood pressure due to a high salt intake because they are more likely to be salt sensitive. In the developed world, salt intake is generally above the recommended intake also among children. Although a positive sodium balance is needed for growth during the first year of life, in older children, a sodium-poor diet seems to have the same cardiovascular protective effects as among adults. This is relevant, since: (1) a blood pressure tracking phenomenon was recognized; (2) the development of taste preferences is important during childhood; and (3) salt intake is often associated with the consumption of sugar-sweetened beverages (predisposing children to weight gain).


Primary and Secondary Yield Losses Caused by Pests and Diseases: Assessment and Modeling in Coffee.
The assessment of crop yield losses is needed for the improvement of production systems that contribute to the incomes of rural families and food security worldwide. However, efforts to quantify yield losses and identify their causes are still limited, especially for perennial crops. Our objectives were to quantify primary yield losses (incurred in the current year of production) and secondary yield losses (resulting from negative impacts of the previous year) of coffee due to pests and diseases, and to identify the most important predictors of coffee yields and yield losses. We established an experimental coffee parcel with full-sun exposure that consisted of six treatments, which were defined as different sequences of pesticide applications. The trial lasted three years (2013-2015) and yield components, dead productive branches, and foliar pests and diseases were assessed as predictors of yield. First, we calculated yield losses by comparing actual yields of specific treatments with the estimated attainable yield obtained in plots which always had chemical protection. Second, we used structural equation modeling to identify the most important predictors. Results showed that pests and diseases led to high primary yield losses (26%) and even higher secondary yield losses (38%). We identified the fruiting nodes and the dead productive branches as the most important and useful predictors of yields and yield losses. These predictors could be added in existing mechanistic models of coffee, or can be used to develop new linear mixed models to estimate yield losses. Estimated yield losses can then be related to production factors to identify corrective actions that farmers can implement to reduce losses. The experimental and modeling approaches of this study could also be applied in other perennial crops to assess yield losses.


Depression and Anxiety Disorders: Benefits of Exercise, Yoga, and Meditation.
Many people with depression or anxiety turn to nonpharmacologic and nonconventional interventions, including exercise, yoga, meditation, tai chi, or qi gong. Meta-analyses and systematic reviews have shown that these interventions can improve symptoms of depression and anxiety disorders. As an adjunctive treatment, exercise seems most helpful for treatment-resistant depression, unipolar depression, and posttraumatic stress disorder. Yoga as monotherapy or adjunctive therapy shows positive effects, particularly for depression. As an adjunctive therapy, it facilitates treatment of anxiety disorders, particularly panic disorder. Tai chi and qi gong may be helpful as adjunctive therapies for depression, but effects are inconsistent. As monotherapy or an adjunctive therapy, mindfulness-based meditation has positive effects on depression, and its effects can last for six months or more. Although positive findings are less common in people with anxiety disorders, the evidence supports adjunctive use. There are no apparent negative effects of mindfulness-based interventions, and their general health benefits justify their use as adjunctive therapy for patients with depression and anxiety disorders.


A statistical method to base nutrient recommendations on meta-analysis of intake and health-related status biomarkers.
Nutrient recommendations in use today are often derived from relatively old data of few studies with few individuals. However, for many nutrients, including vitamin B-12, extensive data have now become available from both observational studies and randomized controlled trials, addressing the relation between intake and health-related status biomarkers. The purpose of this article is to provide new methodology for dietary planning based on dose-response data and meta-analysis. The methodology builds on existing work, and is consistent with current methodology and measurement error models for dietary assessment. The detailed purposes of this paper are twofold. Firstly, to define a Population Nutrient Level (PNL) for dietary planning in groups. Secondly, to show how data from different sources can be combined in an extended meta-analysis of intake-status datasets for estimating PNL as well as other nutrient intake values, such as the Average Nutrient Requirement (ANR) and the Individual Nutrient Level (INL). For this, a computational method is presented for comparing a bivariate lognormal distribution to a health criterion value. Procedures to meta-analyse available data in different ways are described. Example calculations on vitamin B-12 requirements were made for four models, assuming different ways of estimating the dose-response relation, and different values of the health criterion. Resulting estimates of ANRs and less so for INLs were found to be sensitive to model assumptions, whereas estimates of PNLs were much less sensitive to these assumptions as they were closer to the average nutrient intake in the available data.


