Evolutionary and domestication history of Cucurbita (pumpkin and squash) species inferred from 44 nuclear loci.
Phylogenetics can facilitate the study of plant domestication by resolving sister relationships between crops and their wild relatives, thereby identifying the ancestors of cultivated plants. Previous phylogenetic studies of the six Cucurbita crop lineages (pumpkins and squashes) and their wild relatives suggest histories of deep coalescence that complicate uncovering the genetic origins of the six crop taxa. We investigated the evolution of wild and domesticated Cucurbita using the most comprehensive and robust molecular-based phylogeny for Cucurbita to date based on 44 loci derived from introns of single-copy nuclear genes. We discovered novel relationships among Cucurbita species and recovered the first Cucurbita tree with well-supported resolution within species. Cucurbita comprises a clade of mesophytic annual species that includes all six crop taxa and a grade of xerophytic perennial species that represent the ancestral xerophytic habit of the genus. Based on phylogenetic resolution within-species we hypothesize that the magnitude of domestication bottlenecks varies among Cucurbita crop lineages. Our phylogeny clarifies how wild Cucurbita species are related to the domesticated taxa. We find close relationships between two wild species and crop lineages not previously identified. Expanded geographic sampling of key wild species is needed for improved understanding of the evolution of domesticated Cucurbita.


Occupational role stress is associated with higher cortisol reactivity to acute stress.
We investigated whether occupational role stress is associated with differential levels of the stress hormone cortisol in response to acute psychosocial stress. Forty-three medication-free nonsmoking men aged between 22 and 65 years (mean ± SEM: 44.5 ± 2) underwent an acute standardized psychosocial stress task combining public speaking and mental arithmetic in front of an audience. We assessed occupational role stress in terms of role conflict and role ambiguity (combined into a measure of role uncertainty) as well as further work characteristics and psychological control variables including time pressure, overcommitment, perfectionism, and stress appraisal. Moreover, we repeatedly measured salivary cortisol and blood pressure levels before and after stress exposure, and several times up to 60 min thereafter. Higher role uncertainty was associated with a more pronounced cortisol stress reactivity (p = .016), even when controlling for the full set of potential confounders (p < .001). Blood pressure stress reactivity was not associated with role uncertainty. Our findings suggest that occupational role stress in terms of role uncertainty acts as a background stressor that is associated with increased HPA-axis reactivity to acute stress. This finding may represent a potential mechanism regarding how occupational role stress may precipitate adverse health outcomes.


Who receives prescriptions for smoking cessation medications? An association rule mining analysis using a large primary care database.
To use association rule mining methods to investigate prescribing of smoking cessation medication in the UK primary care and to identify the characteristics of numerically important groups of patients who typically do, or do not, receive cessation therapy. An association rule mining study using The Health Improvement Network Database. 282 433 patients aged 16 years and over from 419 UK general practices, who were registered with the practice throughout 2008 and recorded as a current smoker during that year. Prescription for any type of smoking cessation medications in 2008 (nicotine replacement therapy, bupropion or varenicline). Age, gender, lifestyle indicators and co-morbidity. Of the current smokers, 37 731 (13.4%) were given prescriptions for smoking cessation treatment during 2008. Prescriptions were particularly likely to be given to women, those aged 31-60 years, and people with diagnoses of chronic obstructive pulmonary disease and depression. On the contrary, of patients with dementia, with alcohol intake over recommended levels, atrial fibrillation or chronic kidney disease was extremely unlikely to be prescribed a smoking cessation medication. However, the largest group of patients who did not receive therapy was young and otherwise healthy individuals. This novel approach identified sizeable and easily definable groups of patients who are systematically failing to receive support for smoking cessation in primary care. Association rule mining can be used to identify key numerically important groups at high or low risk of receiving treatment and hence potentially to improve healthcare delivery.


Relationship of causative organism and time to infection among children with cerebrospinal fluid shunt infection.
Infection is a common complication of cerebrospinal fluid (CSF) shunts, occurring in 6%-20% of children. Although studies are limited, Staphylococcus aureus is thought to cause more rapid and aggressive infection than coagulase-negative Staphylococcus (CONS) or gram-negative organisms. The authors' objective was to evaluate the relationship between the causative organisms of CSF shunt infection and the timing of infection. The authors performed a retrospective cohort study of children who underwent CSF shunt placement at a tertiary care children's hospital over a 9-year period and subsequently developed a CSF shunt infection. The primary predictor variable was the causative organism recovered from CSF culture, characterized as S. aureus, CONS, or gram-negative organisms. The primary outcome was time to infection, defined as the number of days from most recent shunt intervention to the diagnosis of the infection. The association between causative organism and time to infection was visualized using Kaplan-Meier curves, and statistical comparisons were made using nonparametric Kruskal-Wallis tests. Among 103 children in whom a CSF shunt infection developed, the causative organism was CONS in 57 (55%), S. aureus in 19 (18%), and gram-negative organisms in 9 (9%). The median time to infection did not differ (p = 0.81) for infections caused by CONS (20 days, IQR 11-40), S. aureus (26 days, IQR 12-95), and gram-negative organisms (23 days, IQR 17-34). No significant difference in time to infection based on the causative organism was observed among children with a CSF shunt infection.


Pseudoaneurysm of the Anterior Tibial Artery following Tibio-Talar-Calcaneum Fusion with a Retrograde Nail: A Rare Case and Literature Review.
This study reports the case of an 87-year-old woman who presented with a nonresolving haematoma 13 weeks following tibiotalar arthrodesis surgery on her right ankle using a retrograde nail. This was revealed by angiography to be a pseudoaneurysm of the anterior tibial artery. The patient subsequently underwent endovascular stenting of the pseudoaneurysm and has had a successful recovery. This case highlights the need for awareness of both the normal arterial supply to the leg and ankle as well as the potential for anatomical variations. Arterial variation may be as high as 6.7% based on published findings from cadaveric studies. As pseudoaneurysm is a rare complication, a high index of suspicion is needed in order to avoid a missed or delayed diagnosis. We urge surgeons to keep in mind the potential for pseudoaneurysm when a patient presents with a nonresolving haematoma and arrange appropriate further investigations as needed.


Women's entrepreneurship and intimate partner violence: A cluster randomized trial of microenterprise assistance and partner participation in post-conflict Uganda (SSM-D-14-01580R1).
Intimate partner violence is widespread and represents an obstacle to human freedom and a significant public health concern. Poverty alleviation programs and efforts to economically "empower" women have become popular policy options, but theory and empirical evidence are mixed on the relationship between women's empowerment and the experience of violence. We study the effects of a successful poverty alleviation program on women's empowerment and intimate partner relations and violence from 2009 to 2011. In the first experiment, a cluster-randomized superiority trial, 15 marginalized people (86% women) were identified in each of 120 villages (n = 1800) in Gulu and Kitgum districts in Uganda. Half of villages were randomly assigned via public lottery to immediate treatment: five days of business training, $150, and supervision and advising. We examine intent-to-treat estimates of program impact and heterogeneity in treatment effects by initial quality of partner relations. 16 months after the initial grants, the program doubled business ownership and incomes (p < 0.01); we show that the effect on monthly income, however, is moderated by initial quality of intimate partner relations. We also find small increases in marital control (p < 0.05), self-reported autonomy (p < 0.10), and quality of partner relations (p < 0.01), but essentially no change in intimate partner violence. In a second experiment, we study the impact of a low-cost attempt to include household partners (often husbands) in the process. Participants from the 60 waitlist villages (n = 904) were randomly assigned to participate in the program as individuals or with a household partner. We observe small, non-significant decreases in abuse and marital control and large increases in the quality of relationships (p < 0.05), but no effects on women's attitudes toward gender norms and a non-significant reduction in autonomy. Involving men and changing framing to promote more inclusive programming can improve relationships, but may not change gender attitudes or increase business success. Increasing women's earnings has no effect on intimate partner violence.


Day of the week to tweet: a randomised controlled trial.
To assess the effects of using health social media on different days of the working week on web activity. Individually randomised controlled parallel group superiority trial. Twitter and Weibo. 194 Cochrane Schizophrenia Group full reviews with an abstract and plain language summary web page. There were no human participants. Three randomly ordered slightly different messages (maximum of 140 characters), each containing a short URL to the freely accessible summary page, were sent on specific times on a single day. Each of these messages sent on Tuesday, Wednesday, Thursday and Friday was compared with the one sent on Monday. The primary outcome was visits to the relevant Cochrane summary web page at 1 week. Secondary outcomes were other metrics of web activity at 1 week. There was no evidence that disseminating microblogs on different days of the working week resulted in any differences in target website activity as measured by Google Analytics (n=194, all page views, adjusted ratios of geometric means 0.86 (95% CI 0.63 to 1.18), 0.88 (95% CI 0.64 to 1.21), 0.88 (95% CI 0.65 to 1.21), 0.91 (95% CI 0.66 to 1.24) for Tuesday-Friday, respectively, overall p=0.89). There were consistent findings for all outcomes. However, activity on the review site substantially increased compared with weeks preceding the intervention. There are no clear differences in the effect when 1 weekday is compared with another, but our study suggests that using microblogging social media such as Twitter and Weibo do increase information-seeking behaviour on health. Tweet any day but do Tweet.


Breast and ovarian cancer incidence in BRCA1-mutation carriers. Breast Cancer Linkage Consortium.
Dominant predisposition to early-onset breast cancer and/or ovarian cancer in many families is known to be the result of germ-line mutations in a gene on chromosome 17q, known as BRCA1. In this paper we use data from families with evidence of linkage to BRCA1 to estimate the age-specific risks of breast and ovarian cancer in BRCA1-mutation carriers and to examine the variation in risk between and within families. Under the assumption of no heterogeneity of risk between families, BRCA1 is estimated to confer a breast cancer risk of 54% by age 60 years (95% confidence interval [CI] 27%-71%) and an ovarian cancer risk of 30% by age 60 years (95% CI 8%-47%). Similar lifetime-risk estimates are obtained by examining the risks of contralateral breast cancer and of ovarian cancer, in breast cancer cases in linked families. However, there is significant evidence of heterogeneity of risk between families; a much better fit to the data is obtained by assuming two BRCA1 alleles, one conferring a breast cancer risk of 62% and an ovarian cancer risk of 11% by age 60 years, the other conferring a breast cancer risk of 39% and an ovarian cancer risk of 42%, with the first allele representing 71% of all mutations (95% CI 55%-87%). There is no evidence of clustering of breast and ovarian cancer cases within families.


