A prospective study of the effects of prolonged timolol therapy on alpha- and beta-adrenoceptor and angiotensin II receptor mediated responses in normal subjects.
Long-term treatment with beta 1-selective adrenergic antagonists gives rise to cross-sensitisation of cardiac beta 2-adrenoceptor responses, with no corresponding alteration in beta 1-adrenoceptor responses. We performed a prospective randomised double-blind placebo-controlled cross-over study of the effects of nonselective beta-blockade with timolol on alpha-adrenergic and angiotensin II receptor mediated responses in normal subjects. We also wished to study the time course of beta 1- and beta 2-adrenergic responses after withdrawal of timolol. Six healthy males received timolol 10 mg twice daily or placebo for 14 days. On day 11 of treatment, vascular alpha 1-, alpha 2- and angiotensin II receptor responses were assessed by measuring the blood pressure increases in response to intravenous phenylephrine, alpha-methylnoradrenaline and angiotensin amide respectively, following one dose of timolol 10 mg (to block the beta-adrenergic effects of phenylephrine and alpha-methylnoradrenaline). Both systolic and diastolic blood pressure increased in response to each of these drugs, but these increases were not different on timolol treatment or placebo. Following cessation of treatment with timolol or placebo, beta 1- and beta 2-adrenoceptor mediated responses were assessed by measuring the heart rate responses to treadmill exercise and intravenous salbutamol infusion respectively. Half each of the subjects underwent this 2 days and 3 days respectively, after the end of treatment. Both exercise-induced and salbutamol-induced tachycardia were not different following placebo or 3 days following the end of timolol treatment. However, 2 days following timolol treatment, both were attenuated; the reduction in salbutamol-induced tachycardia was significant, whilst the reduction in exercise tachycardia did not reach statistical significance. We also measured metabolic responses to exercise and to salbutamol infusion. Exercise induced a rise in plasma potassium and noradrenaline. Salbutamol produced a fall in plasma potassium, a rise in plasma glucose and insulin and also a rise in plasma noradrenaline. All of these changes were not different following placebo or 3 days after the end of timolol treatment; by contrast, 2 days following timolol treatment, all were significantly attenuated, with the exception of the rise in plasma glucose. In addition, the rise in both plasma glucose and insulin in response to an oral load of 75 g glucose were not different post-placebo, 2 or 3 days post-timolol. These results show that, following 14 days of nonselective beta-adrenoceptor blockade with timolol, there is evidence of residual beta-adrenoceptor blockade 2 days after drug withdrawal; this finding is in contrast with the known plasma profile of timolol (half-life 3-6 hours), but is consistent with our previous observations of the slow speeds of association and dissociation of timolol with beta-adrenoceptors in vitro. There is no evidence, in this study, of beta-adrenergic sensitisation following timolol withdrawal, nor of cross-regulation of vascular alpha 1-, alpha 2- or angiotensin II receptors in response to nonselective beta-adrenoceptor blockade.


Evaluation of proficiency in using different inhaler devices among intern doctors.
Doctors may have deficiencies in the ability to use different inhalers, which in turn, can result in improper technique by the patients and poorly controlled asthma and chronic obstructive pulmonary disease (COPD). To evaluate intern doctors' proficiency in using various inhaler devices. Seventy interns were evaluated for their proficiency in using pressurized metered dose inhaler (pMDI), pMDI with spacer, rotahaler, turbuhaler, and nebulizer. A structured assessment sheet was scored for identification and preparation of device, administration, coordination, and skill of explanation on a scale of 0-5. Common errors such as failure to shake pMDI before use, inability to identify the empty device, inadequate breath holding, and failure to advise gargles after use were recorded. pMDI and pMDI with spacer were identified correctly by 89% and 79% of interns. Over 90% could identify rotahaler and nebulizer whereas only 9% could identify turbuhaler. 79% and 60% could prepare pMDI and pMDI with spacer appropriately. Nebulizer preparation was performed correctly by 79% and almost all interns could not prepare turbuhaler. Only one intern administered turbuhaler correctly. About half of the participants knew the correct co-ordination for pMDI and pMDI with spacer. Two interns showed proper co-ordination in using turbuhaler. None could provide correct explanation for turbuhaler usage; whereas 76% and 70% did it for nebulizer and rotahaler, respectively. Only 43% of interns remembered to shake pMDI before use. Proficiency in using different inhaler devices amongst interns is poor. It is essential to provide adequate training for inhaler devices usage to medical graduates for proper management of asthma and COPD patients by those future primary care physicians and specialists.


Factors Associated with Maternal Worry about Her Young Child Exhibiting Choosy Feeding Behaviour.
Choosiness in young children is a normal behaviour that sometimes worries parents. The study aimed to investigate factors that are associated with a mother being worried about her child's choosy feeding behaviour. Parents of singleton children from the Avon Longitudinal Study of Parents and Children (n = 5710) completed a questionnaire assessing perception of their child's choosy feeding behaviour at 15 months of age and whether this choosiness worried them. Feeding behaviours and practices throughout the first 15 months were captured. Multinomial logistic regression models with three levels of worry (not at all, a bit and greatly) as the dependent variables tested associations with variables from pregnancy and infancy. Half of the children (56%) were described as choosy at 15 months; of these 27% had mothers who were a bit worried and 5% greatly worried. Mothers showed greater odds of being worried if the child was first born, difficult to feed or refused solids by 6 months of age. Worried mothers had shown greater odds of introducing lumpy foods late (after 9 months). Feeding vegetables regularly by 6 months was associated with lower odds of worry at 15 months. Support and advice to parents at the start of complementary feeding could help to alleviate worry. Parents should be reassured that choosiness is a normal part of child development.


Influence of adhesive cementation systems on the bond strength of relined fiber posts to root dentin.
Glass fiber post cementation procedures have undergone significant development. Relining the post with composite resin is a technique that aims to reduce resin cement thickness and consequently problems inherent to polymerization. Evidence is sparse regarding the efficacy of bonding procedures at increasing depths (from cervical to apical) using different adhesive cementation techniques. The purpose of this in vitro study was to evaluate the push-out bond strength (PBS) of composite resin relined glass fiber posts cemented to bovine root dentin using different adhesive cementation protocols. Eighteen bovine teeth (n=6) were embedded in polystyrene resin blocks, and the crowns were sectioned leaving a root portion of 20 mm in length. Root canals were prepared using rotary instruments provided by the post manufacturer (Whitepost DC #1), resulting in a uniform root canal preparation. The root canals were lubricated with a water-soluble glycerin gel. Silane (Prosil) was applied and the posts relined with a microhybrid composite resin (Filtek Z100) to conform to the root canal anatomy. Three adhesive cementation protocols were evaluated: a 3-step etch-and-rinse adhesive system (Adper Scotchbond Multi Purpose) in combination with a dual polymerizing resin cement (RelyX ARC); a universal adhesive system (Scotchbond Universal) associated with a dual polymerizing resin cement (RelyX Ultimate); and a self-adhesive dual polymerizing resin cement (RelyX Unicem 2). The roots were sectioned, resulting in four 2-mm segments at 4 different depths (cervical to apical) and evaluated by the PBS test, using a universal testing machine (Instron 4411) at 0.5 mm/min, until failure. Interfaces were evaluated by scanning electron microscopy, and failures were classified as cohesive failure in composite resin, cohesive failure in cement, cohesive failure in root dentin, adhesive failure, or mixed. Data were analyzed by 2-way split-plot ANOVA and the Tukey post hoc test (α=.05). No statistical differences were found for PBS when different cementation systems were compared (P=.253). Increased depths resulted in reduced PBS values for all cementation protocols evaluated (P<.001). Regardless the cementation system used, the lowest PBS values were at the apical region of resin relined glass fiber posts bonded to root dentin. Furthermore, the highest PBS is observed at the cervical portion of root dentin.


Patient-centred innovation to ensure access to diabetes care in Cambodia: the case of MoPoTsyo.
The increasing prevalence of chronic diseases puts a high burden on the health care systems of Low and Middle Income Countries which are often not adapted to provide the care needed. Peer support programmes are promoted to address health system constraints. This case study analyses a peer educator diabetes programme in Cambodia, MoPoTsyo, from a health system's perspective. Which strategies were used and how did these strategies change? How is the programme perceived? Data were collected through semi-structured interviews with patients, MoPoTsyo staff and peer educators, contracted pharmacy staff and health workers, health care workers and non-contracted pharmacists and managers and policy makers at district, provincial and national level. Four areas were purposively selected to do the interviews. An inductive content analysis was done independently by two researchers. MoPoTsyo developed into three stages: a focus on diabetes self-management; a widening scope to ensure affordable medicines and access to other health care services; and aiming for sustainability through more integration with the Cambodian public system and further upscaling. All respondents acknowledged the peer educators' role and competence in patient education, but their ideas about additional tasks and their place in the system differed. Indirectly involved stakeholders and district managers emphasized the particular roles and responsibilities of all actors in the system and the particular role of the peer educator in the community. MoPoTsyo's diagnostics and laboratory services were perceived as useful, especially by patients and project staff. Respondents were positive about the revolving drug fund, but expressed concerns about its integration into the government system. The degree of collaboration between health care staff and peer educators varied. MoPoTsyo responds to the needs of people with diabetes in Cambodia. Key success factors were: consistent focus on and involvement of the target group, backed up by a strong organisation; simultaneous reduction of other barriers to care; and the ongoing maintenance of relations at all levels within the health system. Despite resistance, MoPoTsyo has established a more balanced relationship between patients and health service providers, empowering patients to self-manage and access services that meet their needs.


Field-induced vacancy localization in a driven lattice gas: scaling of steady states
With the help of Monte Carlo simulations and a mean-field theory, we investigate the ordered steady-state structures resulting from the motion of a single vacancy on a periodic lattice which is filled with two species of oppositely "charged" particles. An external field biases particle-vacancy exchanges according to the particle's charge, subject to an excluded volume constraint. The steady state exhibits charge segregation, and the vacancy is localized at one of the two characteristic interfaces. Charge and hole density profiles, an appropriate order parameter, and the interfacial regions themselves exhibit characteristic scaling properties with system size and field strength. The lattice spacing is found to play a significant role within the mean-field theory.