Operation of slope-assisted Brillouin optical correlation-domain reflectometry: comparison of system output with actual frequency shift distribution.
Although the proof of concept for slope-assisted (SA-) Brillouin optical correlation-domain reflectometry (BOCDR) has been demonstrated, no reports on its detailed operation have been provided to date. We theoretically and experimentally investigate the relationship between the system output (power-change distribution) of SA-BOCDR and the actual Brillouin frequency shift (BFS) distribution along the sensing fiber and show that these two are not identical. When the strained fiber section is much longer than the nominal spatial resolution, the actual distribution of the BFS (i.e., strain) is well reproduced by the power-change distribution. However, when the length of the strained section is equal to or only a few times the nominal resolution, the correct BFS distribution cannot be directly obtained. Even when the strained section is shorter than the nominal resolution, a shift in the power change can still be observed, which is not the case for standard BOCDR systems. This unique "beyond-nominal-resolution" effect will be of great use in practical applications.


Comparison of meconium and neonatal hair analysis for detection of gestational exposure to drugs of abuse.
Meconium and hair are two biological markers of in utero exposure to illicit drugs. To compare the sensitivity of the two tests for different drugs. Motherisk laboratory which tests in utero drug exposure in Toronto. Cocaine, benzoylecgonine, opiates, cannabis, benzodiazepines, methadone, and barbiturates were measured in pairs of hair and meconium samples from the same neonates. Meconium was marginally more sensitive than neonatal hair for detection of cocaine and cannabis, possibly because it may detect second trimester exposure whereas hair grows only during the third trimester of pregnancy. There was a significant correlation between hair and meconium concentrations of cocaine, cannabis, and opiates. In cases of clinical suspicion and a negative neonatal urine test, both meconium and hair are effective biological markers of in utero illicit drug exposure. Meconium may be more sensitive, but neonatal hair is available for three months whereas meconium is available for only one or two days. In contrast, the use of meconium, being a discarded material, is more acceptable to some parents than hair testing, which entails cutting scalp hair from the newborn.


Prediction, assessment of the Rift Valley fever activity in East and Southern Africa 2006-2008 and possible vector control strategies.
Historical outbreaks of Rift Valley fever (RVF) since the early 1950s have been associated with cyclical patterns of the El Niño/Southern Oscillation (ENSO) phenomenon, which results in elevated and widespread rainfall over the RVF endemic areas of Africa. Using satellite measurements of global and regional elevated sea surface temperatures, elevated rainfall, and satellite derived-normalized difference vegetation index data, we predicted with lead times of 2-4 months areas where outbreaks of RVF in humans and animals were expected and occurred in the Horn of Africa, Sudan, and Southern Africa at different time periods from September 2006 to March 2008. Predictions were confirmed by entomological field investigations of virus activity and by reported cases of RVF in human and livestock populations. This represents the first series of prospective predictions of RVF outbreaks and provides a baseline for improved early warning, control, response planning, and mitigation into the future.


Simultaneous measurement of amyloid fibril formation by dynamic light scattering and fluorescence reveals complex aggregation kinetics.
An apparatus that combines dynamic light scattering and Thioflavin T fluorescence detection is used to simultaneously probe fibril formation in polyglutamine peptides, the aggregating subunit associated with Huntington's disease, in vitro. Huntington's disease is a neurodegenerative disorder in a class of human pathologies that includes Alzheimer's and Parkinson's disease. These pathologies are all related by the propensity of their associated protein or polypeptide to form insoluble, β-sheet rich, amyloid fibrils. Despite the wide range of amino acid sequence in the aggregation prone polypeptides associated with these diseases, the resulting amyloids display strikingly similar physical structure, an observation which suggests a physical basis for amyloid fibril formation. Thioflavin T fluorescence reports β-sheet fibril content while dynamic light scattering measures particle size distributions. The combined techniques allow elucidation of complex aggregation kinetics and are used to reveal multiple stages of amyloid fibril formation.