FTIR spectroscopy as a unified method for simultaneous analysis of intra- and extracellular metabolites in high-throughput screening of microbial bioprocesses.
Analyses of substrate and metabolites are often bottleneck activities in high-throughput screening of microbial bioprocesses. We have assessed Fourier transform infrared spectroscopy (FTIR), in combination with high throughput micro-bioreactors and multivariate statistical analyses, for analysis of metabolites in high-throughput screening of microbial bioprocesses. In our previous study, we have demonstrated that high-throughput (HTS) FTIR can be used for estimating content and composition of intracellular metabolites, namely triglyceride accumulation in oleaginous filamentous fungi. As a continuation of that research, in the present study HTS FTIR was evaluated as a unified method for simultaneous quantification of intra- and extracellular metabolites and substrate consumption. As a proof of concept, a high-throughput microcultivation of oleaginous filamentous fungi was conducted in order to monitor production of citric acid (extracellular metabolite) and triglyceride lipids (intracellular metabolites), as well as consumption of glucose in the cultivation medium. HTS FTIR analyses of supernatant samples was compared with an attenuated total reflection (ATR) FTIR, which is an established method for bioprocess monitoring. Glucose and citric acid content of growth media was quantified by high performance liquid chromatography (HPLC). Partial least square regression (PLSR) between HPLC glucose and citric acid data and the corresponding FTIR spectral data was used to set up calibration models. PLSR results for HTS measurements were very similar to the results obtained with ATR methodology, with high coefficients of determination (0.91-0.98) and low error values (4.9-8.6%) for both glucose and citric acid estimates. The study has demonstrated that intra- and extracellular metabolites, as well as nutrients in the cultivation medium, can be monitored by a unified approach by HTS FTIR. The proof-of-concept study has validated that HTS FTIR, in combination with Duetz microtiter plate system and chemometrics, can be used for high throughput screening of microbial bioprocesses. It can be anticipated that the approach, demonstrated here on single-cell oil production by filamentous fungi, can find general application in screening studies of microbial bioprocesses, such as production of single-cell proteins, biopolymers, polysaccharides, carboxylic acids, and other type of metabolites.


Physical activity and sitting time changes in response to the COVID-19 lockdown in England.
To reduce the spread of the novel coronavirus disease 2019 (COVID-19), national governments implemented measures to limit contact between citizens. This study evaluated changes in physical activity and sitting in response to the first COVID-19 lockdown in England and factors associated with these changes. A cross-sectional online survey-based study collected data from 818 adults between 29 April and 13 May 2020. Participants self-reported demographic information, physical activity and sitting for a 'typical' week before and during lockdown. Participants were grouped into low, moderate and high physical activity, and low and high (≥8 hours/day) sitting. Paired samples t-tests compared physical activity (MET-min/week) before and during lockdown. Pearson's Chi-squared evaluated the proportion of participants in the physical activity and sitting categories. Logistic regression explored associations of demographic and behavioural factors with physical activity and sitting during lockdown. Walking and total physical activity significantly increased during lockdown by 241 (95% confidence interval [CI]: 176, 304) MET-min/week and 302 (CI: 155, 457) MET-min/week, respectively (P < 0.001). There was a 4% decrease in participants engaging in low physical activity and a 4% increase in those engaging in high physical activity from before to during lockdown (P < 0.001). The proportion engaging in high sitting increased from 29% to 41% during lockdown (P < 0.001). Lower education level (odds ratio [OR] = 1.65, P = 0.045) and higher BMI (OR = 1.05, P = 0.020) were associated with increased odds of low physical activity during lockdown, whereas non-White ethnicity (OR = 0.24, P = 0.001) was associated with reduced odds. Younger age was associated with increased odds of high sitting (OR = 2.28, P = 0.008). These findings suggest that physical activity and sitting both increased during lockdown. Demographic and behavioural factors associated with low physical activity and high sitting have been identified that could inform intervention strategies during situations of home confinement.


Functional status at 18 months of age as a predictor of childhood disability after neonatal hypoxic-ischemic encephalopathy.
In children with neonatal hypoxic-ischemic encephalopathy (HIE), we examined the association between 18-month functional status by parental report and disability at 6-7 years. Prospective observational study involving participants in the NICHD randomized controlled trial of hypothermia for HIE. Parent questionnaires-Functional Status-II (FS-II), Impact on Family (IOF) and Family Resource Scale (FRS) at 18 months were correlated with 6- to 7-year developmental assessments. Disability at 6-7 years was defined as IQ < 70, gross motor functional classification scale level III-V, bilateral blindness, deafness, or epilepsy. Rates of severe HIE (32 vs. 15%), public insurance (73% vs. 47%) and IOF scales were higher and mean (SD) FS-II independence (I) {54 (SD 35) vs. 98 (SD 8)} and general health (GH) {87 (SD 14) vs. 98 (SD 6)} scores were significantly lower in children with disability (n=37) at 6-7 years, compared to those (n=74) without disability. FS-II I scores were significantly associated with disability (OR 0.92; 95% CI 0.87-0.97; p=0.003). On path analysis, severe HIE, greater IOF and public insurance were associated with poorer 18-month FS-II I scores, which, in turn, were associated with disability at 6 to 7 years. Poor independent functioning by parental report at 18 months in children with HIE was associated with childhood disability.


The relationship between phonological memory, receptive vocabulary, and fast mapping in young children with specific language impairment.
This study assessed the fast mapping performance of children with specific language impairment (SLI) across the preschool to kindergarten age span in relation to their phonological memory and vocabulary development. Fifty-three children diagnosed with SLI and 53 children with normal language (NL) matched for age and gender (30 three-year-olds, 18 four-year-olds, 28 five-year-olds, and 30 six-year-olds) participated. Children's phonological memory was assessed using nonword repetition and digit span tasks. Receptive vocabulary was assessed using the Peabody Picture Vocabulary Test-III. Children learned the names for 8 objects during 2 fast mapping tasks. Overall, the NL group demonstrated significantly better performance on phonological memory and vocabulary measures across the age span; however, performance on the fast mapping task differed significantly only at age 5. Phonological memory and existing receptive vocabulary did not predict fast mapping ability. The phonological memory skills of preschoolers with NL and SLI followed a similar developmental pattern, but the SLI group consistently scored significantly lower than the NL group. Overall, the NL group showed significantly better receptive vocabulary, with evidence that between-group differences increased at age 6. Neither short-term phonological memory nor receptive vocabulary predicted fast mapping comprehension or production performance, even though both have been shown to correlate with later stages of word learning.


An online tool for improving biospecimen data element reporting.
Detailed documentation of the experimental materials and methods is essential for the validation of scientific papers. Human biospecimens are increasingly utilized as materials in cancer research and information about the biospecimens used is a component of this documentation. We hypothesized that previously reported biospecimen data are inadequate for accurate replication and/or validation of a substantial proportion of studies. To examine this issue, we analyzed biospecimen reporting in a representative cross section of publications over the past 12 years (1998, 2004, 2010) in the journals, Cancer Research (CR, n=46) and Clinical Cancer Research (CCR, n=73). We assessed biospecimen data in relation to the standards outlined as the Tier 1 recommended data elements from the Biospecimen Reporting for Improved Study Quality (BRISQ), in addition to ethics criteria. These data elements encompass features of biospecimens influenced by the patient, medical procedure, and biospecimen acquisition, handling and storage processes. Analysis found that while there was a significant increase in the reporting of ethics board approval status (p<0.008) and name of the ethics board (p<0.0001), there were no significant differences between these journals or over this period in reporting other biospecimen-related data elements. Of the 15 Tier 1 data elements assessed in CR and CCR, the data elements commonly obtained from the "Clinical Chart" (8/15 elements) were significantly better reported than elements that would typically be obtained from the "Biobank" (p<0.0001). Our findings demonstrate that reporting of biospecimen-related data elements has been incomplete. As one part of the solution to this issue, we propose the use of an online data-elements reporting tool (www.biobanking.ca) by biobanks. This BRISQ Report tool aims to help biobanks provide the relevant biospecimen-related data as a structured report, and to promote its inclusion as supplementary material in publications to improve the quality of future research studies.


Promoting the freedom of thought of mental health service users: Nussbaum's capabilities approach meets values-based practice.
This article clarifies how the freedom of thought as a human right can be understood and promoted as a right of mental health service users, especially people with psychotic disorder, by using Martha Nussbaum's capabilities approach and Fulford's and Fulford et al's values-based practice. According to Nussbaum, freedom of thought seems to primarily protect the capability to think, believe and feel. This capability can be promoted in the context of mental health services by values-based practice. The article points out that both Nussbaum's approach and values-based practice recognise that people's values differ. The idea of involving different actors and service users in mental healthcare is also common in both Nussbaum's approach and values-based practice. However, there are also differences in that values-based practice relies on a 'good process' in decision-making, whereas the capabilities approach is oriented towards a 'right outcome'. However, since process and outcome are linked with each other, these two approaches do not necessarily conflict despite this difference. The article suggests that absolute rights are possible within the two approaches. It also recognises that the capabilities approach, values-based practice and human rights approach lean on liberal values and thus can be combined at least in liberal societies.


Characterization of a stable HIV-1 B/C recombinant, soluble, and trimeric envelope glycoprotein (Env) highly resistant to CD4-induced conformational changes.
The HIV-1 envelope (Env) is a glycoprotein consisting of a trimer of heterodimers containing gp120 and gp41 subunits that mediates virus entry and is a major target of broadly neutralizing antibodies (bnAbs) developed during infection in some individuals. The engagement of the HIV-1 gp120 glycoprotein to the host CD4 protein triggers conformational changes in gp120 that allow its binding to co-receptors and is necessary for virus entry to establish infection. Native-like HIV-1 Env immunogens representing distinct clades have been proposed to improve immunogenicity. In the present study, we examined the basis of resistance of an HIV-1 B/C recombinant Env (LT5.J4b12C) to non-neutralizing antibodies targeting CD4-induced Env epitopes in the presence of soluble CD4 (sCD4). Using native polyacrylamide gel shift assay and negative-stain EM, we found that the prefusion conformational state of LT5.J4b12C trimeric Env was largely unaffected in the presence of excess sCD4 with most Env trimers appearing to be in a ligand-free state. This resistance to CD4-induced conformational changes was associated with a lower affinity for CD4. Moreover, the LT5.J4b12C trimeric Env preferentially bound to the neutralizing antibodies compared with non-neutralizing antibodies. Taken together, we report on an HIV-1 B/C recombinant, native-like trimeric Env protein that is highly resistant to CD4-induced conformational changes but displays epitopes recognized by a diverse array of bnAbs. Such features make this B/C recombinant trimeric Env a useful addition to the pool of other recently identified native-like HIV-1 Env trimers suitable for use as antigenic bait for bnAb isolation, structural studies, and use as potential immunogens.