X-space MPI: magnetic nanoparticles for safe medical imaging.
One quarter of all iodinated contrast X-ray clinical imaging studies are now performed on Chronic Kidney Disease (CKD) patients. Unfortunately, the iodine contrast agent used in X-ray is often toxic to CKD patients' weak kidneys, leading to significant morbidity and mortality. Hence, we are pioneering a new medical imaging method, called Magnetic Particle Imaging (MPI), to replace X-ray and CT iodinated angiography, especially for CKD patients. MPI uses magnetic nanoparticle contrast agents that are much safer than iodine for CKD patients. MPI already offers superb contrast and extraordinary sensitivity. The iron oxide nanoparticle tracers required for MPI are also used in MRI, and some are already approved for human use, but the contrast agents are far more effective at illuminating blood vessels when used in the MPI modality. We have recently developed a systems theoretic framework for MPI called x-space MPI, which has already dramatically improved the speed and robustness of MPI image reconstruction. X-space MPI has allowed us to optimize the hardware for fi ve MPI scanners. Moreover, x-space MPI provides a powerful framework for optimizing the size and magnetic properties of the iron oxide nanoparticle tracers used in MPI. Currently MPI nanoparticles have diameters in the 10-20 nanometer range, enabling millimeter-scale resolution in small animals. X-space MPI theory predicts that larger nanoparticles could enable up to 250 micrometer resolution imaging, which would represent a major breakthrough in safe imaging for CKD patients.


Fasudil improves survival and promotes skeletal muscle development in a mouse model of spinal muscular atrophy.
Spinal muscular atrophy (SMA) is the leading genetic cause of infant death. It is caused by mutations/deletions of the survival motor neuron 1 (SMN1) gene and is typified by the loss of spinal cord motor neurons, muscular atrophy, and in severe cases, death. The SMN protein is ubiquitously expressed and various cellular- and tissue-specific functions have been investigated to explain the specific motor neuron loss in SMA. We have previously shown that the RhoA/Rho kinase (ROCK) pathway is misregulated in cellular and animal SMA models, and that inhibition of ROCK with the chemical Y-27632 significantly increased the lifespan of a mouse model of SMA. In the present study, we evaluated the therapeutic potential of the clinically approved ROCK inhibitor fasudil. Fasudil was administered by oral gavage from post-natal day 3 to 21 at a concentration of 30 mg/kg twice daily. The effects of fasudil on lifespan and SMA pathological hallmarks of the SMA mice were assessed and compared to vehicle-treated mice. For the Kaplan-Meier survival analysis, the log-rank test was used and survival curves were considered significantly different at P < 0.05. For the remaining analyses, the Student's two-tail t test for paired variables and one-way analysis of variance (ANOVA) were used to test for differences between samples and data were considered significantly different at P < 0.05. Fasudil significantly improves survival of SMA mice. This dramatic phenotypic improvement is not mediated by an up-regulation of Smn protein or via preservation of motor neurons. However, fasudil administration results in a significant increase in muscle fiber and postsynaptic endplate size, and restores normal expression of markers of skeletal muscle development, suggesting that the beneficial effects of fasudil could be muscle-specific. Our work underscores the importance of muscle as a therapeutic target in SMA and highlights the beneficial potential of ROCK inhibitors as a therapeutic strategy for SMA and for other degenerative diseases characterized by muscular atrophy and postsynaptic immaturity.


Massive rectal bleeding from colonic fistula in pancreatitis.
Two cases of massive hematochezia from pancreatitis-associated colonic fistulae occurred. Diagnosis was made by arteriography; prompt surgical intervention ensued and both patients recovered. This rare complication of pancreatitis should be considered in every patient with rectal bleeding and a history consistent with pancreatitis, especially when an abdominal mass is present. Contrast enema examinations may help to make the diagnosis, but visceral arteriography is preferred because it defines the source of bleeding and guides the operative plan. The minimal surgical treatment consists of ligating bleeding vessels, debriding necrotic tissue, widely draining the peripancreatic space, and creating a totally diverting colostomy. All involved organs should be resected when technically feasible, since this eliminates abnormal tissue and minimizes the chances that hemorrhage will occur.


Causes of job stress in nurses: A cross-sectional study.
Nursing is naturally a stressful job. Stress in nurses can cause depression, isolation from patients, absence and decrease in their qualification. This study aimed to determine the causes of job stress in nurses of Kashan, Iran. In this cross-sectional study, 189 nurses from Kashan hospitals of different wards were studied. The information collection tool was Occupational Stress Inventory-Revised™ (OSI-R™). The most important job stress aspects in female nurses were range of roles (48.4%), role duality (40.9%) and job environment (39.6%). In men, range of roles (57.5%), job environment (50%) and responsibility (45%) were the most significant aspects. In addition, lack of balance between skill and education and job environment requirements in both genders was the least important aspect of job stress. The results showed that the level of stress in most of the nurses was in medium level. Job factors were more involved in job stress than demographic and other factors.


2D-Organic Hybrid Heterostructures for Optoelectronic Applications.
The unique properties of hybrid heterostructures have motivated the integration of two or more different types of nanomaterials into a single optoelectronic device structure. Despite the promising features of organic semiconductors, such as their acceptable optoelectronic properties, availability of low-cost processes for their fabrication, and flexibility, further optimization of both material properties and device performances remains to be achieved. With the emergence of atomically thin 2D materials, they have been integrated with conventional organic semiconductors to form multidimensional heterostructures that overcome the present limitations and provide further opportunities in the field of optoelectronics. Herein, a comprehensive review of emerging 2D-organic heterostructures-from their synthesis and fabrication to their state-of-the-art optoelectronic applications-is presented. Future challenges and opportunities associated with these heterostructures are highlighted.


The epidemiology of nonviral microbial keratitis in a tertiary care center in Muscat, Oman.
The objective of this study is to describe the epidemiology, risk factors, etiology, and outcome of microbial keratitis in a tertiary care center in Muscat, Oman. The electronic records of all patients diagnosed with keratitis or corneal ulcer between January 2013 and January 2016 in Al-Nahdha Hospital were retrospectively reviewed. Patients who presented with a corneal ulcer requiring admission and who underwent culture and sensitivity studies were included in the study. Patients with viral keratitis or sterile corneal ulcers were excluded from the study. A total of 606 electronic medical records of all presumed microbial keratitis were reviewed. Out of these, 304 met the eligibility criteria. The mean age of patients was 52.2 years (standard deviation [SD]: ±23.2 years; range: 0.1-89 years). A total of 198 (65%) microbial cultures yielded positive results. Of these, 182 (92%) were bacterial, 13 (7%) were fungal, and 3 (1%) cases were due to a combined (bacterial and fungal) etiology. Gram-positive bacteria accounted for 102 (55.1%), of which the majority was due to Streptococcus pneumoniae. Gram-negative bacteria accounted for 77 (41.6%) cases; half were caused by Pseudomonas aeruginosa. Keratitis in patients aged 18 years and younger was more likely to be associated with trauma (48.3%, P < 0.001) in young adults with contact lens wear (64%, P < 0.001) and in adults over 40 years with blepharitis (55.6%), sequelae of previous trachoma infection (26.3%), and eyelid abnormalities (18.4%). Following recovery, corneal scarring was seen in 63.2% of patients. Microbial keratitis affects patients of all age groups but is more common in older adults. The vast majority of culture-proven cases are due to bacterial infections. Children and teenagers are more likely to develop keratitis following eye trauma whereas young adults mostly develop the condition in association with contact lens wear. Ocular surface disease is the most important risk factor in older adults. The majority of patients end up with corneal scarring.


Dose-response of Cotton Dust Exposure with Lung Function among Textile Workers: MultiTex Study in Karachi, Pakistan.
Cotton dust exposure among textile mill workers lead to impaired lung function. However, only few studies have investigated the dose-response relationship between cotton dust and lung function. To determine the dose-response relationship between cotton dust exposure and lung function among textile workers. This cross-sectional survey was conducted from January to March 2016 and included 303 adult male textile workers from spinning and weaving sections of 5 mills in Karachi, Pakistan. We collected data through a translated version of the American Thoracic Society respiratory questionnaire (ATS-DLD-78A) and using spirometry. Mill-level airborne cotton dust was measured over an 8-12-hour shift through UCB-PATS (University of California, Berkeley-Particle, and Temperature Monitoring System). Multiple linear regression was used to determine the association between cotton dust exposure and lung function assessed through the 3 indices: forced expiratory volume in the first second (FEV1), forced vital capacity (FVC), and their ratio (FEV1/FVC). The mean age of the workers was 32.5 (SD 10.5) years. The mean spirometry indices expressed in percent predicted values were FEV1 82.6 (SD 14.0); FVC 90.3 (14.7), and FEV1/FVC 94.9 (10.5). The median cotton dust concentration was 0.61 (IQR 0.2 to 1.3) mg/m3. The frequency of respiratory symptoms was 15% for cough, 20% for phlegm, and 20% for wheezing. After adjustment for covariates, every mg/m3 increase in dust concentration was associated with 5.4% decline in FEV1. This study quantifies the exposure-dependent relationship between cotton dust and lung function; which has implications for regulations and standards in the textile industry in Pakistan and similar cotton-processing countries.


The PROSITE database, its status in 2002.
PROSITE [Bairoch and Bucher (1994) Nucleic Acids Res., 22, 3583-3589; Hofmann et al. (1999) Nucleic Acids Res., 27, 215-219] is a method of identifying the functions of uncharacterized proteins translated from genomic or cDNA sequences. The PROSITE database (http://www.expasy.org/prosite/) consists of biologically significant patterns and profiles designed in such a way that with appropriate computational tools it can rapidly and reliably help to determine to which known family of proteins (if any) a new sequence belongs, or which known domain(s) it contains.


Cyclic nucleotides differentially regulate the synthesis of tumour necrosis factor-alpha and interleukin-1 beta by human mononuclear cells.
Recent reports have shown that phosphodiesterase (PDE) inhibitors suppress production of tumour necrosis factor-alpha (TNF-alpha) in mouse macrophages. In the present study we show that theophylline, pentoxifylline and 3-isobutyl-1-methylxanthine markedly suppress the lipopolysaccharide (LPS)-induced synthesis of TNF-alpha (also) in human mononuclear cells. This effect is selective for TNF-alpha since up to several-fold higher concentrations of these PDE inhibitors do not affect production of interleukin-1 beta (IL-1 beta) in the same system. The observed effect of PDE inhibitors appears to be mediated by accumulation of cAMP since (i) addition of PDE inhibitors increases cAMP while cGMP levels are only marginally elevated; (ii) raising cAMP by another mechanism (enhanced formation induced by prostaglandin E2; PGE2) leads to a similar suppression of TNF-alpha production; and (iii) raising cGMP by activating the soluble guanylate cyclase by 3-morpholinosydnonimine (SIN 1) does not inhibit TNF-alpha synthesis. However, SIN 1 suppressed the synthesis of IL-1 beta. Selective suppression of TNF-alpha synthesis by PDE inhibitors may contribute to their beneficial effects in animal models of septic shock or lung injury and may thus have clinical implications.