Toward controlling gene expression at will: selection and design of zinc finger domains recognizing each of the 5'-GNN-3' DNA target sequences.
We have taken a comprehensive approach to the generation of novel DNA binding zinc finger domains of defined specificity. Herein we describe the generation and characterization of a family of zinc finger domains developed for the recognition of each of the 16 possible 3-bp DNA binding sites having the sequence 5'-GNN-3'. Phage display libraries of zinc finger proteins were created and selected under conditions that favor enrichment of sequence-specific proteins. Zinc finger domains recognizing a number of sequences required refinement by site-directed mutagenesis that was guided by both phage selection data and structural information. In many cases, residues not expected to make base-specific contacts had effects on specificity. A number of these domains demonstrate exquisite specificity and discriminate between sequences that differ by a single base with >100-fold loss in affinity. We conclude that the three helical positions -1, 3, and 6 of a zinc finger domain are insufficient to allow for the fine specificity of the DNA binding domain to be predicted. These domains are functionally modular and may be recombined with one another to create polydactyl proteins capable of binding 18-bp sequences with subnanomolar affinity. The family of zinc finger domains described here is sufficient for the construction of 17 million novel proteins that bind the 5'-(GNN)6-3' family of DNA sequences. These materials and methods should allow for the rapid construction of novel gene switches and provide the basis for a universal system for gene control.


Formation of holographic memory for defect tolerance in optically reconfigurable gate arrays.
Holographic polymer-dispersed liquid-crystal (HPDLC) memory using liquid-crystal composites is proposed for new optical information processing. Formation of HPDLC memory using a photomask is discussed for parallel programmability to realize fast reconfiguration of optically reconfigurable gate arrays (ORGAs). The defect tolerance of HPDLC memory is investigated to clarify the defect limitation of holographic configurations using ORGAs. Experimental results show that the noise ratio less than 15% applied to HPDLC memory rarely affects its diffraction pattern or a reconfiguration context.


A double dissociation between the effects of sub-pyrogenic systemic inflammation and hippocampal lesions on learning.
Immune system activation has been found to affect the function of the hippocampus. Sub-pyrogenic systemic inflammation impairs performance of species-typical behaviours that are also disrupted by hippocampal lesions in rodents. In a series of experiments the effect of a low, sub-pyrogenic dose of lipopolysaccharide (LPS) on hippocampus-dependent learning and memory was tested. LPS failed to impair hippocampus-dependent spatial reference memory and working memory. However, LPS affected learning a simple side-discrimination task in which an arm of a T-maze was rewarded (correct arm), and the other arm was never rewarded (incorrect arm). Whereas LPS actually enhanced performance when reward was available on every trial in the correct arm, LPS impaired learning when the correct arm was rewarded on 50% of trials. Hippocampal lesions did not impair either the continuous or partial reinforcement versions of the task. These results demonstrate that a low, sub-pyrogenic dose of LPS can impair cognitive function, but can, depending on the demands of the task, also facilitate learning. However, the double dissociation between the effects of LPS and hippocampal lesions demonstrate that sub-pyrogenic inflammation does not affect learning by disrupting hippocampal function.


Nectar Sugar Composition in Relation to Pollination Syndromes in Sinningieae (Gesneriaceae).
A putative correlation between nectar sugar composition and pollination syndrome was evaluated in the tribe Sinningieae (Neotropical Gesneriaceae). Sucrose, fructose and glucose were quantified in the nectar of 45 species using high performance anion-exchange chromatography. Representative species of the hummingbird, bee, bat and moth pollination syndromes were sampled in relation to their numeric importance in the tribe. In hummingbird and bee flowers, which represent 95% of the species in Sinningieae, nectar was sucrose-dominant (ratio [sucrose]/[hexose] > 1). Sugar ratios below one were only found in the nectar of three species with moth and bat syndromes. Sugar concentration averaged 23.9 ± 10.6% (wt/total wt) in hummingbird flowers and 28.7 ± 10.6% in bee flowers, whereas diluted nectar (7.1 ± 3.4%) was restricted to bat flowers. Similarities in the nectar of hummingbird and bee flowers contrast with the presence of specific morphological traits associated with these two syndromes, indicating that plant-pollinator relationships rely on flower display rather than on nectar characteristics. By contrast, distinct nectar chemistry is correlated with the bat syndrome in which a particularly low sucrose production is responsible for hexose dominance.