In vivo and in vitro characterization of a Plasmodium liver stage-specific promoter.
Little is known about stage-specific gene regulation in Plasmodium parasites, in particular the liver stage of development. We have previously described in the Plasmodium berghei rodent model, a liver stage-specific (lisp2) gene promoter region, in vitro. Using a dual luminescence system, we now confirm the stage specificity of this promoter region also in vivo. Furthermore, by substitution and deletion analyses we have extended our in vitro characterization of important elements within the promoter region. Importantly, the dual luminescence system allows analyzing promoter constructs avoiding mouse-consuming cloning procedures of transgenic parasites. This makes extensive mutation and deletion studies a reasonable approach also in the malaria mouse model. Stage-specific expression constructs and parasite lines are extremely valuable tools for research on Plasmodium liver stage biology. Such reporter lines offer a promising opportunity for assessment of liver stage drugs, characterization of genetically attenuated parasites and liver stage-specific vaccines both in vivo and in vitro, and may be key for the generation of inducible systems.


Treatment and prophylaxis of catheter-related thromboembolic events in children.
The therapeutic management of catheter-related thromboembolic events in children is still a challenge due to the large number of potentially effective pharmacological alternatives and the insufficient scientific evidence available. A bibliographic review was performed in order to identify the available pharmacological alternatives for the prophylaxis and therapeutic management of catheter-related thrombosis in children. A literature search was carried out on MEDLINE using the medical subject heading (MeSH) central venous catheter thrombosis and on Google Scholar. The search was limited to review papers, meta-analyses, clinical practice guidelines, and randomized controlled trials performed on pediatric populations until November 2011. The different options for anticoagulation include unfractionated heparin, low molecular weight heparin and vitamin K antagonists. Thrombus resolution is stimulated more rapidly with thrombolytic agents than with anticoagulants, but the risk-benefit ratio must be considered. Streptokinase is not considered an optimal alternative due to the risk of anaphylactic reactions and has been replaced by urokinase, alteplase or the newer reteplase. Preventive strategies have been considered and most centers have protocols for routine flushing of the catheter with heparin or normal saline. Intraluminal application of urokinase and alteplase has also been studied. The wide range of options available for the pharmacotherapeutic management of catheter-related thromboembolism in children and the lack of strong evidence on the comparative efficacy and safety of the different therapeutic options, make its positioning rather difficult. Randomized controlled trials and national plans should be set up urgently.


Experience with the antibiotic resistance analysis and DNA fingerprinting in tracking faecal pollution at two lake beaches.
Posting or closing of swimming beaches because of faecal contamination is a widespread problem reported in many locations. In a risk-based approach to this problem, the risk to swimmers' health is assessed by field monitoring of indicator bacteria and the associated risks are managed by source controls and other remedial measures. In risk assessment, great advances have been made in recent years with the introduction of microbial source tracking (MST) techniques. Two such techniques, antibiotic resistance analysis and DNA fingerprinting, were applied in a study of causes of faecal contamination at two lake beaches in Toronto, Ontario. Both methods identified bird faeces as the dominant sources of E. coli. Coping with this type of pollution presents a major environmental challenge.


Contribution of the different modules in the utrophin carboxy-terminal region to the formation and regulation of the DAP complex.
The carboxy-terminal region of utrophin, like the homologous proteins dystrophin, Drp2 and dystrobrevins, contains structural domains frequently involved in protein-protein interaction. These domains (WW, EF hands, ZZ and H1-H2) mediate recognition and binding to a multicomponent complex of proteins, also known as dystrophin-associated proteins (DAPs) for their association with dystrophin, the product of the gene, mutated in Duchenne muscular dystrophy. We have exploited phage display and in vitro binding assays to study the recognition specificity of the different domains of the utrophin carboxy-terminus. We found that none of the carboxy-terminal domains of utrophin, when isolated from its structural context, selects specific ligand peptides from a phage-displayed peptide library. By contrast, panning with an extended region containing the WW, EF hands, and ZZ domain defines the consensus binding motif, PPxY which is also found in beta-dystroglycan, a component of the DAP complex that interacts with utrophin in several tissues. WW-mediated binding to PPxY peptides and to beta-dystroglycan requires the presence of the EF hands and ZZ domain. When the ZZ domain is either deleted or engaged in binding to calmodulin, the utrophin beta-dystroglycan complex cannot be formed. These findings suggest a potential regulatory mechanism by means of which the attachment of utrophin to the DAP complex can be modulated by the Ca(2+)-dependent binding of calmodulin. The remaining two motifs found in the carboxy-terminus (H1-H2) mediate the formation of utrophin-dystrobrevin hybrids but do not select ligands in a repertoire of random nonapeptides.


Tolerable Levels of Nonclinical Vehicles and Formulations Used in Studies by Multiple Routes in Multiple Species With Notes on Methods to Improve Utility.
Formulation of nonclinical evaluations is a challenge, with the fundamental need to achieve multiples of the clinical exposure complicated by differences in species and routes of administration-specific tolerances, depending on concentrations, volumes, dosing regimen, duration of each administration, and study duration. Current practice to approach these differences is based on individual experience and scattered literature with no comprehensive data source (the most notable exception being our 2006 publication on this same subject). Lack of formulation tolerance data results in excessive animal use, unplanned delays in the evaluation and development of drugs, and vehicle-dependent results. A consulting firm, a chemical company, and 4 contract research organizations conducted a rigorous data mining operation of vehicle data from studies dating from 1991 to 2015, enhancing the data from this author's 2006 publication (3 of the six 2015 contributors were also 2006 contributors). Additional data were found in the published literature. The results identified 108 single-component vehicles (and 305 combination formulations) used in more than 1,040 studies across multiple species (dog, primate, rat, mouse, rabbit, guinea pig, minipig, pig, chick embryo, and cat) by multiple routes for a wide range of study durations. The tabulated data include maximum tolerated use levels by species, route, duration of study, dose-limiting toxicity where reported, review of the available literature on each vehicle, guidance on syringe selection, volume and pH limits by route with basic guidance on nonclinical formulation development, and guidance on factors to be considered in nonclinical route selection.


Epidemiology of systemic sclerosis.
There have been few recent studies of the descriptive epidemiology of systemic sclerosis, but in recent work the limited form of the disease seems more prominent than reported in previous studies. Molecular genetic investigation of systemic sclerosis remains disappointing in identifying susceptibility alleles. There are some associations in relation to HLA class II alleles, specifically DP, DQ, and DR. These associations, however, seem to be more important in predicting the nature of the autoimmune response rather than describing disease susceptibility itself. The study of occupational and environmental influences has been dominated by studies on the role of silicone gel breast implants. These studies, driven by medicolegal constraints, have overwhelmingly failed to prove any association. Other studies confirm the continuing likelihood that organic solvents are implicated, at least in a proportion of cases.


Finger width as a measure of femoral block puncture site: an ultrasonographic anatomical-anthropometric study.
Femoral nerve blockade is a regional anesthetic procedure that may be used in prehospital and emergency settings in cases of femoral trauma. Its speed and performance depend on how well the puncture site can be accurately located, something that usually is achieved via visible landmarks and/or by combining various universal preestablished measurements. Most of these methods have been derived from cadaver studies, which often suffer limitations in clinical settings. To facilitate a quick and easy determination of the puncture site, we here attempt to find an in vivo anthropometric measure that closely corresponds to the distance between the femoral artery and femoral nerve. This is a prospective observational study. The study includes 67 patients presenting for elective surgery. The distance from the femoral nerve to the femoral artery, projected to the skin, was measured by a 13-MHz ultrasonographic linear probe. Anthropometric measurements of the width of the hand fingers were carried out at the distal interphalangeal joints. The distance from the femoral artery to the femoral nerve projected to the skin was found to closely correspond to the width of the fifth finger of the dominant hand measured at the distal interphalangeal joint. Because it relies on individual anthropometric information, this finding offers an individualized approach to determining the puncture site in a given patient. We believe that such an approach can improve and simplify femoral nerve blockade procedures in prehospital and emergency settings.


Estrogen increases smooth muscle expression of alpha2C-adrenoceptors and cold-induced constriction of cutaneous arteries.
Raynaud's phenomenon, which is characterized by intense cold-induced constriction of cutaneous arteries, is more common in women compared with men. Cold-induced constriction is mediated in part by enhanced activity of alpha(2C)-adrenoceptors (alpha(2C)-ARs) located on vascular smooth muscle cells (VSMs). Experiments were therefore performed to determine whether 17beta-estradiol regulates alpha(2C)-AR expression and function in cutaneous VSMs. 17beta-Estradiol (0.01-10 nmol/l) increased expression of the alpha(2C)-AR protein and the activity of the alpha(2C)-AR gene promoter in human cultured dermal VSMs, which was assessed following transient transfection of the cells with a promoter-reporter construct. The effect of 17beta-estradiol was associated with increased accumulation of cAMP and activation of the cAMP-responsive Rap2 GTP-binding protein. Transient transfection of VSMs with a dominant-negative mutant of Rap2 inhibited the 17beta-estradiol-induced activation of the alpha(2C)-AR gene promoter, whereas a constitutively active mutant of Rap2 increased alpha(2C)-AR promoter activity. The effects of 17beta-estradiol were inhibited by the estrogen receptor (ER) antagonist, ICI-182780 (1 micromol/l), and were mimicked by a cell-impermeable form of the hormone (estrogen:BSA) or by the selective ER-alpha receptor agonist 4,4',4'''-(4-propyl-[(1)H]-pyrazole-1,3,5-triyl)tris-phenol (PPT; 10 nmol/l) or the selective ER-beta receptor agonist 2,3-bis(4-hydroxyphenyl)-propionitrile (DPN; 10 nmol/l). Therefore, 17beta-estradiol increased expression of alpha(2C)-ARs by interacting with cell surface receptors to cause a cAMP/Rap2-dependent increase in alpha(2C)-AR transcription. In mouse tail arteries, 17beta-estradiol (10 nmol/l) increased alpha(2C)-AR expression and selectively increased the cold-induced amplification of alpha(2)-AR constriction, which is mediated by alpha(2C)-ARs. An estrogen-dependent increase in expression of cold-sensitive alpha(2C)-ARs may contribute to the increased activity of cold-induced vasoconstriction under estrogen-replete conditions.