Quetiapine alone and added to a mood stabilizer for serious mood disorders.
Use of antipsychotic medication intermittently or over the long term may be necessary in treating patients with bipolar disorder whose symptoms have responded suboptimally to standard mood-stabilizing agents. Quetiapine fumarate is an effective novel antipsychotic with mixed serotonergic (5-HT2) and dopaminergic (D2) activity. This is an open-label, 12-week prospective study to assess the efficacy and tolerability of quetiapine in the treatment of patients with bipolar and schizoaffective disorder who were suboptimally responsive to mood stabilizers alone. Participants in the study were inpatients or outpatients with a DSM-IV diagnosis of bipolar or schizoaffective disorder. Baseline psychopathology was evaluated with the Brief Psychiatric Rating Scale (BPRS), the Young Mania Rating Scale (YMRS), and the Hamilton Rating Scale for Depression (HAM-D). Involuntary movements were rated with the Simpson-Angus Neurologic Rating Scale. Quetiapine was added on an open-label basis and increased to optimum clinical dosage. Psychopathology and Abnormal Involuntary Movement Scale ratings were repeated weekly for the first 4 weeks and then again at weeks 8 and 12. Ten individuals with bipolar disorder and 10 with schizoaffective disorder received quetiapine therapy. Overall, patients improved, with significant improvement in BPRS (p < .001), YMRS (p = .043), and HAM-D scores (p = .002). Simpson-Angus score also significantly decreased (p = .02). Overall. quetiapine was well tolerated by patients in this group with serious mood disorders. The mean +/- SD quetiapine dose was 202.9 +/- 124.3 mg/day (range, 50-400 mg/day). Mean weight gain was 10.9 lb (4.9 kg). Although limited by its small size, open-label design, and relative gender homogeneity, this study suggests that quetiapine therapy may be useful in the treatment of individuals with serious mood disorders who are suboptimally responsive to mood stabilizers alone. These preliminary findings should be explored in larger, controlled trials.


Repeatability and standardization in cattle blood typing.
Thirteen laboratories engaged in cattle blood typing have participated in tests to compare their blood-typing reagents. Over 75,000 individual tests of cattle erythrocytes were made. When the laboratories tested duplicate samples without knowing they were duplicates, the results were in agreement 99 percent of the time. Tests on samples from the same 199 animals with 56 different reagents from two or more of the laboratories showed agreement 89 percent of the time. The agreement was unexpectedly good, since the primary purpose of the tests was to allow comparison of independently developed reagents and since the sources of error were numerous.


Structure-based engineering of a minimal porin reveals loop-independent channel closure.
Porins, like outer membrane protein G (OmpG) of Escherichia coli, are ideal templates among ion channels for protein and chemical engineering because of their robustness and simple architecture. OmpG shows fast transitions between open and closed states, which were attributed to loop 6 (L6). As flickering limits single-channel-based applications, we pruned L6 by either 8 or 12 amino acids. While the open probabilities of both L6 variants resemble that of native OmpG, their gating frequencies were reduced by 63 and 81%, respectively. Using the 3.2 Å structure of the shorter L6 variant in the open state, we engineered a minimal porin (220 amino acids), where all remaining extramembranous loops were truncated. Unexpectedly, this minimized porin still exhibited gating, but it was 5-fold less frequent than in OmpG. The residual gating of the minimal pore is hence independent of L6 rearrangements and involves narrowing of the ion conductance pathway most probably driven by global stretching-flexing deformations of the membrane-embedded β-barrel.


Utilization of surgical treatment for local and locoregional esophageal cancer: Analysis of the National Cancer Data Base.
Previous studies have suggested that esophagectomy is severely underused for patients with resectable esophageal cancer. The recent expansion of endoscopic local therapies, advances in surgical techniques, and improved postoperative outcomes have changed the therapeutic landscape. The impact of these developments and evolving treatment guidelines on national practice patterns is unknown. Patients diagnosed with clinical stage 0 to III esophageal cancer were identified from the National Cancer Database (2004-2013). The receipt of potentially curative surgical treatment over time was analyzed, and multivariate logistic regression was used to identify factors associated with surgical treatment. The analysis included 52,122 patients. From 2004 to 2013, the overall rate of potentially curative surgical treatment increased from 36.4% to 47.4% (P < .001). For stage 0 disease, the receipt of esophagectomy decreased from 23.8% to 17.9% (P < .001), whereas the use of local therapies increased from 34.3% to 58.8% (P < .001). The use of surgical treatment increased from 43.4% to 61.8% (P < .001), from 36.1% to 45.0% (P < .001), and from 30.8% to 38.6% (P < .001) for patients with stage I, II, and III disease, respectively. In the multivariate analysis, divergent practice patterns and adherence to national guidelines were noted between academic and community facilities. The use of potentially curative surgical treatment has increased for patients with stage 0 to III esophageal cancer. The expansion of local therapies has driven increased rates of surgical treatment for early-stage disease. Although the increased use of esophagectomy for more advanced disease is encouraging, significant variation persists at the patient and facility levels. Cancer 2017;123:410-419. © 2016 American Cancer Society.


Thoracic and abdominal aortas stiffen through unique extracellular matrix changes in intrauterine growth restricted fetal sheep.
Intrauterine growth restriction (IUGR) is a fetal complication of pregnancy epidemiologically linked to cardiovascular disease in the newborn later in life. However, the mechanism is poorly understood with very little research on the vascular structure and function during development in healthy and IUGR neonates. Previously, we found vascular remodeling and increased stiffness in the carotid and umbilical arteries, but here we examine the remodeling and biomechanics in the larger vessels more proximal to the heart. To study this question, thoracic and abdominal aortas were collected from a sheep model of placental insufficiency IUGR (PI-IUGR) due to exposure to elevated ambient temperatures. Aortas from control (n = 12) and PI-IUGR fetuses (n = 10) were analyzed for functional biomechanics and structural remodeling. PI-IUGR aortas had a significant increase in stiffness (P < 0.05), increased collagen content (P < 0.05), and decreased sulfated glycosaminoglycan content (P < 0.05). Our derived constitutive model from experimental data related increased stiffness to reorganization changes of increased alignment angle of collagen fibers and increased elastin (P < 0.05) in the thoracic aorta and increased concentration of collagen fibers in the abdominal aorta toward the circumferential direction verified through use of histological techniques. This fetal vascular remodeling in PI-IUGR may set the stage for possible altered growth and development and help to explain the pathophysiology of adult cardiovascular disease in previously IUGR individuals.


Reasoning about truth-telling in end-of-life care of patients with acute stroke.
Ethical problems are a universal phenomenon but rarely researched concerning patients dying from acute stroke. These patients often have a reduced consciousness from stroke onset and thereby lack ability to convey their needs and could be described as 'incompetent' decision makers regarding their own care. The aim of the study was to deepen the understanding of stroke team members' reasoning about truth-telling in end-of-life care due to acute stroke. Qualitative study based on individual interviews utilizing combined deductive and inductive content analysis. Participants and research context: A total of 15 stroke team members working in stroke units of two associated county hospitals in western Sweden participated. Ethical considerations: The study was approved by the Regional Ethics Review Board, Gothenburg, Sweden. The main findings were the team members' dynamic movement between the categories 'Truth above all' and 'Hide truth to protect'. Honesty was highly valued and considered as a reason for always telling the truth, with the argument of truth as common morality. However, the carers also argued for hiding the truth for different reasons such as not adding extra burden in the sorrow, awaiting a timely moment and not being a messenger of bad news. Withholding truth could both be seen as a way of protecting themselves from difficult conversations and to protect others. The results indicate that there are various barriers for truthfulness. Interpreted from a virtue of ethics perspective, withholding of truth might also be seen as an expression of sound judgement to put the patient's best interest first. The carers may need support in the form of supervision to be given space to reflect on their experience and thereby promote ethically justified care. Here, the multi-professional team can be of great value and contribute through inter-professional sharing of knowledge.


12-lead ECG training: the way forward.
The teaching of electrocardiography (ECG) monitoring has not changed for decades and still very much relies on access to real patients for practice. However there is nowadays an even greater need for modern training tools in this field as more healthcare professionals than ever before need to be trained on 12-lead ECG monitoring techniques. For example in many parts of the UK ambulance paramedics use features observed from 12-lead ECG monitoring equipment to determine whether or not a patient can receive pre-hospital thrombolytic therapy. Because important decisions are made without the presence of a cardiologist, it is essential that the training is carried out with the most realistic tools, including tools which give realistic feedback of the consequences of incorrect electrode placement. Current mannequins for ECG training are designed with protruding electrodes on the chest, which act as cues for trainees. There is therefore a need for a realistic simulation training tool to teach 12-lead ECG interpretation which includes the ability to give this feedback. We are currently working on the development of such a training tool and it is expected that it will be of great interest to medical, nursing and paramedic schools.


Low-cost industrially available molybdenum boride and carbide as "platinum-like" catalysts for the hydrogen evolution reaction in biphasic liquid systems.
Rarely reported low-cost molybdenum boride and carbide microparticles, both of which are available in abundant quantities due to their widespread use in industry, adsorb at aqueous acid-1,2-dichloroethane interfaces and efficiently catalyse the hydrogen evolution reaction in the presence of the organic electron donor - decamethylferrocene. Kinetic studies monitoring biphasic reactions by UV/vis spectroscopy, and further evidence provided by gas chromatography, highlight (a) their superior rates of catalysis relative to other industrially significant transition metal carbides and silicides, as well as a main group refractory compound, and (b) their highly comparable rates of catalysis to Pt microparticles of similar dimensions. Insight into the catalytic processes occurring for each adsorbed microparticle was obtained by voltammetry at the liquid-liquid interface.