Multicriteria decision-aid method to evaluate the performance of stormwater infiltration systems over the time.
Nowadays, stormwater infiltration systems are frequently used because of their ability to reduce flows and volumes in downstream sewers, decrease overflows in surface waters and make it possible to recharge groundwater. Moreover, they come in various forms with different uses. Despite these advantages the long term sustainability of these systems is questionable and their real performances have to be assessed taking into account various and sometimes conflicting aspects. To address this problem a decision support system is proposed. It is based on a multicriteria method built to help managers to evaluate the performance of an existing infiltration system at different stages of its lifespan and identify whether it performs correctly or not, according to environmental, socio-economic, technical and sanitary aspects. The paper presents successively: the performance indicators and the way they were built, the multicriteria method to identify if the system works properly and a case study.


Association between clusters of diseases and polypharmacy in hospitalized elderly patients: results from the REPOSI study.
Although the association between multimorbidity and polypharmacy has been clearly documented, no study has analyzed whether or not specific combinations of diseases influence the prescription of polypharmacy in older persons. We assessed which clusters of diseases are associated with polypharmacy in acute-care elderly in-patients. This cross-sectional study was held in 38 Italian internal medicine and geriatric wards participating in the Registro Politerapie SIMI (REPOSI) study during 2008. The study sample included 1155 in-patients aged 65 years or older. Clusters of diseases, defined as two or more co-occurring specific chronic diseases, were identified using the odds ratio (OR) for the associations between pairs of diseases followed by cluster analysis. Polypharmacy was defined as the prescription of five or more different medications at hospital discharge. Logistic regression models were run to analyze the association between clusters of diseases and polypharmacy. Among clusters of diseases, the highest mean number of drugs (>8) was found in patients affected by heart failure (HF) plus chronic obstructive pulmonary disease (COPD), HF plus chronic renal failure (CRF), COPD plus coronary heart disease (CHD), diabetes mellitus plus CRF, and diabetes mellitus plus CHD plus cerebrovascular disease (CVD). The strongest association between clusters of diseases and polypharmacy was found for diabetes mellitus plus CHD plus CVD, diabetes plus CHD, and HF plus atrial fibrillation (AF). The observed knowledge of the relationship among co-occurring diseases and polypharmacy should help to identify and monitor older in-patients at risk of polypharmacy.


Susceptibility to paratuberculosis infection in cattle is associated with single nucleotide polymorphisms in Toll-like receptor 2 which modulate immune responses against Mycobacterium avium subspecies paratuberculosis.
Paratuberculosis is a chronic intestinal infection in ruminants, caused by Mycobacterium avium subspecies paratuberculosis (Map). To study the role of host genetics in disease susceptibility, the Toll-like receptor 2 (TLR2) gene, selected based on its potential role in immunity to mycobacterial infections, was analyzed for single nucleotide polymorphisms (SNP) and their potential association with disease. For SNP discovery and to study SNP association with disease, a case-control study including 24 cows from farms with paratuberculosis was conducted. Sequence analysis of the TLR2 genes from 12 paratuberculosis-infected animals and 12 age-matched healthy herd mates revealed 21 different SNP. The TLR2-1903 T/C SNP was significantly associated with resistance to Map. This and four additional TLR2 SNP were studied in a subsequent observational field study with 553 cows from farms with paratuberculosis. The allelic distribution of the TLR2-1903 T/C SNP was confirmed to be significantly different between the infected and non-infected animals. For the TLR2-1903 T/C SNP the odds ratio was calculated, and similar to the dominance model in the association study, the CT and CC genotypes were compared to the TT genotype. Cows with the TLR2-1903 T/C mutation (i.e., the CT and CC genotypes) were at 1.7 (95% CI: 1.2, 2.8) times the odds of being Map-infected compared to cows with the TT genotype. In in vitro functional assays, monocyte-derived macrophages from animals with a TLR2-1903 TT genotype produced more IL12p40 and IL1beta when stimulated with Map compared to cells derived from TLR2-1903 CT and CC genotypes. Also, T cell proliferative responses to mycobacterial antigens were higher in animals with a TLR2-1903 TT genotype. In conclusion, we have found a significant association between SNP TLR2-1903 T/C in the bovine TLR2 gene and bovine paratuberculosis infection. This SNP and other genetic markers could be useful in marker-assisted breeding strategies as an additional tool in paratuberculosis control strategies. In addition, the functional studies suggest that genetic polymorphisms in bovine TLR2 which result in higher macrophage activity may contribute to enhanced T cell activation and a lower susceptibility to paratuberculosis in cattle.