Multi-sensor image registration based on algebraic projective invariants.
A new automatic feature-based registration algorithm is presented for multi-sensor images with projective deformation. Contours are firstly extracted from both reference and sensed images as basic features in the proposed method. Since it is difficult to design a projective-invariant descriptor from the contour information directly, a new feature named Five Sequential Corners (FSC) is constructed based on the corners detected from the extracted contours. By introducing algebraic projective invariants, we design a descriptor for each FSC that is ensured to be robust against projective deformation. Further, no gray scale related information is required in calculating the descriptor, thus it is also robust against the gray scale discrepancy between the multi-sensor image pairs. Experimental results utilizing real image pairs are presented to show the merits of the proposed registration method.


Mutational analysis of sites in the translational regulator, PHAS-I, that are selectively phosphorylated by mTOR.
Results obtained with PHAS-I proteins having Ser to Ala mutations in the five known phosphorylation sites indicate that mTOR preferentially phosphorylates Thr36 and Thr45. The effects of phosphorylating these sites on eIF4E binding were assessed in a far-Western analysis with a labeled eIF4E probe. Phosphorylation of Thr36 only slightly attenuated binding of PHAS-I to eIF4E, while phosphorylation of Thr45 markedly inhibited binding. Phosphorylation of neither site affected the electrophoretic mobility of the protein, indicating that results of studies that rely solely on a gel-shift assay to assess changes in PHAS-I phosphorylation must be interpreted with caution.


Cytomegalovirus (CMV) Epitope-Specific CD4+ T Cells Are Inflated in HIV+ CMV+ Subjects.
Select CMV epitopes drive life-long CD8+ T cell memory inflation, but the extent of CD4 memory inflation is poorly studied. CD4+ T cells specific for human CMV (HCMV) are elevated in HIV+ HCMV+ subjects. To determine whether HCMV epitope-specific CD4+ T cell memory inflation occurs during HIV infection, we used HLA-DR7 (DRB1*07:01) tetramers loaded with the glycoprotein B DYSNTHSTRYV (DYS) epitope to characterize circulating CD4+ T cells in coinfected HLA-DR7+ long-term nonprogressor HIV subjects with undetectable HCMV plasma viremia. DYS-specific CD4+ T cells were inflated among these HIV+ subjects compared with those from an HIV- HCMV+ HLA-DR7+ cohort or with HLA-DR7-restricted CD4+ T cells from the HIV-coinfected cohort that were specific for epitopes of HCMV phosphoprotein-65, tetanus toxoid precursor, EBV nuclear Ag 2, or HIV gag protein. Inflated DYS-specific CD4+ T cells consisted of effector memory or effector memory-RA+ subsets with restricted TCRβ usage and nearly monoclonal CDR3 containing novel conserved amino acids. Expression of this near-monoclonal TCR in a Jurkat cell-transfection system validated fine DYS specificity. Inflated cells were polyfunctional, not senescent, and displayed high ex vivo levels of granzyme B, CX3CR1, CD38, or HLA-DR but less often coexpressed CD38+ and HLA-DR+ The inflation mechanism did not involve apoptosis suppression, increased proliferation, or HIV gag cross-reactivity. Instead, the findings suggest that intermittent or chronic expression of epitopes, such as DYS, drive inflation of activated CD4+ T cells that home to endothelial cells and have the potential to mediate cytotoxicity and vascular disease.


Unusual chirality transfer from silica to metallic nanoparticles with formation of distorted atomic array in crystal lattice structure.
Transfer of chirality from chiral organic molecules to metallic nanoparticles (NPs) is a very attractive field of research and some unique approaches to obtaining chiral metallic NPs have been developed. However, to date, there has been no report in the literature that the chiral information of silica can be transferred into metallic NPs. In this work, a new chirality transfer system to metallic NPs from chiral silica has been achieved. The chiral transfer was performed by simple two steps: (1) trapping metal cations of silver (Ag) and gold (Au) in chiral silica of nano fibrous bundles embedding poly(ethyleneimine) inside and (2) thermoreducing the metal ions into metallic NPs. The metallic NPs of Au and Ag grown around a silica frame, using a thermo-reduction (calcination) process, showed a spherical shape with a size of about 30 nm. Interestingly, the metallic NPs detached or isolated from the silica via crushing and/or hydrolysis of the silica showed remarkable circular dichroism activity in their plasmon absorption band with an exciton coupling feature. Using an atomic resolution scanning transmission protocol, it was found that the chiral metallic NPs have a definite distortion in the atomic array in their crystal lattice structures. In comparison, achiral metallic NPs, which were prepared using a similar method around achiral silica bundles, showed a precisely ordered atomic line without distortion.


Factors associated with deep venous thrombosis in patients infected with coronavirus disease 2019: a meta-analysis.
Coronavirus disease 2019 (COVID-19) has affected more than 6 million patients worldwide. Deep venous thrombosis (DVT) has been increasingly recognized complication in these patients and is associated with increased morbidity and mortality. However, the factors associated with development of DVT in patients with COVID-19 have not been elucidated due to the novelty of the virus. We performed a meta-analysis of published studies comparing laboratory results in COVID-19 patients with and without DVT with the aim of identifying risk factors. We searched major databases for studies evaluating DVT in COVID-positive patients and performed a meta-analysis of baseline laboratory markers associated with development of DVT. A total of six studies with 678 patients were included in the pooled analyses. Of the 678 patients, 205 of patients had a DVT. Patients diagnosed with DVT were more likely to be older [mean difference 4.59 years, 95% confidence interval (CI) 1.25-7.92], and needing admission to ICU (relative risk 1.96, 95% CI 1.09-3.51). Patients with DVT had significantly higher white cell count (mean difference 1.36 × 109/l, 95% CI 0.33-2.40) and d-dimer levels (mean difference 3229.8, 95% CI 1501.5-4958.1). Lymphocyte count was lower in patients with DVT (mean difference -0.19 × 109/l, 95% CI -0.37 to -0.02). Patients with COVID-19 who develop DVT are more likely to be older and have leukocytosis with lymphopenia. Moreover, d-dimer is statistically higher and patients that are admitted to the ICU are at great risk to develop DVT.


Structural dynamics control the MicroRNA maturation pathway.
MicroRNAs (miRNAs) are crucial gene expression regulators and first-order suspects in the development and progression of many diseases. Comparative analysis of cancer cell expression data highlights many deregulated miRNAs. Low expression of miR-125a was related to poor breast cancer prognosis. Interestingly, a single nucleotide polymorphism (SNP) in miR-125a was located within a minor allele expressed by breast cancer patients. The SNP is not predicted to affect the ground state structure of the primary transcript or precursor, but neither the precursor nor mature product is detected by RT-qPCR. How this SNP modulates the maturation of miR-125a is poorly understood. Here, building upon a model of RNA dynamics derived from nuclear magnetic resonance studies, we developed a quantitative model enabling the visualization and comparison of networks of transient structures. We observed a high correlation between the distances between networks of variants with that of their respective wild types and their relative degrees of maturation to the latter, suggesting an important role of transient structures in miRNA homeostasis. We classified the human miRNAs according to pairwise distances between their networks of transient structures.


Cell wall assembly and intracellular trafficking in plant cells are directly affected by changes in the magnitude of gravitational acceleration.
Plants are able to sense the magnitude and direction of gravity. This capacity is thought to reside in selected cell types within the plant body that are equipped with specialized organelles called statoliths. However, most plant cells do not possess statoliths, yet they respond to changes in gravitational acceleration. To understand the effect of gravity on the metabolism and cellular functioning of non-specialized plant cells, we investigated a rapidly growing plant cell devoid of known statoliths and without gravitropic behavior, the pollen tube. The effects of hyper-gravity and omnidirectional exposure to gravity on intracellular trafficking and on cell wall assembly were assessed in Camellia pollen tubes, a model system with highly reproducible growth behavior in vitro. Using an epi-fluorescence microscope mounted on the Large Diameter Centrifuge at the European Space Agency, we were able to demonstrate that vesicular trafficking is reduced under hyper-gravity conditions. Immuno-cytochemistry confirmed that both in hyper and omnidirectional gravity conditions, the characteristic spatial profiles of cellulose and callose distribution in the pollen tube wall were altered, in accordance with a dose-dependent effect on pollen tube diameter. Our findings suggest that in response to gravity induced stress, the pollen tube responds by modifying cell wall assembly to compensate for the altered mechanical load. The effect was reversible within few minutes demonstrating that the pollen tube is able to quickly adapt to changing stress conditions.


Safety and biomarker effects of solanezumab in patients with Alzheimer's disease.
To assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of 12 weekly infusions of solanezumab, an anti-β-amyloid (Aβ) antibody, in patients with mild-to-moderate Alzheimer's disease. Cognitive measures were also obtained. In this phase 2, randomized, double-blind, placebo-controlled clinical trial, 52 patients with Alzheimer's disease received placebo or antibody (100 mg every 4 weeks, 100 mg weekly, 400 mg every 4 weeks, or 400 mg weekly) for 12 weeks. Safety and biomarker evaluations continued until 1 year after randomization. Both magnetic resonance imaging and cerebrospinal fluid (CSF) examinations were conducted at baseline and after the active treatment period. The Aβ concentrations were measured in plasma and CSF, and the Alzheimer's Disease Assessment Scale-cognitive portion was administered. Clinical laboratory values, CSF cell counts, and magnetic resonance imaging scans were unchanged by treatment, and no adverse events could be clearly related to antibody administration. Total (bound to antibody and unbound) Aβ(1-40) and Aβ(1-42) in plasma increased in a dose-dependent manner. Antibody treatment similarly increased total Aβ(1-40) and Aβ(1-42) in CSF. For patients taking 400 mg weekly, antibody treatment decreased unbound Aβ(1-40) in CSF (P < .01), but increased unbound Aβ(1-42) in CSF in a dose-dependent manner. The Alzheimer's Disease Assessment Scale-cognitive portion was unchanged after the 12-week antibody administration. Antibody administration was well tolerated with doses up to 400 mg weekly. The dose-dependent increase in unbound CSF Aβ(1-42) suggests that this antibody may shift Aβ equilibria sufficiently to mobilize Aβ(1-42) from amyloid plaques.