Dietary fish oil positively regulates plasma leptin and adiponectin levels in sucrose-fed, insulin-resistant rats.
Insulin resistance and adiposity induced by a long-term sucrose-rich diet (SRD) in rats could be reversed by fish oil (FO). Regulation of plasma leptin and adiponectin levels, as well as their gene expression, by FO might be implicated in these findings. This study was designed to evaluate the long-term regulation of leptin and adiponectin by dietary FO in a dietary model of insulin resistance induced by long-term SRD in rats and to determine their impact on adiposity and insulin sensitivity. Rats were randomized to consume a control diet (CD; n = 25) or an SRD (n = 50) for 7 mo. Subsequently, the SRD-fed rats were randomized to consume SRD+FO or to continue on SRD for an additional 2 mo. Long-term SRD induced overweight and decreased both plasma leptin and adiponectin levels without change in gene expression. Dyslipidemia, adiposity, and insulin resistance accompanied these modifications. Shifting the source of fat to FO for 2 mo increased plasma levels of both adipokines, reversed insulin resistance and dyslipidemia, and improved adiposity. These results were not associated with modifications in gene expression. These results suggest that increasing both adipokines by dietary FO might play an essential role in the normalization of insulin resistance and adiposity in dietary-induced, insulin-resistant models.


Giant arachnoid granulation with a thrombosed dural arteriovenous fistula.
Arachnoid granulations are common incidentally detected small dural lesions which are usually asymptomatic and follow cerebrospinal fluid density/signal intensity on CT/MRI. Such lesions reaching a size of more than 1 cm are termed as giant arachnoid granulations (GAGs) which have been previously reported to cause venous hypertension and headaches. We report a case of GAG involving the proximal half of the superior sagittal sinus in a 45-year-old male patient which was associated with left temporal thrombosed dural arteriovenous fistula (AVF) whose thrombosed draining veins were seen converging towards the site of GAG. The patient presented with three episodes of generalised tonic-clonic seizures and improved with conservative treatment. No reports of such association of GAG with AVF is available in the literature, and we believe it could have occurred due to venous hypertension induced by GAG.


Different Biomechanical Variables Explain Within-Subjects Versus Between-Subjects Variance in Step Length Asymmetry Post-Stroke.
Step length asymmetry (SLA) is common in most stroke survivors. Several studies have shown that factors such as paretic propulsion can explain between-subjects differences in SLA. However, whether the factors that account for between-subjects variance in SLA are consistent with those that account for within-subjects, stride-by-stride variance in SLA has not been determined. SLA direction is heterogeneous, and different impairments likely contribute to differences in SLA direction. Here, we identified common predictors between-subjects that explain within-subjects variance in SLA using sparse partial least squares regression (sPLSR). We determined whether the SLA predictors differ based on SLA direction and whether predictors obtained from within-subjects analyses were the same as those obtained from between-subjects analyses. We found that for parti-cipants who walked with longer paretic steps paretic double support time, braking impulse, peak vertical ground reaction force, and peak plantarflexion moment explained 59% of the within-subjects variance in SLA. However the within-subjects variance accounted for by each individual predictor was less than 10%. Peak paretic plantarflexion moment accounted for 4% of the within-subjects variance and 42% of the between-subjects variance in SLA. In participants who walked with shorter paretic steps, paretic and non-paretic braking impulse explained 18% of the within-subjects variance in SLA. Conversely, paretic braking impulse explained 68% of the between-subjects variance in SLA, but the association between SLA and paretic braking impulse was in the opposite direction for within-subjects vs. between-subjects analyses. Thus, the relationships that explain between-subjects variance might not account for within-subjects stride-by-stride variance in SLA.


Environmental modifications to increase physical activity during recess: preliminary findings from ready for recess.
The purpose of this study was to determine the effectiveness of Ready for Recess: an elementary school recess intervention targeting staff training (ST) and providing recreational equipment (EQ). Ready for Recess had 4 intervention schools: 1) EQ+ST, 2) EQ, 3) ST, and 4) control. Moderate-to-vigorous physical activity (MVPA) was assessed with accelerometers at the four schools in 257 3rd- to 6th-grade children. Random intercept models for overweight/obese (OWOB) and healthy weight (HW) for boys and girls separately, examined change in percentage of time spent in MVPA during recess across EQ+ST, EQ, and ST compared with the control from baseline to postintervention. HW boys receiving EQ+ST increased MVPA by 19.4%, OWOB boys receiving ST increased MVPA by 4.5%, OWOB girls receiving EQ-ST increased MVPA by 6.0%, while HW girls receiving EQ decreased MVPA by 13.6% in comparison with the control. Ready for Recess represents a possible means to increase MVPA in OWOB girls/boys, populations least likely to meet MVPA recommendations. However, the effect of the intervention was not uniform across all subgroups.


ATP-powered molecular recognition to engineer transient multivalency and self-sorting 4D hierarchical systems.
Biological systems organize multiple hierarchical structures in parallel, and create dynamic assemblies and functions by energy dissipation. In contrast, emerging artificial non-equilibrium self-assembling systems have remained relatively simplistic concerning hierarchical design, and non-equilibrium multi-component systems are uncharted territory. Here we report a modular DNA toolbox allowing to program transient non-equilibrium multicomponent systems across hierarchical length scales by introducing chemically fueled molecular recognition orchestrated by reaction networks of concurrent ATP-powered ligation and cleavage of freely programmable DNA building blocks. Going across hierarchical levels, we demonstrate transient side-chain functionalized nucleic acid polymers, and further introduce the concept of transient cooperative multivalency as a key to bridge length scales to pioneer fuel-driven encapsulation, self-assembly of colloids, and non-equilibrium transient narcissistic colloidal self-sorting on a systems level. The fully programmable and functionalizable DNA components pave the way to design chemically fueled 4D (3 space, 1 time) molecular multicomponent systems and autonomous materials.


Inhibition of local hemorrhage and dermonecrosis induced by Bothrops asper snake venom: effectiveness of early in situ administration of the peptidomimetic metalloproteinase inhibitor batimastat and the chelating agent CaNa2EDTA.
The effectiveness of the chelating agent CaNa2EDTA and the peptidomimetic matrix metalloproteinase inhibitor batimastat (BB-94) to inhibit local tissue damage induced by Bothrops asper snake venom was studied in mice. Both compounds totally inhibited proteolytic, hemorrhagic, and dermonecrotic effects, and partially reduced edema-forming activity, when incubated with venom prior to injection. Much lower concentrations of batimastat than of CaNa2EDTA were required to inhibit these effects. In addition, batimastat, but not CaNa2EDTA, partially reduced myotoxic activity of the venom. When the inhibitors were administered at various time intervals after envenomation at the same site of venom injection, both compounds were effective in neutralizing local hemorrhage and dermonecrosis if administered rapidly after venom. Inhibition was not as effective as the time lapse between venom and inhibitor injections increased. Owing to the relevance of metalloproteinases in the pathogenesis of local tissue damage induced by B. asper and other pit viper venoms, it is suggested that administration of peptidomimetic metalloproteinase inhibitors or CaNa2EDTA at the site of venom injection may represent a useful alternative to complement antivenoms in the neutralization of venom-induced local tissue damage.


Pro-inflammatory and oxidative stress pathways which compromise sperm motility and survival may be altered by L-carnitine.
The testis is an immunologically privileged organ. Sertoli cells can form a blood-testis barrier and protect sperm cells from self-immune system attacks. Spermatogenesis may be inhibited by severe illness, bacterial infections and chronic inflammatory diseases but the mechanism(s) is poorly understood. Our objective is to help in understanding such mechanism(s) to develop protective agents against temporary or permanent testicular dysfunction. Lipopolysaccaride (LPS) is used as a model of animal sepsis while L-carnitine (LCR) is used as a protective agent. A total of 60 male Swiss albino rats were divided into four groups (15/group). The control group received Saline; the 2(nd) group was given LCR (500 mg/kg i.p, once). The third group was treated with LPS (5 mg/kg i.p once) and the fourth group received LCR then LPS after three hours. From each group, five rats were used for histopathological examination. Biochemical parameters were assessed in the remaining ten rats. At the end of the experiment, animals were lightly anaesthetized with ether where blood samples were collected and testes were dissected on ice. Sperm count and motility were evaluated from cauda epididymis in each animal. Also, oxidative stress was evaluated by measuring testicular contents of reduced glutathione (GSH), malondialdehyde (MDA) and 8-hydroxydeoxyguanosine (8-HDG, the DNA adduct for oxidative damage) in testicular DNA. The pro-inflammatory mediator nitric oxide (NO) in addition to lactate dehydrogenase (LDHx) isoenzyme-x activity as an indicator for normal spermatozoal metabolism were assessed in testicular homogenate. Serum interlukin (IL)-2 level was also assessed as a marker for T-helper cell function. The obtained data revealed that LPS induced marked reductions in sperm's count and motility, obstruction in seminiferous tubules, hypospermia and dilated congested blood vessels in testicular sections concomitant with decreased testicular GSH content and LDHx activity. Moreover, the testicular levels of MDA, 8-HDG (in testicular DNA) and NO as well as serum IL-2 level were increased. Administration of LCR before LPS returned both sperm count and motility to normal levels. Also, contents of testicular GSH, MDA, 8-HDG and NO returned back to the corresponding control values. In addition, serum IL-2 level as well as histological abnormalities were markedly improved in LCR + LPS-treated rats. In conclusion, LPS increased proinflammatory and oxidative stress markers in the testis leading to a marked testicular dysfunction. L-carnitine administration ameliorates these effects by antioxidant and/or anti-inflammatory mechanisms suggesting a protective role against male infertility in severely infected or septic patients.