Intrahost dynamics of antiviral resistance in influenza A virus reflect complex patterns of segment linkage, reassortment, and natural selection.
Resistance following antiviral therapy is commonly observed in human influenza viruses. Although this evolutionary process is initiated within individual hosts, little is known about the pattern, dynamics, and drivers of antiviral resistance at this scale, including the role played by reassortment. In addition, the short duration of human influenza virus infections limits the available time window in which to examine intrahost evolution. Using single-molecule sequencing, we mapped, in detail, the mutational spectrum of an H3N2 influenza A virus population sampled from an immunocompromised patient who shed virus over a 21-month period. In this unique natural experiment, we were able to document the complex dynamics underlying the evolution of antiviral resistance. Individual resistance mutations appeared weeks before they became dominant, evolved independently on cocirculating lineages, led to a genome-wide reduction in genetic diversity through a selective sweep, and were placed into new combinations by reassortment. Notably, despite frequent reassortment, phylogenetic analysis also provided evidence for specific patterns of segment linkage, with a strong association between the hemagglutinin (HA)- and matrix (M)-encoding segments that matches that previously observed at the epidemiological scale. In sum, we were able to reveal, for the first time, the complex interaction between multiple evolutionary processes as they occur within an individual host. Understanding the evolutionary forces that shape the genetic diversity of influenza virus is crucial for predicting the emergence of drug-resistant strains but remains challenging because multiple processes occur concurrently. We characterized the evolution of antiviral resistance in a single persistent influenza virus infection, representing the first case in which reassortment and the complex patterns of drug resistance emergence and evolution have been determined within an individual host. Deep-sequence data from multiple time points revealed that the evolution of antiviral resistance reflects a combination of frequent mutation, natural selection, and a complex pattern of segment linkage and reassortment. In sum, these data show how immunocompromised hosts may help reveal the drivers of strain emergence.


Individual differences within and across feedback suppression hearing aids.
New and improved methods of feedback suppression are routinely introduced in hearing aids; however, comparisons of additional gain before feedback (AGBF) values across instruments are complicated by potential variability across subjects and measurement methods. To examine the variability in AGBF values across individual listeners and an acoustic manikin. A descriptive study of the reliability and variability of the AGBF measured within six commercially available feedback suppression (FS) algorithms using probe microphone techniques. Sixteen participants and an acoustic manikin. The range of AGBF across the six FS algorithms was 0 to 15 dB, consistent with other recent studies. However, measures made in the participants ears and on the acoustic manikin within the same instrument suggest that across instrument comparisons of AGBF measured using acoustic manikin techniques may be misleading, especially when differences between hearing aids are small (i.e., less than 6 dB). Individual subject results also revealed considerable variability within the same FS algorithms. The range of AGBF values was as small as 7 dB and as large as 16 dB depending on the specific FS algorithm, suggesting that some models are much more robust than others. These results suggest caution when selecting FS algorithms clinically since different models can demonstrate similar AGBF when averaging across ears, but result in quite different AGBF values in a single individual ear.