The emperor's new drugs: medication and placebo in the treatment of depression.
Antidepressants are supposed to work by fixing a chemical imbalance, specifically, a lack of serotonin in the brain. Indeed their supposed effectiveness is the primary evidence for the chemical imbalance theory. But analyses of the published data and the unpublished data that were hidden by the drug companies reveal that most (if not all) of the benefits are due to the placebo effect. Some antidepressants increase serotonin levels, some decrease it, and some have no effect at all on serotonin. Nevertheless, they all show the same therapeutic benefit. Even the small statistical difference between antidepressants and placebos may be an enhanced placebo effect, due to the fact that most patients and doctors in clinical trials successfully break blind. The serotonin theory is as close to any theory in the history of science having been proved wrong. Instead of curing depression, popular antidepressants may induce a biological vulnerability making people more likely to become depressed in the future.


Fibrosis reversal after hepatitis C virus elimination.
Hepatitis C virus (HCV) infection has been the leading cause of cirrhosis in the United States now for the last several decades. With the introduction of highly effective direct acting antiviral (DAA) drugs, cure rates are now almost 100%. With this explosion of effective therapy, it is possible that many patients with HCV may have reversion in fibrosis. The purpose of this review is, therefore, to report on recent findings in this field. Older data that examined the effect of interferon-based HCV therapy indicate that fibrosis reverses after HCV eradication. More recent work in the DAA era similarly indicates that fibrosis is reversible. A caveat is that DAA therapy causes rapid viral clearance, and appears to lead to rapid reductions in inflammation. Some tools (such as transient elastography), which may also reflect the inflammatory response, and thus may 'overestimate' of fibrosis reversal. However, emerging data suggesting improved outcomes in patients with cirrhosis after HCV clearance support the concept that even cirrhosis reverses in some patients. Fibrosis (and cirrhosis) reversion, to some extent, occurs after HCV clearance. This topic is vitally important and information continues to emerge; more data on this subject are expected and needed.


Estimates of age-related memory decline are inflated by unrecognized Alzheimer's disease.
Cognitive decline is considered an inevitable consequence of aging; however, estimates of cognitive aging may be influenced negatively by undetected preclinical Alzheimer's disease (AD). This study aimed to determine the extent to which estimates of cognitive aging were biased by preclinical AD. Cognitively normal older adults (n = 494) with amyloid-β status determined from positron emission tomography neuroimaging underwent serial neuropsychological assessment at 18-month intervals over 72 months. Estimates of the effects of age on verbal memory, working memory, executive function, and processing speed were derived using linear mixed models. The presence of preclinical AD and clinical progression to mild cognitive impairment or dementia during the study were then added to these models as covariates. Initially, age was associated with decline across all 4 cognitive domains. With the effects of elevated amyloid-β and clinical progression controlled, age was no longer associated with decline in verbal or working memory. However, the magnitude of decline was reduced only slightly for executive function and was unchanged for processing speed. Thus, considered together, the results of the study indicate that undetected preclinical AD negatively biases estimates of age-related cognitive decline for verbal and working memory.


Release of hepatocyte growth factor from mechanically stretched skeletal muscle satellite cells and role of pH and nitric oxide.
Application of mechanical stretch to cultured adult rat muscle satellite cells results in release of hepatocyte growth factor (HGF) and accelerated entry into the cell cycle. Stretch activation of cultured rat muscle satellite cells was observed only when medium pH was between 7.1 and 7.5, even though activation of satellite cells was accelerated by exogenous HGF over a pH range from 6.9 to 7.8. Furthermore, HGF was only released in stretched cultures when the pH of the medium was between 7.1 and 7.4. Conditioned medium from stretched satellite cell cultures stimulated activation of unstretched satellite cells, and the addition of anti-HGF neutralizing antibodies to stretch-conditioned medium inhibited the stretch activation response. Conditioned medium from satellite cells that were stretched in the presence of nitric-oxide synthase (NOS) inhibitor N(omega)-nitro-L-arginine methyl ester hydrochloride did not accelerate activation of unstretched control satellite cells, and HGF was not released into the medium. Conditioned medium from unstretched cells that were treated with a nitric oxide donor, sodium nitroprusside dihydrate, was able to accelerate the activation of satellite cells in vitro, and HGF was found in the conditioned medium. Immunoblot analysis indicated that both neuronal and endothelial NOS isoforms were present in satellite cell cultures. Furthermore, assays of NOS activity in stretched satellite cell cultures demonstrated that NOS is stimulated when satellite cells are stretched in vitro. These experiments indicate that stretch triggers an intracellular cascade of events, including nitric oxide synthesis, which results in HGF release and satellite cell activation.


Long-term protection against carriage of hepatitis B virus after infant vaccination.
Carriage of hepatitis B virus (HBV) is a major risk factor for liver cirrhosis and hepatocellular carcinoma. Infant vaccination has been effective in preventing horizontal transmission during early childhood. It is unknown whether protection is maintained into early adulthood. In 1984, early childhood vaccination was introduced in 2 rural Gambian villages. In 2003, serological assessment of 81.5% of 1,350 eligible participants 1-24 years old was done, to determine vaccine efficacy against infection and carriage. Overall vaccine efficacy against infection and carriage was 83.4% (95% confidence interval [CI], 79.8%-86.6%) and 96.5% (85% CI, 93.9%-98.9%), respectively. Vaccine efficacy against infection was similar when restricted to primary responders (85.3%), but a significant effect of peak antibody concentration was found. Both vaccine efficacy and levels of hepatitis B surface antibody (anti-HBs) decreased with age, resulting in a vaccine efficacy against infection and carriage among 20-24-year-old participants of 70.9% (95% CI, 60.4%-80.5%) and 91.1% (95% CI, 75.8%-100%), respectively. Fifteen years after vaccination, fewer than half of the vaccinees had detectable anti-HBs. The prevalence of carriage in the unvaccinated population was similar to the prevalence 20 years earlier. HBV vaccination early during life can provide long-lasting protection against carriage, despite decreasing antibody levels. The role played by subclinical boosting and the necessity of a booster need to be evaluated.


Immunopathological manifestations in Kabuki syndrome: a registry study of 177 individuals.
Kabuki syndrome (KS) (OMIM 147920 and 300867) is a rare genetic disorder characterized by specific facial features, intellectual disability, and various malformations. Immunopathological manifestations seem prevalent and increase the morbimortality. To assess the frequency and severity of the manifestations, we measured the prevalence of immunopathological manifestations as well as genotype-phenotype correlations in KS individuals from a registry. Data were for 177 KS individuals with KDM6A or KMT2D pathogenic variants. Questionnaires to clinicians were used to assess the presence of immunodeficiency and autoimmune diseases both on a clinical and biological basis. Overall, 44.1% (78/177) and 58.2% (46/79) of KS individuals exhibited infection susceptibility and hypogammaglobulinemia, respectively; 13.6% (24/177) had autoimmune disease (AID; 25.6% [11/43] in adults), 5.6% (10/177) with ≥2 AID manifestations. The most frequent AID manifestations were immune thrombocytopenic purpura (7.3% [13/177]) and autoimmune hemolytic anemia (4.0% [7/177]). Among nonhematological manifestations, vitiligo was frequent. Immune thrombocytopenic purpura was frequent with missense versus other types of variants (p = 0.027). The high prevalence of immunopathological manifestations in KS demonstrates the importance of systematic screening and efficient preventive management of these treatable and sometimes life-threatening conditions.


Sulphadoxine-pyrimethamine plus azithromycin for the prevention of low birthweight in Papua New Guinea: a randomised controlled trial.
Intermittent preventive treatment in pregnancy has not been evaluated outside of Africa. Low birthweight (LBW, <2,500 g) is common in Papua New Guinea (PNG) and contributing factors include malaria and reproductive tract infections. From November 2009 to February 2013, we conducted a parallel group, randomised controlled trial in pregnant women (≤ 26 gestational weeks) in PNG. Sulphadoxine-pyrimethamine (1,500/75 mg) plus azithromycin (1 g twice daily for 2 days) (SPAZ) monthly from second trimester (intervention) was compared against sulphadoxine-pyrimethamine and chloroquine (450 to 600 mg, daily for three days) (SPCQ) given once, followed by SPCQ placebo (control). Women were assigned to treatment (1:1) using a randomisation sequence with block sizes of 32. Participants were blinded to assignments. The primary outcome was LBW. Analysis was by intention-to-treat. Of 2,793 women randomised, 2,021 (72.4%) were included in the primary outcome analysis (SPCQ: 1,008; SPAZ: 1,013). The prevalence of LBW was 15.1% (305/2,021). SPAZ reduced LBW (risk ratio [RR]: 0.74, 95% CI: 0.60-0.91, P = 0.005; absolute risk reduction (ARR): 4.5%, 95% CI: 1.4-7.6; number needed to treat: 22), and preterm delivery (0.62, 95% CI: 0.43-0.89, P = 0.010), and increased mean birthweight (41.9 g, 95% CI: 0.2-83.6, P = 0.049). SPAZ reduced maternal parasitaemia (RR: 0.57, 95% CI: 0.35-0.95, P = 0.029) and active placental malaria (0.68, 95% CI: 0.47-0.98, P = 0.037), and reduced carriage of gonorrhoea (0.66, 95% CI: 0.44-0.99, P = 0.041) at second visit. There were no treatment-related serious adverse events (SAEs), and the number of SAEs (intervention 13.1% [181/1,378], control 12.7% [174/1,374], P = 0.712) and AEs (intervention 10.5% [144/1,378], control 10.8% [149/1,374], P = 0.737) was similar. A major limitation of the study was the high loss to follow-up for birthweight. SPAZ was efficacious and safe in reducing LBW, possibly acting through multiple mechanisms including the effect on malaria and on sexually transmitted infections. The efficacy of SPAZ in the presence of resistant parasites and the contribution of AZ to bacterial antibiotic resistance require further study. The ability of SPAZ to improve pregnancy outcomes warrants further evaluation. ClinicalTrials.gov NCT01136850 (06 April 2010).