ALOX12 in human toxoplasmosis.
ALOX12 is a gene encoding arachidonate 12-lipoxygenase (12-LOX), a member of a nonheme lipoxygenase family of dioxygenases. ALOX12 catalyzes the addition of oxygen to arachidonic acid, producing 12-hydroperoxyeicosatetraenoic acid (12-HPETE), which can be reduced to the eicosanoid 12-HETE (12-hydroxyeicosatetraenoic acid). 12-HETE acts in diverse cellular processes, including catecholamine synthesis, vasoconstriction, neuronal function, and inflammation. Consistent with effects on these fundamental mechanisms, allelic variants of ALOX12 are associated with diseases including schizophrenia, atherosclerosis, and cancers, but the mechanisms have not been defined. Toxoplasma gondii is an apicomplexan parasite that causes morbidity and mortality and stimulates an innate and adaptive immune inflammatory reaction. Recently, it has been shown that a gene region known as Toxo1 is critical for susceptibility or resistance to T. gondii infection in rats. An orthologous gene region with ALOX12 centromeric is also present in humans. Here we report that the human ALOX12 gene has susceptibility alleles for human congenital toxoplasmosis (rs6502997 [P, <0.000309], rs312462 [P, <0.028499], rs6502998 [P, <0.029794], and rs434473 [P, <0.038516]). A human monocytic cell line was genetically engineered using lentivirus RNA interference to knock down ALOX12. In ALOX12 knockdown cells, ALOX12 RNA expression decreased and levels of the ALOX12 substrate, arachidonic acid, increased. ALOX12 knockdown attenuated the progression of T. gondii infection and resulted in greater parasite burdens but decreased consequent late cell death of the human monocytic cell line. These findings suggest that ALOX12 influences host responses to T. gondii infection in human cells. ALOX12 has been shown in other studies to be important in numerous diseases. Here we demonstrate the critical role ALOX12 plays in T. gondii infection in humans.


Risk of serious injury for young baseball pitchers: a 10-year prospective study.
The risk of elbow or shoulder injury for young baseball pitchers is unknown. PURPOSE/ HYPOTHESIS: The purpose of this study was to quantify the cumulative incidence of throwing injuries in young baseball pitchers who were followed for 10 years. Three hypotheses were tested: Increased amount of pitching, throwing curveballs at a young age, and concomitantly playing catcher increase a young pitcher's risk of injury. Cohort study; Level of evidence, 3. In sum, 481 youth pitchers (aged 9 to 14 years) were enrolled in a 10-year follow-up study. Participants were interviewed annually. Injury was defined as elbow surgery, shoulder surgery, or retirement due to throwing injury. Fisher exact test compared the risk of injury between participants who pitched at least 4 years during the study and those who pitched less. Fisher exact tests were used to investigate risks of injury for pitching more than 100 innings in at least 1 calendar year, starting curveballs before age 13 years, and playing catcher for at least 3 years. The cumulative incidence of injury was 5.0%. Participants who pitched more than 100 innings in a year were 3.5 times more likely to be injured (95% confidence interval = 1.16 to 10.44). Pitchers who concomitantly played catcher seemed to be injured more frequently, but this trend was not significant with the study sample size. Pitching more than 100 innings in a year significantly increases risk of injury. Playing catcher appears to increase a pitcher's risk of injury, although this trend is not significant. The study was unable to demonstrate that curveballs before age 13 years increase risk of injury. The risk of a youth pitcher sustaining a serious throwing injury within 10 years is 5%. Limiting the number of innings pitched per year may reduce the risk of injury. Young baseball pitchers are encouraged to play other positions as well but might avoid playing catcher.


Comparison of Cardiovascular Risk Factors for Coronary Heart Disease and Stroke Type in Women.
Background Cardiovascular risk factors have differential effects on various manifestations of cardiovascular disease, but to date direct formal comparisons are scarce, have been conducted primarily in men, and include only traditional risk factors. Methods and Results Using data from the multi-ethnic Women's Health Initiative Observational Study, we used a case-cohort design to compare 1731 women with incident cardiovascular disease during follow-up to a cohort of 1914 women. The direction of effect of all 24 risk factors (including various apolipoproteins, hemoglobin A1c, high-sensitivity C-reactive protein, N-terminal pro-brain natriuretic peptide, and tissue plasminogen activator antigen) was concordant for coronary heart disease (CHD, defined as myocardial infarction and CHD death) and ischemic stroke; however, associations were generally stronger with CHD. Significant differences for multiple risk factors, including blood pressure, lipid levels, and measures of inflammation, were observed when comparing the effects on hemorrhagic stroke with those on ischemic outcomes. For instance, multivariable adjusted hazard ratios per standard deviation increase in non-high-density lipoprotein cholesterol were 1.16 (95% confidence interval, 1.06-1.28) for CHD, 0.97 (0.88-1.07) for ischemic stroke, and 0.76 (0.63-0.91) for hemorrhagic stroke ( P<0.05 for equal association). Model discrimination was better for models predicting CHD or ischemic stroke than for models predicting hemorrhagic stroke or a combined end point. Conclusions Cardiovascular risk factors have largely similar effects on incidence of CHD and ischemic stroke in women, although the magnitude of association varies. Determinants of ischemic and hemorrhagic stroke substantially differ, underscoring their distinct biology. Cardiovascular disease risk may be more accurately reflected when combined cardiovascular disease or cerebrovascular outcomes are broken down into different first manifestations, or when restricted to ischemic outcomes.


The genetic landscape of mutations in Burkitt lymphoma.
Burkitt lymphoma is characterized by deregulation of MYC, but the contribution of other genetic mutations to the disease is largely unknown. Here, we describe the first completely sequenced genome from a Burkitt lymphoma tumor and germline DNA from the same affected individual. We further sequenced the exomes of 59 Burkitt lymphoma tumors and compared them to sequenced exomes from 94 diffuse large B-cell lymphoma (DLBCL) tumors. We identified 70 genes that were recurrently mutated in Burkitt lymphomas, including ID3, GNA13, RET, PIK3R1 and the SWI/SNF genes ARID1A and SMARCA4. Our data implicate a number of genes in cancer for the first time, including CCT6B, SALL3, FTCD and PC. ID3 mutations occurred in 34% of Burkitt lymphomas and not in DLBCLs. We show experimentally that ID3 mutations promote cell cycle progression and proliferation. Our work thus elucidates commonly occurring gene-coding mutations in Burkitt lymphoma and implicates ID3 as a new tumor suppressor gene.


Disparities in chronic disease among Canada's low-income populations.
Many studies have found inequities in health among income groups in Canada. We report the variations in the major chronic disease risks among low-income populations, by province of residence, as a proxy measure of social environment. We used estimates from the 2005 Canadian Community Health Survey to study residents who were aged 45 years or older and from the lowest income quintile nationally. Multivariate logistic regression was used to examine the relationship between province of residence and risk of chronic diseases. British Columbia is the healthiest province overall but not in terms of its low-income residents, whereas Quebec's low-income residents are at the least risk for major chronic diseases. The significant differences in risk of hypertension, diabetes, and heart disease in favor of British Columbia over Quebec for the entire population disappear when considering only the low-income subset. Quebec's antipoverty strategy, formalized as law in 2002, has led to social and health care policies that appear to give its low-income residents advantages in chronic disease prevention. Our findings demonstrate that chronic disease prevalence is associated with investment in social supports to vulnerable populations.


Yellow fever vaccination elicits broad functional CD4+ T cell responses that recognize structural and nonstructural proteins.
Yellow fever virus (YFV) can induce acute, life-threatening disease that is a significant health burden in areas where yellow fever is endemic, but it is preventable through vaccination. The live attenuated 17D YFV strain induces responses characterized by neutralizing antibodies and strong T cell responses. This vaccine provides an excellent model for studying human immunity. While several studies have characterized YFV-specific antibody and CD8(+) T cell responses, less is known about YFV-specific CD4(+) T cells. Here we characterize the epitope specificity, functional attributes, and dynamics of YFV-specific T cell responses in vaccinated subjects by investigating peripheral blood mononuclear cells by using HLA-DR tetramers. A total of 112 epitopes restricted by seven common HLA-DRB1 alleles were identified. Epitopes were present within all YFV proteins, but the capsid, envelope, NS2a, and NS3 proteins had the highest epitope density. Antibody blocking demonstrated that the majority of YFV-specific T cells were HLA-DR restricted. Therefore, CD4(+) T cell responses could be effectively characterized with HLA-DR tetramers. Ex vivo tetramer analysis revealed that YFV-specific T cells persisted at frequencies ranging from 0 to 100 cells per million that are detectable years after vaccination. Longitudinal analysis indicated that YFV-specific CD4(+) T cells reached peak frequencies, often exceeding 250 cells per million, approximately 2 weeks after vaccination. As frequencies subsequently declined, YFV-specific cells regained CCR7 expression, indicating a shift from effector to central memory. Cells were typically CXCR3 positive, suggesting Th1 polarization, and produced gamma interferon and other cytokines after reactivation in vitro. Therefore, YFV elicits robust early effector CD4(+) T cell responses that contract, forming a detectable memory population.


Low mineral density of a weight-bearing bone among adult women in a high fertility population.
Evolutionary theories of aging posit that greater reproductive effort causes somatic decline given a fundamental trade-off between investing energy in reproduction and repair. Few studies in high fertility human populations support this hypothesis, and problems of phenotypic correlation can obscure the expected trade-off between reproduction and somatic condition. This cross-sectional study investigates whether greater reproductive effort is associated with reduced calcaneal bone mineral density (BMD) among female Tsimane forager-farmers of lowland Bolivia. We also investigate whether female Tsimane BMD values are lower than sex- and age-matched US reference values, despite the fact that Tsimane engage in higher physical activity levels that can increase mechanical loading. To measure calcaneal BMD, quantitative ultrasonography was performed on 130 women (mean ± SD age = 36.6 ± 15.7, range = 15-75) that were recruited regardless of past or current reproductive status. Anthropometric and demographic data were collected during routine medical exams. As predicted, higher parity, short inter-birth interval, and earlier age at first birth are associated with reduced BMD among Tsimane women after adjusting for potential confounders. Population-level differences are apparent prior to the onset of reproduction, and age-related decline in BMD is greater among Tsimane compared with American women. Greater cumulative reproductive burden may lower calcaneal BMD individually and jointly with other lifestyle and heritable factors. Fitness impacts of kin transfers in adulthood may determine the value of investments in bone remodeling, and thus affect selection on age-profiles of bone mineral loss.


On the spontaneous stochastic dynamics of a single gene: complexity of the molecular interplay at the promoter.
Gene promoters can be in various epigenetic states and undergo interactions with many molecules in a highly transient, probabilistic and combinatorial way, resulting in a complex global dynamics as observed experimentally. However, models of stochastic gene expression commonly consider promoter activity as a two-state on/off system. We consider here a model of single-gene stochastic expression that can represent arbitrary prokaryotic or eukaryotic promoters, based on the combinatorial interplay between molecules and epigenetic factors, including energy-dependent remodeling and enzymatic activities. We show that, considering the mere molecular interplay at the promoter, a single-gene can demonstrate an elaborate spontaneous stochastic activity (eg. multi-periodic multi-relaxation dynamics), similar to what is known to occur at the gene-network level. Characterizing this generic model with indicators of dynamic and steady-state properties (including power spectra and distributions), we reveal the potential activity of any promoter and its influence on gene expression. In particular, we can reproduce, based on biologically relevant mechanisms, the strongly periodic patterns of promoter occupancy by transcription factors (TF) and chromatin remodeling as observed experimentally on eukaryotic promoters. Moreover, we link several of its characteristics to properties of the underlying biochemical system. The model can also be used to identify behaviors of interest (eg. stochasticity induced by high TF concentration) on minimal systems and to test their relevance in larger and more realistic systems. We finally show that TF concentrations can regulate many aspects of the stochastic activity with a considerable flexibility and complexity. This tight promoter-mediated control of stochasticity may constitute a powerful asset for the cell. Remarkably, a strongly periodic activity that demonstrates a complex TF concentration-dependent control is obtained when molecular interactions have typical characteristics observed on eukaryotic promoters (high mobility, functional redundancy, many alternate states/pathways). We also show that this regime results in a direct and indirect energetic cost. Finally, this model can constitute a framework for unifying various experimental approaches. Collectively, our results show that a gene - the basic building block of complex regulatory networks - can itself demonstrate a significantly complex behavior.


Effect of load carrying on required coefficient of friction.
A load carrying task was identified as a major factor leading to slip and fall injuries such as overexertion and bodily reaction. Holding a load in front of the body while walking would shift the whole body center-of-mass to the front, loading additional rotational torque at the foot-ground contact. The present study evaluated if carrying a load would increase the likelihood of slip initiation and the slip severity. Eleven young and 10 older adults participated in the present study. A dry surface or a slippery surface was introduced while walking. Slip distance, peak sliding heel velocity, heel contact velocity, and required coefficient of friction were measured to test the study hypotheses. The results showed that significant main effects were found in slip distance, and peak sliding heel velocity and no main effect were found in heel contact velocity and required coefficient of friction. In conclusion, younger adults were found to slip longer and faster on the slippery surface while carrying a load. On the contrary, the older adults employed a safety-centered gait adaptation while carrying, to maintain slip initiation and severity characteristics at the same level as normal walking. Furthermore, light load carriage at 10% of body weight was suggested as a safe task for the elderly.


Spatial and temporal patterns of c-kit-expressing cells in WlacZ/+ and WlacZ/WlacZ mouse embryos.
In the mouse, the Kit receptor and its ligand, the stem cell factor (SCF), are encoded at the W/Kit and Steel loci, respectively. The Kit/SCF transduction pathway is involved in promoting cellular migration, proliferation and/or survival of melanoblasts, hematopoietic progenitors and primordial germ cells. Furthermore, a functional Kit/SCF pathway is required for the development of interstitial cells of Cajal (ICC) in the small intestine. Whereas all c-kit-expressing cells in embryogenesis were not identified, previous studies clearly demonstrated that the c-kit expression pattern extends well beyond cells known to be affected by W mutations. To investigate further Kit function, we specifically marked the c-kit-expressing cells and followed their fate during embryogenesis. A mutation was introduced by gene targeting at the W/Kit locus in mouse embryonic stem cells. The lacZ reporter gene was inserted into the first exon of c-kit, thus creating a null allele, called WlacZ. The lacZ expression reflects normal expression of the c-kit gene in WlacZ/+ embryos. The comparison of the patterns of lacZ-expressing cells between WlacZ/+ and WlacZ/WlacZ embryos allowed us to detect where and when melanoblasts, primordial germ cells and hematopoietic progenitors failed to survive in the absence of Kit. We also observed that ICC express c-kit during embryogenesis. ICC are found identically in WlacZ/+ and WlacZ/WlacZ embryos. Therefore, ICC do not depend on Kit expression during embryogenesis. These results indicate that the function of the c-kit gene is only required for the postnatal development of the ICC. Unexpected sites of c-kit expression were uncovered in embryos, including endothelial, epithelial and endocrine cells. None of these cells are dependent on Kit expression for their migration, proliferation and/or survival during embryogenesis. Nevertheless, we assume that the Kit/SCF pathway could be involved in the growth of transformed endothelial, epithelial and endocrine cells.


Risk Factors of Hepatotoxicity During Anti-tuberculosis Treatment.
Antituberculosis treatment (ATT) induced hepato-toxicity is common, but risk factors predicting its development are poorly understood. The present study evaluates the clinical risk factors predicting the development of hepatotoxicity in Indian patients with tuberculosis on antituberculosis treatment. Three groups of patients were studied at three service hospitals over a 3 year period from 2000-2002. Patients given ATT were followed up with monthly LFTs. Consecutive patients who developed Liver dysfunction (rise in SGPT > 5 times upper limit of normal) were studied, along with matched controls who did not. Markers for hepatitis B were also noted in these patients once in 6 months. A third group of patients who did not receive ATT but were HBsAg positive, were also similarly followed up. The possible association of age and sex of the patient, alcoholism, unrecognized chronic liver disease, hepatitis B virus carrier status and nutritional status with ATT-induced hepatitis was assessed. Statistical analysis was carried out by Chi square test/Fisher's exact test using WHO provided software Epi Info 6. Sixty-nine patients with ATT-induced hepatotoxicity were prospectively studied. In addition 128 patients on anti-tuberculosis drugs without hepatotoxicity and 39 HBsAg carriers not on ATT were followed up for 1 year. Age, Sex, history of alcohol intake and BMI were not found to be related to development of hepatotoxicity. Presence of HBV infection or an underlying silent chronic liver disease were found to significantly increase the risk of development of ATT-induced hepatotoxicity. Continuation of ATT after development of jaundice was associated with a high fatality rate. It was possible to re-introduce isoniazid in 96% and rifampicin in 88% of patients with ATT induced hepatotoxicity. ATT-induced hepatitis is common and is potentially fatal. It is likely to occur in those with underlying silent chronic liver disease, HBV infection and have been given ATT without a definite evidence of tuberculosis. Discontinuation of ATT leads to rapid recovery in most cases and drugs can safely be introduced after recovery in a majority of cases.


Miniaturized, biopsy-implantable chemical sensor with wireless, magnetic resonance readout.
Biopsy is an important diagnostic tool for a broad range of conditions. Cancer diagnoses, for example, are confirmed using tissue explanted with biopsy. Here we demonstrate a miniaturized wireless sensor that can be implanted during a biopsy procedure and return chemical information from within the body. Power and readout are wireless via weak magnetic resonant coupling to an external reader. The sensor is filled with responsive nuclear magnetic resonance (NMR) contrast agents for chemical sensitivity, and on-board circuitry constrains the NMR measurement to the contents. This sensor enables longitudinal monitoring of the same location, and its simple readout mechanism is ideal for applications not requiring the spatial information available through imaging techniques. We demonstrated the operation of this sensor by measuring two metabolic markers, both in vitro and in vivo: pH in flowing fluid for over 25 days and in a xenograft tumor model in mice, and oxygen in flowing gas and in a rat hind-limb constriction experiment. The results suggest that this in vivo sensing platform is generalizable to other available NMR contrast agents. These sensors have potential for use in biomedicine, environmental monitoring and quality control applications.


In vitro analysis of the herbal compound Essiac.
Despite the recommendation of the Task Force on Alternative Therapies of the Canadian Breast Cancer Research Initiative, little research has been published on the widely used herbal compound Essiac. We aimed to address this deficiency by conducting a series of assays to determine some of the purported activities of Essiac in vitro. The activity of Essiac was measured using established assays to assess anti-oxidant, fibrinolytic, anti-microbial, anti-inflammatory, immune modulation, cell-specific cytotoxicity, and impact on cytochrome P450 (CYP450) enzyme pathways. Essiac exhibited significant antioxidant activity in the ABTS assay. A 20-fold dilution of Essiac also exhibited significant immunomodulatory effects, specifically through stimulation of granulocyte phagocytosis, increases in CD8+ cell activation, and moderately inhibiting inflammatory pathways. Essiac exhibited significant cell-specific cytotoxicity towards ovarian epithelial carcinoma cells (A2780). Importantly, a 20-fold dilution of Essiac showed significant inhibition of several CYP450 enzymes, most notably CYP1A2 (37%) and CYP2C19 (24%). Essiac demonstrated dose-dependent inhibition of clot fibrinolysis. In vitro analysis of Essiac indicates significant antioxidant and immunomodulatory properties, as well as neoplastic cell specific cytotoxicity consistent with the historical properties ascribed to this compound. Importantly, significant CYP450 and fibrinolysis inhibition were also observed. This is the first comprehensive investigation of the in vitro effects of Essiac.


What determines the income gap between French male and female GPs - the role of medical practices.
In many OECD countries, the gender differences in physicians' pay favour male doctors. Due to the feminisation of the doctor profession, it is essential to measure this income gap in the French context of Fee-for-service payment (FFS) and then to precisely identify its determinants. The objective of this study is to measure and analyse the 2008 income gap between males and females general practitioners (GPs). This paper focuses on the role of gender medical practices differentials among GPs working in private practice in the southwest region of France. Using data from 339 private-practice GPs, we measured an average gender income gap of approximately 26% in favour of men. Using the decomposition method, we examined the factors that could explain gender disparities in income. The analysis showed that 73% of the income gap can be explained by the average differences in doctors' characteristics; for example, 61% of the gender income gap is explained by the gender differences in workload, i.e., number of consultations and visits, which is on average significantly lower for female GPs than for male GPs. Furthermore, the decomposition method allowed us to highlight the differences in the marginal returns of doctors' characteristics and variables contributing to income, such as GP workload; we found that female GPs have a higher marginal return in terms of earnings when performing an additional medical service. The findings of this study help to understand the determinants of the income gap between male and female GPs. Even though workload is clearly an essential determinant of income, FFS does not reduce the gender income gap, and there is an imperfect relationship between the provision of medical services and income. In the context of feminisation, it appears that female GPs receive a lower income but attain higher marginal returns when performing an additional consultation.