Combatting type 2 diabetes by turning up the heat.
In our westernised society, the level of physical activity is low. Interventions that increase energy expenditure are generally associated with an improvement in metabolic health. Exercise and exercise training increase energy metabolism and are considered to be among the best strategies for prevention of type 2 diabetes mellitus. More recently, cold exposure has been suggested to have a therapeutic value in type 2 diabetes. At a cellular level, there is evidence that increasing the turnover of cellular substrates such as fatty acids is associated with preventive effects against lipid-induced insulin resistance. Cellular energy sensors may underlie the effects linking energy turnover with metabolic health effects. Here we review data supporting the hypothesis that increasing energy and substrate turnover has beneficial effects on insulin sensitivity and should be considered a target for the prevention and treatment of type 2 diabetes.


The RBP-Jκ binding sites within the RTA promoter regulate KSHV latent infection and cell proliferation.
Kaposi's sarcoma-associated herpesvirus (KSHV) is tightly linked to at least two lymphoproliferative disorders, primary effusion lymphoma (PEL) and multicentric Castleman's disease (MCD). However, the development of KSHV-mediated lymphoproliferative disease is not fully understood. Here, we generated two recombinant KSHV viruses deleted for the first RBP-Jκ binding site (RTA(1st)) and all three RBP-Jκ binding sites (RTA(all)) within the RTA promoter. Our results showed that RTA(1st) and RTA(all) recombinant viruses possess increased viral latency and a decreased capability for lytic replication in HEK 293 cells, enhancing colony formation and proliferation of infected cells. Furthermore, recombinant RTA(1st) and RTA(all) viruses showed greater infectivity in human peripheral blood mononuclear cells (PBMCs) relative to wt KSHV. Interestingly, KSHV BAC36 wt, RTA(1st) and RTA(all) recombinant viruses infected both T and B cells and all three viruses efficiently infected T and B cells in a time-dependent manner early after infection. Also, the capability of both RTA(1st) and RTA(all) recombinant viruses to infect CD19+ B cells was significantly enhanced. Surprisingly, RTA(1st) and RTA(all) recombinant viruses showed greater infectivity for CD3+ T cells up to 7 days. Furthermore, studies in Telomerase-immortalized human umbilical vein endothelial (TIVE) cells infected with KSHV corroborated our data that RTA(1st) and RTA(all) recombinant viruses have enhanced ability to persist in latently infected cells with increased proliferation. These recombinant viruses now provide a model to explore early stages of primary infection in human PBMCs and development of KSHV-associated lymphoproliferative diseases.


Telomerase catalytic subunit homologs from fission yeast and human.
Catalytic protein subunits of telomerase from the ciliate Euplotes aediculatus and the yeast Saccharomyces cerevisiae contain reverse transcriptase motifs. Here the homologous genes from the fission yeast Schizosaccharomyces pombe and human are identified. Disruption of the S. pombe gene resulted in telomere shortening and senescence, and expression of mRNA from the human gene correlated with telomerase activity in cell lines. Sequence comparisons placed the telomerase proteins in the reverse transcriptase family but revealed hallmarks that distinguish them from retroviral and retrotransposon relatives. Thus, the proposed telomerase catalytic subunits are phylogenetically conserved and represent a deep branch in the evolution of reverse transcriptases.


Small molecule drug A-769662 and AMP synergistically activate naive AMPK independent of upstream kinase signaling.
The AMP-activated protein kinase (AMPK) is a metabolic stress-sensing αβγ heterotrimer responsible for energy homeostasis, making it a therapeutic target for metabolic diseases such as type 2 diabetes and obesity. AMPK signaling is triggered by phosphorylation on the AMPK α subunit activation loop Thr172 by upstream kinases. Dephosphorylated, naive AMPK is thought to be catalytically inactive and insensitive to allosteric regulation by AMP and direct AMPK-activating drugs such as A-769662. Here we show that A-769662 activates AMPK independently of α-Thr172 phosphorylation, provided β-Ser108 is phosphorylated. Although neither A-769662 nor AMP individually stimulate the activity of dephosphorylated AMPK, together they stimulate >1,000-fold, bypassing the requirement for β-Ser108 phosphorylation. Consequently A-769662 and AMP together activate naive AMPK entirely allosterically and independently of upstream kinase signaling. These findings have important implications for development of AMPK-targeting therapeutics and point to possible combinatorial therapeutic strategies based on AMP and AMPK drugs.


A systematic review of surface electromyography analyses of the bench press movement task.
The bench press exercise (BP) plays an important role in recreational and professional training, in which muscle activity is an important multifactorial phenomenon. The objective of this paper is to systematically review electromyography (EMG) studies performed on the barbell BP exercise to answer the following research questions: Which muscles show the greatest activity during the flat BP? Which changes in muscle activity are related to specific conditions under which the BP movement is performed? PubMed, Scopus, Web of Science and Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library were searched through June 10, 2016. A combination of the following search terms was used: bench press, chest press, board press, test, measure, assessment, dynamometer, kinematics and biomechanics. Only original, full-text articles were considered. The search process resulted in 14 relevant studies that were included in the discussion. The triceps brachii (TB) and pectoralis major (PM) muscles were found to have similar activity during the BP, which was significantly higher than the activity of the anterior deltoid. During the BP movement, muscle activity changes with exercise intensity, velocity of movement, fatigue, mental focus, movement phase and stability conditions, such as bar vibration or unstable surfaces. Under these circumstances, TB is the most common object of activity change. PM and TB EMG activity is more dominant and shows greater EMG amplitude than anterior deltoid during the BP. There are six factors that can influence muscle activity during the BP; however, the most important factor is exercise intensity, which interacts with all other factors. The research on muscle activity in the BP has several unresolved areas, such as clearly and strongly defined guidelines to perform EMG measurements (e.g., how to elaborate with surface EMG limits) or guidelines for the use of exact muscle models.


Proportionality at birth and left ventricular hypertrophy in healthy adolescents.
Perinatal growth has important implications for cardiac development. Low birth weight is associated with cardiovascular (CV) events and mortality, and animal studies have shown that fetal growth restriction is associated with cardiac remodeling in the perinatal period leading to a permanent loss of cardiomyocyte endowment and compensatory hypertrophy. To determine associations of birthweight (BW) and multiple proportionality indexes (body mass index (BMI); weight/length2 and Ponderal index (PI); weight/length3) at birth on one hand, with left ventricular (LV) structure and function during adolescence. 379 healthy adolescents aged 14-18 years in Augusta, Georgia. LV structure and function parameters, including intraventricular septal thickness in diastole (IVSd), LV internal dimension in diastole (LVIDd), LV internal diameter in systole (LVIDs), LV posterior wall thickness in diastole (LVPWd), relative wall thickness (RWT), midwall fractional shortening (MFS), and ejection fraction, were assessed by echocardiography. When associations of birthweight, birth BMI, and birth PI with LV structure and function parameters were separately evaluated with linear regression adjusting for age, sex, race, Tanner stage, socioeconomic status, and physical activity, significant positive associations of BW with LVIDd (P = 0.004), birth BMI with LV mass index (P = 0.01), and birth PI with IVSd (P = 0.02), LVPWd (P = 0.03), and LV mass index (P = 0.002) were identified. When LV structure and function parameters were compared across PI tertiles, a significant U-shaped trend for LV mass index (Pquadratic = 0.04) was identified. Our adolescent data suggest that proportionality at birth may identify associations between perinatal growth and cardiac remodeling independent of birthweight alone.


Perianal abscesses and fistulas. A study of 1023 patients.
In a five and one-half year period, 1023 patients with anorectal abscesses and fistulas were treated. Under regional anesthesia the abscesses were unroofed and debrided and a primary fistulotomy was performed whenever a low fistula was identified. In 355 (34.7 per cent) an internal fistulous opening was demonstrated at the time of abscess drainage. Thirty-two patients had suprasphincteric fistulas and underwent two-stage fistulotomy using a seton. Perianal abscesses were encountered in 42.7 per cent of the patients, followed by ischiorectal (22.7 per cent), intersphincteric (21.4 per cent), and supralevator (7.33 per cent). The patients with supralevator and intersphincteric abscesses had a high incidence of fistula identified during abscess drainage. The recurrence rates were 3.7 per cent in the group with abscess drainage only and 1.8 per cent in the group that had primary fistulotomy along with abscess drainage. The follow-up period averaged 36 months. To accomplish adequate drainage and identify the deeper components and associated fistulous opening (34.7 per cent of the entire group), careful examination under regional anesthesia is recommended. Early aggressive treatment of an anorectal abscess and fistula significantly reduces the possibility of recurrent abscesses and/or the need for further surgery.


The associations between exposure to tobacco coupons and predictors of smoking behaviours among US youth.
A recent report showed that 13.1% of US middle and high school students were exposed to tobacco coupons in the past 30 days in 2012. The current study reanalysed data from the National Youth Tobacco Survey 2012 to examine the associations between exposure to tobacco coupons in the past 30 days and predictors of smoking among US youth, by smoking status. 24 658 middle and high school students were asked if and where they had received tobacco coupons in the past 30 days. Demographics, smoking behaviours, smoking-related beliefs, susceptibility to smoking and confidence in quitting smoking were assessed. Analyses were stratified by smoking status (never smokers, experimenters and current smokers). Data were weighted to be representative of the US youth. Exposure to tobacco coupons was associated with lower likelihood of denying the social benefits of cigarette smoking and believing all tobacco products are dangerous; higher likelihood of being susceptible to smoking (among never smokers); lower likelihood to feel confident in quitting cigarettes completely (among current smokers); and higher likelihood to intend to purchase cigarettes in the next 30 days (among experimenters and current smokers; p<0.05). Tobacco coupons may promote smoking and hinder smoking cessation among youth. Regulating tobacco coupons may reduce youth smoking in the USA. Further research is needed to determine the effect of tobacco coupons on youth tobacco use globally.