Biocompatible artificial DNA linker that is read through by DNA polymerases and is functional in Escherichia coli.
A triazole mimic of a DNA phosphodiester linkage has been produced by templated chemical ligation of oligonucleotides functionalized with 5'-azide and 3'-alkyne. The individual azide and alkyne oligonucleotides were synthesized by standard phosphoramidite methods and assembled using a straightforward ligation procedure. This highly efficient chemical equivalent of enzymatic DNA ligation has been used to assemble a 300-mer from three 100-mer oligonucleotides, demonstrating the total chemical synthesis of very long oligonucleotides. The base sequences of the DNA strands containing this artificial linkage were copied during PCR with high fidelity and a gene containing the triazole linker was functional in Escherichia coli.


Optical plastic refractive measurements in the visible and the near-infrared regions.
Some new refractometric results are obtained in the visible and the near-infrared spectral regions. The main optical plastics are analyzed: poly(methyl methacrylate), polystyrene, polycarbonate, and styrene acrylonitrile. New materials, such as methyl methacrylate styrene copolmer, CTE-Richardson, Zeonex, Optorez, and Bayer are examined. The refractive indices are measured for wavelengths from 435.8 to 1052 nm with a new device. Abbe constants and dispersion coefficients are calculated. The measured and computed data is intended for designers and technologists.


Spondylitis transmitted from infected aortic grafts: a review.
Graft infection following aortic aneurysms repair is an uncommon but devastating complication; its incidence ranges from <1% to 6% (mean 4%), with an associated perioperative and overall mortality of 12% and 17.5-20%, respectively. The most common causative organisms are Staphylococcus aureus and Escherichia coli; causative bacteria typically arise from the skin or gastrointestinal tract. The pathogenetic mechanisms of aortic graft infections are mainly breaks in sterile technique during its implantation, superinfection during bacteremia from a variety of sources, severe intraperitoneal or retroperitoneal inflammation, inoculation of bacteria during postoperative percutaneous interventions to manage various types of endoleaks, and external injury of the vascular graft. Mechanical forces in direct relation to the device were implicated in fistula formation in 35% of cases of graft infection. Partial rupture and graft migration leading to gradual erosion of the bowel wall and aortoenteric fistulas have been reported in 30.8% of cases. Rarely, infection via continuous tissues may affect the spine, resulting in spondylitis. Even though graft explantation and surgical debridement is usually the preferred course of action, comorbidities and increased perioperative risk may preclude patients from surgery and endorse a conservative approach as the treatment of choice. In contrast, conservative treatment is the treatment of choice for spondylitis; surgery may be indicated in approximately 8.5% of patients with neural compression or excessive spinal infection. To enhance the literature, we searched the related literature for published studies on continuous spondylitis from infected endovascular grafts aiming to summarize the pathogenesis and diagnosis, and to discuss the treatment and outcome of the patients with these rare and complex infections.


Incidence rates of surgically treated rhegmatogenous retinal detachment among manual workers, non-manual workers and housewives in Tuscany, Italy.
Candidate risk factors for idiopathic rhegmatogenous retinal detachment (RRD) include heavy manual handling (requiring Valsalva's maneuver). We assessed incidence rates of surgically treated idiopathic RRD among manual workers, non-manual workers and housewives resident in Tuscany, Italy. We retrieved all hospital discharge records bearing a principal diagnosis corresponding to RRD coupled with retinal surgery for any resident of Tuscany during 1997-2009. After elimination of repeated admissions and patients with coexistent, associated conditions (including recent trauma), subjects aged 25-59 years were classified as manual workers, non-manual workers or housewives. Population data were extracted from the 2001 census. We identified 1,946 eligible cases (1,142 men). Among men, manual workers experienced a 1.8-fold higher age-standardized rate per 100,000 person-years than non-manual workers [17.4 (95 % confidence interval (CI) 16.1-18.7) vs. 9.8 (95 % CI 8.8-10.8)]. Age-standardized rates among women were 1.9-fold higher for manual workers [11.1 (95 % CI 9.8-12.3)] and 1.7-fold higher for housewives [9.5 (95 % CI 8.3-10.8)] than in non-manual workers [5.7 (95 % CI 4.8-6.6)]. This large population-based study suggests that manual workers are affected by idiopathic RRD requiring surgical treatment more often than non-manual workers. The higher rates of surgically treated RRD experienced by manual workers are in accord with the hypothesis that heavy manual handling may have a causal role.


XMAP215 regulates microtubule dynamics through two distinct domains.
XMAP215 belongs to a family of proteins involved in the regulation of microtubule dynamics. In this study we analyze the function of different parts of XMAP215 in vivo and in Xenopus egg extracts. XMAP215 has been divided into three fragments, FrN, FrM and FrC (for N-terminal, middle and C-terminal, respectively). FrN co-localizes with microtubules in egg extracts but not in cells, FrC co- localizes with microtubules and centrosomes both in egg extracts and in cells, while FrM does not co- localize with either centrosomes or microtubules. In Xenopus egg extracts, FrN stimulates microtubule growth at plus-ends by inhibiting catastrophes, while FrM has no effect, and FrC suppresses microtubule growth by promoting catastrophes. Our results suggest that XMAP215 is targeted to centrosomes and microtubules mainly through its C-terminal domain, while the evolutionarily conserved N-terminal domain contains its microtubule-stabilizing activity.


After 30 years of dissemination, have we achieved sustained practice change in motivational interviewing?
Motivational interviewing (MI) is the most successfully disseminated evidence-based practice in the substance use disorder (SUD) treatment field. This systematic review considers two questions relevant to policymakers and service providers: (1) does training in MI achieve sustained practice change in clinicians delivering SUD treatment; and (2) do clinicians achieve a level of competence after training in MI that impacts upon client outcomes? A systematic review was conducted and reported in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement, examining training outcomes for MI in the SUD treatment sector, and for clinicians working in a SUD treatment role. We determined a training method to have resulted in sustained practice change when over 75% of participants met beginning proficiency in MI spirit at a follow-up time-point. Of the 20 studies identified, 15 measured training at a follow-up time-point using standard fidelity measures. The proportion of clinicians who reached beginning proficiency was either reported or calculated for 11 of these studies. Only two studies met our criterion of 75% of clinicians achieving beginning proficiency in MI spirit after training. Of the 20 studies identified, two measured client substance use outcomes with mixed results. A broad range of training studies failed to achieve sustained practice change in MI according to our criteria. It is unlikely that 75% of clinicians can achieve beginning proficiency in MI spirit after training unless competency is benchmarked and monitored and training is ongoing. The impact of training on client outcomes requires future examination.


Controlling amyloid formation of intrinsically disordered proteins and peptides: slowing down or speeding up?
The pathological assembly of intrinsically disordered proteins/peptides (IDPs) into amyloid fibrils is associated with a range of human pathologies, including neurodegeneration, metabolic diseases and systemic amyloidosis. These debilitating disorders affect hundreds of millions of people worldwide, and the number of people affected is increasing sharply. However, the discovery of therapeutic agents has been immensely challenging largely because of (i) the diverse number of aggregation pathways and the multi-conformational and transient nature of the related proteins or peptides and (ii) the under-development of experimental pipelines for the identification of disease-modifying molecules and their mode-of-action. Here, we describe current approaches used in the search for small-molecule modulators able to control or arrest amyloid formation commencing from IDPs and review recently reported accelerators and inhibitors of amyloid formation for this class of proteins. We compare their targets, mode-of-action and effects on amyloid-associated cytotoxicity. Recent successes in the control of IDP-associated amyloid formation using small molecules highlight exciting possibilities for future intervention in protein-misfolding diseases, despite the challenges of targeting these highly dynamic precursors of amyloid assembly.


Are we failing vulnerable workers? The case of black women in poultry processing in rural North Carolina.
In 1989, North Carolina Occupational Safety and Health Administration (OSHA) inspectors cited two poultry processing plants in northeastern North Carolina for serious repetitive motion problems. In 1990, investigators from the National Institute for Occupational Safety and Health confirmed significant upper extremity musculoskeletal symptoms and disorders among workers. We now report on analyses of baseline data collected from a cohort of women employed in one of these plants. The plant, which is the largest employer of women in the area, is located in a sparsely populated area with a black majority where nearly one-third of the population lives below the poverty level. Conditions we report suggest failure of existing health and safety systems, both regulatory and consultative, to prevent morbidity among vulnerable women in this industry, as well as social and economic conditions that influence availability of work and use of benefits to which they are entitled.


Multi-centre parallel arm randomised controlled trial to assess the effectiveness and cost-effectiveness of a group-based cognitive behavioural approach to managing fatigue in people with multiple sclerosis.
Fatigue is one of the most commonly reported and debilitating symptoms of multiple sclerosis (MS); approximately two-thirds of people with MS consider it to be one of their three most troubling symptoms. It may limit or prevent participation in everyday activities, work, leisure, and social pursuits, reduce psychological well-being and is one of the key precipitants of early retirement. Energy effectiveness approaches have been shown to be effective in reducing MS-fatigue, increasing self-efficacy and improving quality of life. Cognitive behavioural approaches have been found to be effective for managing fatigue in other conditions, such as chronic fatigue syndrome, and more recently, in MS. The aim of this pragmatic trial is to evaluate the clinical and cost-effectiveness of a recently developed group-based fatigue management intervention (that blends cognitive behavioural and energy effectiveness approaches) compared with current local practice. This is a multi-centre parallel arm block-randomised controlled trial (RCT) of a six session group-based fatigue management intervention, delivered by health professionals, compared with current local practice. 180 consenting adults with a confirmed diagnosis of MS and significant fatigue levels, recruited via secondary/primary care or newsletters/websites, will be randomised to receive the fatigue management intervention or current local practice. An economic evaluation will be undertaken alongside the trial. Primary outcomes are fatigue severity, self-efficacy and disease-specific quality of life. Secondary outcomes include fatigue impact, general quality of life, mood, activity patterns, and cost-effectiveness. Outcomes in those receiving the fatigue management intervention will be measured 1 week prior to, and 1, 4, and 12 months after the intervention (and at equivalent times in those receiving current local practice). A qualitative component will examine what aspects of the fatigue management intervention participants found helpful/unhelpful and barriers to change. This trial is the fourth stage of a research programme that has followed the Medical Research Council guidance for developing and evaluating complex interventions. What makes the intervention unique is that it blends cognitive behavioural and energy effectiveness approaches. A potential strength of the intervention is that it could be integrated into existing service delivery models as it has been designed to be delivered by staff already working with people with MS. Service users will be involved throughout this research. Current Controlled Trials ISRCTN76517470.