Vital signs for children at triage: a multicentre validation of the revised South African Triage Scale (SATS) for children.
To validate a revised version of the paediatric South African Triage Scale (SATS) against admission as a reference standard and compare the sensitivity of triage using: (i) clinical discriminators; (ii) an age-appropriate physiological composite score; and (iii) a combination of both. A prospective cohort study was undertaken validating the revised paediatric SATS against outcome markers of children at six emergency centres during a 2-month period in 2011. The primary outcome marker was the proportion of children admitted. Validity indicators including sensitivity (Se), specificity, positive predictive value and negative predictive value (NPV) were used to estimate the validity. Associated percentages for over-/under-triage were used to further assess practical application of the paediatric SATS. A total of 2 014 children were included. The percentage of hospital admissions increased with an increase in the level of urgency from 5% in the non-urgent patients to 73% in the emergency patients. The data demonstrated that sensitivity increased substantially when using the SATS, which is a combination of clinical discriminators and the Triage Early Warning Score (TEWS) (Se 91.0%, NPV 95.3%), compared with use of clinical discriminators in isolation (Se 57.1%, NPV 86.3%) or the TEWS in isolation (Se 75.6%, NPV 89.1%). The results of this study illustrate that the revised paediatric SATS is a safe and robust triage tool.


Efficacy and safety of current treatment options for peripheral retinal haemangioblastomas: a systematic review.
Approximately twenty per cent of Von Hippel-Lindau patients with retinal haemangioblastomas (RH) suffer from visual impairment. Various treatment options are available for peripheral RH. However, management of peripheral RH is complex due to multifocality and bilaterality. To summarize published evidence on efficacy and safety of different interventions for peripheral RH and to provide treatment recommendations for specialists. Comprehensive searches were performed using Medline, Embase, Web of Science and Google Scholar database on 4 March 2020. English publications that described outcomes related to efficacy or complications in at least two patients with peripheral RH were included. Efficacy and safety were estimated by complete tumour eradication rate, pretherapeutic and treatment-related complication rate. Odds ratios (OR) with 95% confidence intervals (CI) were calculated to calculate the risk estimate of complications between treatment options. Twenty-seven articles were included in this review describing nine different treatment options for peripheral RH: laser photocoagulation (n = 230), cryotherapy (n = 50), plaque radiotherapy (n = 27), vitreoretinal surgery (n = 88), photodynamic therapy (PDT; n = 14), transpupillary thermotherapy (TTT; n = 10), external beam radiotherapy (n = 3), systemic treatment (n = 7) and intravitreal anti-VEGF (n = 2). Complete tumour eradication was achieved in 86.7% (95% CI: 83.5-89.9%) of all eyes. For the different treatments, this was after laser photocoagulation 89.9% (86.1-93.7%), cryotherapy 70.2% (57.0-83.4%), plaque radiotherapy 96.3% (89.1-100.0%), vitreoretinal surgery (100.0%), PDT 64.3% (38.3-90.3%) and TTT 80.0% (53.8-100.0%). No complete tumour eradication was achieved after systemic therapy, external beam radiotherapy or intravitreal anti-VEGF. Photodynamic therapy and vitreoretinal surgery showed the highest complication rate after treatment compared to the other treatments (OR 10.5 [95% CI: 2.9-38.4]) and (OR 5.9 [95% CI: 3.4-9.9]), respectively. Cases that had pretherapeutic complications showed a higher treatment-related complication rate (OR 14.8 [95% CI: 7.3-30.0]) than cases without complications before treatment. These findings suggest that laser photocoagulation is the safest and most effective treatment method for peripheral RH up to 1.5 mm in diameter. Vitreoretinal surgery has the highest success rate for complete tumour eradication and may be the most suitable treatment option in the presence of pretherapeutic complications and for larger tumours.


SBA-15 confined synthesis of TiNb2O7 nanoparticles for lithium-ion batteries.
Unlike most conventional anode materials, the newly developed TiNb2O7 (TNO) does not form a solid electrolyte interface (SEI) layer, which makes it safe for high power requiring lithium-ion batteries. In this paper, we demonstrated an SBA-15 confined synthetic approach to prepare TNO nanoparticles (S-TNO) with a small particle size around 10 nm and a large BET surface area of 79.5 m(2) g(-1). It is worth mentioning that this is the smallest size reported so far for TNO. In contrast, the TNO (L-TNO) synthesized without SBA-15 has a particle size above 100 nm and a BET surface area of only 4.3 m(2) g(-1). The S-TNO shows better lithium-ion storage properties than L-TNO. The excellent electrochemical performance of S-TNO is attributed to its small crystalline size, which not only provides a larger effective area for better contact between the electrode material and the electrolyte, but also reduces the rate-limiting Li diffusion path. Moreover, S-TNO shows a high Coulombic efficiency (above 98% over 300 cycles) and negligible increase of impedance after cycling, which confirms no SEI layer formation in the operational voltage (1-3 V) of TNO.


Wnt signaling in normal and malignant hematopoiesis.
One of the most remarkable characteristics of stem cells is their ability to perpetuate themselves through self-renewal while concomitantly generating differentiated cells. In the hematopoietic system, stem cells balance these mechanisms to maintain steady-state hematopoiesis for the lifetime of the organism, and to effectively regenerate the system following injury. Defects in the proper control of self-renewal and differentiation can be potentially devastating and contribute to the development of malignancies. In this review, we trace the emerging role of Wnt signaling as a critical regulator of distinct aspects of self-renewal and differentiation, its contribution to the maintenance of homeostasis and regeneration, and how the pathway can be hijacked to promote leukemia development. A better understanding of these processes could pave the way to enhancing recovery after injury and to developing better therapeutic approaches for hematologic malignancies.


Community-based interventions to promote increased physical activity: a primer.
Current recommendations, based on an abundance of empirical data documenting the impact of physical activity (PA) on preventing morbidity and mortality associated with common chronic diseases, indicate that adults should accumulate 30 minutes of moderate-intensity PA > or =5 days per week. However, worldwide rates of PA remain low, indicating a great need for large-scale implementation of evidence-based PA interventions. We briefly present practical aspects of intervention planning, implementation and evaluation within common community settings. The first stage of intervention planning is formative research, which allows for a better understanding of the elements needed for a successful intervention. Partnering with community settings (schools, worksites, faith-based organizations and healthcare organizations) offers many benefits and the opportunity to reach specific populations. Setting-based approaches allow for multilevel strategies, ranging from individual-based programmes and educational initiatives to physical and social environmental changes. Various settings such as healthcare, worksite, and school- and community-based settings are discussed. Intervention delivery methods and strategies can range, depending on the population and setting targeted, from small-group approaches to mediated methods (e.g. print, telephone, electronic). The final phase of intervention planning and implementation is evaluation. Several objective and subjective methods of PA assessment are available to determine the effectiveness of the intervention. We have highlighted the need for process evaluation of intervention implementation to provide valuable information for the dissemination and sustainability of successful interventions. Although there are numerous considerations for the design, implementation, assessment and evaluation of PA interventions, the potential for positive impact on the overall health of the public indicates the necessity for programmes designed to increase PA.


Women and heart disease: missed opportunities.
One woman dies of cardiovascular disease (CVD) every minute in the United States. CVD is the primary cause of mortality in US women, substantially affecting the lives of African American women compared to other ethnic groups. In a national survey conducted by the American Heart Association, 87% of women surveyed failed to cite heart disease as a major threat to their health. These misperceptions may lead women to underestimate their risk for CVD, resulting in a delay in seeking medical care, thus increasing their morbidity and mortality rates. Professional association guidelines and Internet resources for women and their health care providers are available to address the risk factors of smoking, diabetes mellitus, obesity, hypertension, hyperlipidemia, and physical inactivity. Unless women are informed and educated about these risk factors, they are unable to modify their lifestyles, be proactive in their health care, or reduce their cardiovascular risks.


Availability and price of healthier food choices and association with obesity prevalence in New Zealand Māori.
Examine availability and price of healthier foods-vs-regular counterparts and their association with obesity. A cross-sectional survey of weight and height among Māori in 2 urban and 96 rural areas in the Waikato/Lakes Districts-NZ (year 2004-06) was undertaken. Concurrently, availability of 11 'healthier' food in fast-food-outlets was examined by location (urban vs rural) and median income (high-low). In supermarkets, five-specific 'regular' foods were scored against 'healthier' counterparts (white-vs-wholemeal bread, with-skin-vs-skinless chicken, regular-vs-trim meat, standard-vs-trim milk, sugarsweetened- beverages vs-water) for in-store availability and price according to the Nutrition Environment Measures Survey. Overall, 3,817 Māori (BMI: women: 32.9±7.8 kg/m2; men: 33.1±6.7 kg/m2) were included with 451 food-outlets in two urban-clusters and 698 food-outlets in 96 rural-clusters. Fast-foods: The availability of healthier food choices was higher for 8/11 items in rural and low-income areas than urban and high-income areas. Multivariate analysis considered location and income as cofactors. No association between number of fast-food-outlets/cluster and healthier foods/cluster with obesity prevalence (General/Māori BMI cutoffs) was observed. Supermarkets: Water was cheaper than sugar-sweetened-beverages and negatively associated with obesity prevalence (General r=-0.53, p=0.03; Māori r=-0.53, p=0.03); high availability scores for trim milk compared to standard milk correlated with higher obesity prevalence (General r=0.49, p=0.04; Māori r=0.57, p=0.01). Bottled water vs sugar-sweetened-beverages prices were inversely associated with obesity. This supports the argument to regulate the availability and price of sugar-sweetened-beverages in NZ. The positive association of the availability of trim milk with the prevalence of obesity warrants investigation into individual's dietary and food-purchase behaviour.


Biodegradation of metal-nitrilotriacetate complexes by a Pseudomonas species: mechanism of reaction.
A nitrilotriacetate (NTA)-degrading Pseudomonas species was shown to degrade Ca, Mn, Mg, Cu, Zn, Cd, Fe, and Na chelates of NTA at nearly equal rates when the appropriate metal concentrations are low enough to avoid toxicity from the freed metal. Ni-NTA, however, was not degraded. When higher concentrations of metal-NTA substrates were used, soil stimulated degradation of Cu, Zn, and Cd complexes, probably as a result of binding toxic freed metals. The metal associated with the NTA substrate does not appear to be transported into the cell, since metals do not accumulate in the cells and the presence of NTA reduces metal toxicity. The data are consistent with the hypothesis that an envelope-associated component, probably a transport protein involved in binding, is responsible for the disassociation of the metal from the NTA. Both soil and this NTA-degrading organism destabilize the metal-NTA complex, which suggests that in the natural environment both would act to limit mobilization of metals as soluble NTA chelates. Crude soluble enzyme preparations degrade Fe-, Mn-, and Na-NTA complexes but not Cu-NTA.