Efficacy and safety of vamorolone in Duchenne muscular dystrophy: An 18-month interim analysis of a non-randomized open-label extension study.
Treatment with corticosteroids is recommended for Duchenne muscular dystrophy (DMD) patients to slow the progression of weakness. However, chronic corticosteroid treatment causes significant morbidities. Vamorolone is a first-in-class anti-inflammatory investigational drug that has shown evidence of efficacy in DMD after 24 weeks of treatment at 2.0 or 6.0 mg/kg/day. Here, open-label efficacy and safety experience of vamorolone was evaluated over a period of 18 months in trial participants with DMD. A multicenter, open-label, 24-week trial (VBP15-003) with a 24-month long-term extension (VBP15-LTE) was conducted by the Cooperative International Neuromuscular Research Group (CINRG) and evaluated drug-related effects of vamorolone on motor outcomes and corticosteroid-associated safety concerns. The study was carried out in Canada, US, UK, Australia, Sweden, and Israel, from 2016 to 2019. This report covers the initial 24-week trial and the first 12 months of the VBP15-LTE trial (total treatment period 18 months). DMD trial participants (males, 4 to <7 years at entry) treated with 2.0 or 6.0 mg/kg/day vamorolone for the full 18-month period (n = 23) showed clinical improvement of all motor outcomes from baseline to month 18 (time to stand velocity, p = 0.012 [95% CI 0.010, 0.068 event/second]; run/walk 10 meters velocity, p < 0.001 [95% CI 0.220, 0.491 meters/second]; climb 4 stairs velocity, p = 0.001 [95% CI 0.034, 0.105 event/second]; 6-minute walk test, p = 0.001 [95% CI 31.14, 93.38 meters]; North Star Ambulatory Assessment, p < 0.001 [95% CI 2.702, 6.662 points]). Outcomes in vamorolone-treated DMD patients (n = 46) were compared to group-matched participants in the CINRG Duchenne Natural History Study (corticosteroid-naïve, n = 19; corticosteroid-treated, n = 68) over a similar 18-month period. Time to stand was not significantly different between vamorolone-treated and corticosteroid-naïve participants (p = 0.088; least squares [LS] mean 0.042 [95% CI -0.007, 0.091]), but vamorolone-treated participants showed significant improvement compared to group-matched corticosteroid-naïve participants for run/walk 10 meters velocity (p = 0.003; LS mean 0.286 [95% CI 0.104, 0.469]) and climb 4 stairs velocity (p = 0.027; LS mean 0.059 [95% CI 0.007, 0.111]). The vamorolone-related improvements were similar in magnitude to corticosteroid-related improvements. Corticosteroid-treated participants showed stunting of growth, whereas vamorolone-treated trial participants did not (p < 0.001; LS mean 15.86 [95% CI 8.51, 23.22]). Physician-reported incidences of adverse events (AEs) for Cushingoid appearance, hirsutism, weight gain, and behavior change were less for vamorolone than published incidences for prednisone and deflazacort. Key limitations to the study were the open-label design, and use of external comparators. We observed that vamorolone treatment was associated with improvements in some motor outcomes as compared with corticosteroid-naïve individuals over an 18-month treatment period. We found that fewer physician-reported AEs occurred with vamorolone than have been reported for treatment with prednisone and deflazacort, and that vamorolone treatment did not cause the stunting of growth seen with these corticosteroids. This Phase IIa study provides Class III evidence to support benefit of motor function in young boys with DMD treated with vamorolone 2.0 to 6.0 mg/kg/day, with a favorable safety profile. A Phase III RCT is underway to further investigate safety and efficacy. Clinical trials were registered at www.clinicaltrials.gov, and the links to each trial are as follows (as provided in manuscript text): VBP15-002 [NCT02760264] VBP15-003 [NCT02760277] VBP15-LTE [NCT03038399].


Affective style, psychopathology, and resilience: brain mechanisms and plasticity.
The brain circuitry underlying emotion includes several territories of the prefrontal cortex (PFC), the amygdala, hippocampus, anterior cingulate, and related structures. In general, the PFC represents emotion in the absence of immediately present incentives and thus plays a crucial role in the anticipation of the future affective consequences of action, as well as in the persistence of emotion following the offset of an elicitor. The functions of the other structures in this circuit are also considered. Individual differences in this circuitry are reviewed, with an emphasis on asymmetries within the PFC and activation of the amygdala as 2 key components of affective style. These individual differences are related to both behavioral and biological variables associated with affective style and emotion regulation. Plasticity in this circuitry and its implications for transforming emotion and cultivating positive affect and resilience are considered.


Follow my eyes: the gaze of politicians reflexively captures the gaze of ingroup voters.
Studies in human and non-human primates indicate that basic socio-cognitive operations are inherently linked to the power of gaze in capturing reflexively the attention of an observer. Although monkey studies indicate that the automatic tendency to follow the gaze of a conspecific is modulated by the leader-follower social status, evidence for such effects in humans is meager. Here, we used a gaze following paradigm where the directional gaze of right- or left-wing Italian political characters could influence the oculomotor behavior of ingroup or outgroup voters. We show that the gaze of Berlusconi, the right-wing leader currently dominating the Italian political landscape, potentiates and inhibits gaze following behavior in ingroup and outgroup voters, respectively. Importantly, the higher the perceived similarity in personality traits between voters and Berlusconi, the stronger the gaze interference effect. Thus, higher-order social variables such as political leadership and affiliation prepotently affect reflexive shifts of attention.


How many testers are needed to assure the usability of medical devices?
Before releasing a product, manufacturers have to follow a regulatory framework and meet standards, producing reliable evidence that the device presents low levels of risk in use. There is, though, a gap between the needs of the manufacturers to conduct usability testing while managing their costs, and the requirements of authorities for representative evaluation data. A key issue here is the number of users that should complete this evaluation to provide confidence in a product's safety. This paper reviews the US FDA's indication that a sample composed of 15 participants per major group (or a minimum of 25 users) should be enough to identify 90-97% of the usability problems and argues that a more nuanced approach to determining sample size (which would also fit well with the FDA's own concerns) would be beneficial. The paper will show that there is no a priori cohort size that can guarantee a reliable assessment, a point stressed by the FDA in the appendices to its guidance, but that manufacturers can terminate the assessment when appropriate by using a specific approach - illustrated in this paper through a case study - called the 'Grounded Procedure'.


A modified crash brace position for aircraft passengers.
In 1989, a Boeing 737-400 aircraft crashed at Kegworth, near Nottingham, England. The survivors suffered a large number of pelvic and lower limb injuries, and approximately one-third of the passengers died. Subsequent research has suggested that the "brace-for-impact" position that passengers are advised to adopt prior to a crash landing might be modified in order to reduce the incidence of such injuries. The aim of this research was to evaluate biomechanically such a modified crash brace position. A modified brace position would help to prevent injuries to some passengers in the event of an impact aircraft accident. Impact testing on forward-facing seats was performed at the Royal Air Force Institute of Aviation Medicine, Farnborough, England. Aircraft seats, mounted on a sled, were propelled down a track to impact at -16 Gx. A test dummy was used as the experimental model. Four dummy positions were investigated: a) upper torso braced forward and lower legs inclined slightly rearward of the vertical; b) upper torso braced forward and lower legs inclined forward; c) upper torso upright and lower legs inclined slightly rearward of the vertical; and d) upper torso upright and lower legs inclined forward. The impact pulses used were based on Federal Aviation Administration guidelines. Transducers located in the head, spine, and lower limbs of the dummy recorded the forces to which each body segment was exposed during the impact. These forces were compared for each brace position. Impact testing revealed that the risk of a head injury as defined by the head injury criterion was greater in the upright position than in the braced forward position. The risk of injury to the lower limbs was dependent in part on the flailing behavior of the limbs. Flailing did not occur when the dummy was placed in a braced, legs-back position. A modified brace position would involve passengers sitting with the upper torso inclined forward so that the passenger's head rested against the structure in front, if possible. The legs would be positioned with the feet resting on the floor in a position slightly behind the knee. The position differs from those previously recommended in that the feet are positioned behind the knee. This study suggests that such a position would reduce the potential for head and lower limb injury in some passengers, given that only a single seat type and single size of occupant have been evaluated. Standardization to such a position would improve passenger understanding and compliance. Such a recommendation should not obscure the fact that an occupant seated in a forward-facing aircraft seat, restrained only by a lap belt, is exposed to considerable forces during an impact accident. Such forces are capable of producing injuries in the femur, pelvis, and lumbar spine.


Continuous subcutaneous glucose monitoring improved metabolic control in pediatric patients with type 1 diabetes: a controlled crossover study.
To improve metabolic control and prevent complications, both acute and late, we need to adjust treatment on the basis of the blood glucose (BG) profile, as not even the most active BG self-monitoring gives sufficient information. We have used Continuous Glucose Monitoring System (CGMS; Medtronic MiniMed, Northridge, CA) in a controlled crossover study including 27 diabetic patients aged 12.5 +/- 3.3 (mean; standard deviation; range: 5-19) years. All patients were treated with intensive insulin therapy, 14 with multiple injections, and 13 with pumps. The patients were randomized into an open or blind study arm. Both arms wore the CGMS sensor for 3 days every 2 weeks. CGMS profiles were used in the open study arm to adjust insulin therapy at follow-up visits every 6 weeks. Both the patients and the diabetes team were masked to the CGMS profiles in the blinded arm, and insulin therapy adjustments were based solely on 7-point BG profiles performed by the patients. At 3 months the 2 study arms were crossed over. Despite initial problems with a device new to both patients and the diabetes team, hemoglobin A(1)C decreased significantly in the open arm (from 7.70%-7.31%) but not in the blind arm (7.75%-7.65%). A total of 26/27 patients experienced daytime low subcutaneous glucose (<3.0 mmol/L;.8 episodes/day; duration 58 +/- 29 minutes; 5.5% of total time), and 27/27 patients had at least 1 nocturnal episode of low subcutaneous glucose (.4 episodes/night; duration 132 +/- 81 minutes; 10.1% of total time). Use of CGMS facilitated an improved treatment, and patients received new insight and increased motivation. In this study, we found CGMS to be a useful tool for education and improving metabolic control.