Telomeric and rDNA silencing in Saccharomyces cerevisiae are dependent on a nuclear NAD(+) salvage pathway.
The Sir2 protein is an NAD(+)-dependent protein deacetylase that is required for silencing at the silent mating-type loci, telomeres, and the ribosomal DNA (rDNA). Mutations in the NAD(+) salvage gene NPT1 weaken all three forms of silencing and also cause a reduction in the intracellular NAD(+) level. We now show that mutation of a highly conserved histidine residue in Npt1p results in a silencing defect, indicating that Npt1p enzymatic activity is required for silencing. Deletion of another NAD(+) salvage pathway gene called PNC1 caused a less severe silencing defect and did not significantly reduce the intracellular NAD(+) concentration. However, silencing in the absence of PNC1 was completely dependent on the import of nicotinic acid from the growth medium. Deletion of a gene in the de novo NAD(+) synthesis pathway BNA1 resulted in a significant rDNA silencing defect only on medium deficient in nicotinic acid, an NAD(+) precursor. By immunofluorescence microscopy, Myc-tagged Bna1p was localized throughout the whole cell in an asynchronously growing population. In contrast, Myc-tagged Npt1p was highly concentrated in the nucleus in approximately 40% of the cells, indicating that NAD(+) salvage occurs in the nucleus in a significant fraction of cells. We propose a model in which two components of the NAD(+) salvage pathway, Pnc1p and Npt1p, function together in recycling the nuclear nicotinamide generated by Sir2p deacetylase activity back into NAD(+).


Rhythmic Activity and Individual Variability in Recognition Memory: Theta Oscillations Correlate with Performance whereas Alpha Oscillations Correlate with ERPs.
During study trials of a recognition memory task, alpha (∼10 Hz) oscillations decrease, and concurrently, theta (4-8 Hz) oscillations increase when later memory is successful versus unsuccessful (subsequent memory effect). Likewise, at test, reduced alpha and increased theta activity are associated with successful memory (retrieval success effect). Here we take an individual-differences approach to test three hypotheses about theta and alpha oscillations in verbal, old/new recognition, measuring the difference in oscillations between hit trials and miss trials. First, we test the hypothesis that theta and alpha oscillations have a moderately mutually exclusive relationship; but no support for this hypothesis was found. Second, we test the hypothesis that theta oscillations explain not only memory effects within participants, but also individual differences. Supporting this prediction, durations of theta (but not alpha) oscillations at study and at test correlated significantly with d' across participants. Third, we test the hypothesis that theta and alpha oscillations reflect familiarity and recollection processes by comparing oscillation measures to ERPs that are implicated in familiarity and recollection. The alpha-oscillation effects correlated with some ERP measures, but inversely, suggesting that the actions of alpha oscillations on memory processes are distinct from the roles of familiarity- and recollection-linked ERP signals. The theta-oscillation measures, despite differentiating hits from misses, did not correlate with any ERP measure; thus, theta oscillations may reflect elaborative processes not tapped by recollection-related ERPs. Our findings are consistent with alpha oscillations reflecting visual inattention, which can modulate memory, and with theta oscillations supporting recognition memory in ways that complement the most commonly studied ERPs.


Ultrasound of the elbow with emphasis on the sonoanatomy of the distal biceps tendon and its importance for the surgical treatment of tendon lesions.
Degenerative or traumatic ruptures of the distal biceps tendon are less common than proximal lesions. Distal lesions lead to a significant loss of function with usually considerable discomfort for patients. Therefore, precise diagnostics using operator-dependent high-resolution musculoskeletal ultrasound with illustration of the extent of the affected tendon lesion are important for optimizing patient management. In this article, we discuss the precise high-resolution musculoskeletal ultrasound and sonoanatomy of the distal biceps tendon and emphasize its importance for the surgical treatment of tendon lesions. In this review and pictorial essay, we first focus on the description of the precise anatomy and ultrasound anatomy of this clinically important region. Furthermore, we highlight different ultrasound scanning techniques for the correct assessment of the distal biceps tendon. Various approaches for optimal sonographic assessment of the distal biceps tendon have been suggested in the literature: the anterior approach, the lateral access, the medial access and the posterior approach. In the second part of the article, we focus on the evaluation of surgical repair techniques of distal biceps tendon lesions considering the extent of the rupture zone of the distal biceps tendon based on the ultrasound findings. Surgical techniques are explained from the orthopedic surgical point of view. Degenerative or traumatic ruptures of the distal biceps tendon are less common than proximal lesions. Distal lesions lead to a significant loss of function with usually considerable discomfort for patients. Therefore, precise diagnostics using operator-dependent high-resolution musculoskeletal ultrasound with illustration of the extent of the affected tendon lesion are important for optimizing patient management. In this article, we discuss the precise high-resolution musculoskeletal ultrasound and sonoanatomy of the distal biceps tendon and emphasize its importance for the surgical treatment of tendon lesions. In this review and pictorial essay, we first focus on the description of the precise anatomy and ultrasound anatomy of this clinically important region. Furthermore, we highlight different ultrasound scanning techniques for the correct assessment of the distal biceps tendon. Various approaches for optimal sonographic assessment of the distal biceps tendon have been suggested in the literature: the anterior approach, the lateral access, the medial access and the posterior approach. In the second part of the article, we focus on the evaluation of surgical repair techniques of distal biceps tendon lesions considering the extent of the rupture zone of the distal biceps tendon based on the ultrasound findings. Surgical techniques are explained from the orthopedic surgical point of view.


Non-steroidal anti-inflammatory drug-induced diaphragm disease: an uncommon cause of small bowel obstruction.
Surgeons frequently deal with small bowel obstruction. However, small bowel obstruction caused by non-steroidal anti-inflammatory drug (NSAID)-induced diaphragm disease is very rare. The diagnosis is challenging, as symptoms are often non-specific and radiological studies remain inconclusive. We present a case of a 63-year-old man who, after an extensive diagnostic work-up and small bowel resection for obstructive symptoms, was finally diagnosed with NSAID-induced diaphragm disease as confirmed by histology. An unusual aspect of this case is that the patient stopped using NSAIDs after he was diagnosed with a gastric ulcer 2-years previously. This suggests that NSAID-induced diaphragms of the small bowel take some time to develop and underlines the importance of careful history taking.


A decade of intestinal protozoan epidemiology among settled immigrants in Qatar.
The World Health Organization estimates that about 3.5 billion people worldwide are affected by intestinal parasitic infections. Reports have already emphasized the role of immigrants in outbreaks of parasitic diseases in industrialized countries. With the mass influx of immigrants to Qatar, patent intestinal parasitic infections have been observed. Herein, the prevalence of intestinal protozoan infections was analysed in 29,286 records of subjects referred for stool examination at the Hamad Medical Corporation over the course of a decade (2005 to 2014, inclusive). Overall prevalence of combined protozoan infections was 5.93 % but there were significant temporal trends, age and sex effects and those arising from the region of origin of the subjects. The most common protozoan was Blastocystis hominis (overall prevalence 3.45 %). Giardia duodenalis, Chilomastix mesnili, Entamoeba coli, Entamoeba hartmanni, Endolimax nana, Iodamoeba butschlii, Entamoeba histolytica/dispar, Cryptosporidium sp. and a single case of Isospora were also detected. The prevalence of combined protozoan infections, G. duodenalis and the non-pathogenic amoebae all declined significantly across the decade. That of B. hominis varied between years but showed no directional trend across years and there was no evidence that prevalence of E. histolyitica/dispar changed significantly. Protozoan infections were observed among all regional groups, but prevalence was higher among subjects from the Arabian Peninsula, Africa and Asia compared to those from the Eastern Mediterranean and Qatar. Prevalence was higher among male subjects in all cases, but age-prevalence profiles differed between the taxa. These results offer optimism that prevalence will continue to decline in the years ahead.


The role of BRAF V600 mutation in melanoma.
BRAF is a serine/threonine protein kinase activating the MAP kinase/ERK-signaling pathway. About 50 % of melanomas harbors activating BRAF mutations (over 90 % V600E). BRAFV600E has been implicated in different mechanisms underlying melanomagenesis, most of which due to the deregulated activation of the downstream MEK/ERK effectors. The first selective inhibitor of mutant BRAF, vemurafenib, after highly encouraging results of the phase I and II trial, was compared to dacarbazine in a phase III trial in treatment-naïve patients (BRIM-3). The study results showed a relative reduction of 63 % in risk of death and 74 % in risk of tumor progression. Considering all trials so far completed, median overall survival reached approximately 16 months for vemurafenib compared to less than 10 months for dacarbazine treatment. Vemurafenib has been extensively tested on melanoma patients expressing the BRAFV600E mutated form; it has been demonstrated to be also effective in inhibiting melanomas carrying the V600K mutation. In 2011, both FDA and EMA therefore approved vemurafenib for metastatic melanoma carrying BRAFV600 mutations. Some findings suggest that continuation of vemurafenib treatment is potentially beneficial after local therapy in a subset of patients with disease progression (PD). Among who continued vemurafenib >30 days after local therapy of PD lesion(s), a median overall survival was not reached, with a median follow-up of 15.5 months from initiation of BRAF inhibitor therapy. For patients who did not continue treatment, median overall survival from the time of disease progression was 1.4 months. A clinical phase I/II trial is evaluating the safety, tolerability and efficacy of vemurafenib in combination with the CTLA-4 inhibitor mAb ipilimumab. In the BRIM-7 trial vemurafenib is tested in association with GDC-0973, a potent and highly selective inhibitor of MEK1/2. Preliminary data seem to indicate that an additional inhibitor of mutated BRAF, GSK2118436, might be also active on a wider range of BRAF mutations (V600E-K-D-R); actually, treatment with such a compound is under evaluation in a phase III study among stage III-IV melanoma patients positive for BRAF mutations. Overall, BRAF inhibitors were well tolerated; common adverse events are arthralgia, rash, fatigue, alopecia, keratoacanthoma or cutaneous squamous-cell carcinoma, photosensitivity, nausea, and diarrhea, with some variants between different inhibitors.