Effect of Depression and Antidepressants on Sexual Dysfunction in Men with Diabetes: A National Population-Based Cohort Study.
This study explored and compared the effects of depression and antidepressants on sexual dysfunction in men with diabetes mellitus (DM). Patients older than 18 years who had been newly diagnosed with DM (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] code 250) between 1999 and 2010 were identified from Taiwan's National Health Insurance Research Database and were followed up until 2013. Patients with preexisting depression or sexual dysfunction were excluded. A total of 636,210 patients with DM were enrolled. These patients were divided into two groups: DM with comorbid depression and a matched cohort without depression. The groups were followed up until the end of 2010 for the first diagnosis of sexual dysfunction (ICD-9-CM codes 302.70, 302.71, 302.72, 302.74, 302.75, 302.76, 302.79, 607.84, and V417). A Cox proportional hazard model and a Cox regression model with time-dependent covariates were applied. Patients with DM and depression had a higher risk of sexual dysfunction than those with DM without depression (hazard ratio [HR] = 1.44; 95% confidence interval [CI], 1.33-1.55). The risk of sexual dysfunction was lower in the subgroup who used antidepressants (per 28 cumulative defined daily doses [cDDDs]), HR = 0.96; 95% CI, 0.94-0.97). A significantly lower incidence of sexual dysfunction was also associated with the use of selective serotonin reuptake inhibitors (SSRIs, per 28 cDDD). The adjusted HR was 0.95 (95% CI, 0.93-0.97). Subgroup analysis indicated that SSRI use was significantly associated with an amelioration of erectile dysfunction (per 28 cDDD), with an HR of 0.95 (95% CI, 0.92-0.97). Male patients with DM and depression are at increased risk of sexual dysfunction. Antidepressant use had a small inverse association with the risk of sexual dysfunction in men with DM and depression. Antidepressants, in particular SSRIs, did not increase the risk of sexual dysfunction in this population.


Efficacy and Safety Outcomes of Direct Oral Anticoagulants and Amiodarone in Patients with Atrial Fibrillation.
Direct oral anticoagulants (DOACs) and amiodarone are widely used in the treatment of nonvalvular atrial fibrillation. The DOACs are P-glycoprotein (P-gp) and cytochrome p-450 (CYP3A4) substrates. Direct oral anticoagulant levels may be increased by the concomitant use of potent dual P-gp/CYP3A4 inhibitors, such as amiodarone, which can potentially translate into adverse clinical outcomes. We aimed to assess the efficacy and safety of drug-drug interaction by the concomitant use of DOACs and amiodarone. We performed a systematic review of MEDLINE, the Cochrane Central Register of Clinical Trials, and Embase, limiting our search to randomized controlled trials of patients with atrial fibrillation that have compared DOACs versus warfarin for prophylaxis of stroke or systemic embolism, to analyze the impact on stroke or systemic embolism, major bleeding, and intracranial bleeding risk in patients with concomitant use of amiodarone. Risk ratio (RR) 95% confidence intervals were measured using the Mantel-Haenszel method. The fixed effects model was used owing to heterogeneity (I2) < 25%. Four trials with a total of 71,683 patients were analyzed, from which 5% of patients (n = 3212) were concomitantly taking DOAC and amiodarone. We found no statistically significant difference for any of the clinical outcomes (stroke or systemic embolism [RR 0.85; 95% CI, 0.67-1.06], major bleeding [RR 0.91; 95% CI, 0.77-1.07], or intracranial bleeding [RR 1.10; 95% CI, 0.68-1.78]) among patients taking DOAC and amiodarone versus DOAC without amiodarone. On the basis of the results of this meta-analysis, co-administration of DOACs and amiodarone, a dual P-gp/CYP3A4 inhibitor, does not seem to affect efficacy or safety outcomes in patients with atrial fibrillation.


Crystal structures of human adenosine kinase inhibitor complexes reveal two distinct binding modes.
Adenosine kinase (AK) is an enzyme responsible for converting endogenous adenosine (ADO) to adenosine monophosphate (AMP) in an adenosine triphosphate- (ATP-) dependent manner. The structure of AK consists of two domains, the first a large alpha/beta Rossmann-like nucleotide binding domain that forms the ATP binding site, and a smaller mixed alpha/beta domain, which, in combination with the larger domain, forms the ADO binding site and the site of phosphoryl transfer. AK inhibitors have been under investigation as antinociceptive, antiinflammatory, and anticonvulsant as well as antiinfective agents. In this work, we report the structures of AK in complex with two classes of inhibitors: the first, ADO-like, and the second, a novel alkynylpyrimidine series. The two classes of structures, which contain structurally similar substituents, reveal distinct binding modes in which the AK structure accommodates the inhibitor classes by a 30 degrees rotation of the small domain relative to the large domain. This change in binding mode stabilizes an open and a closed intermediate structural state and provide structural insight into the transition required for catalysis. This results in a significant rearrangement of both the protein active site and the orientation of the alkynylpyrimidine ligand when compared to the observed orientation of nucleosidic inhibitors or substrates.


Prophylactic antibiotics to prevent surgical site infection after breast cancer surgery.
This systematic review includes 11 randomized, controlled trials of mixed patient groups, including patients with or without breast cancer. Studies were included in the review only if data from patients with breast cancer could be separated from patients without breast cancer. The intervention included pre- or perioperative antibiotics used as prophylaxis for the surgery. A range of antibiotic regimens were assessed in the 11 studies, and 5 of the studies defined a similar antibiotic strategy. Five of the studies had similar choice of antibiotic, type of surgery, and length of follow-up. The reviewers excluded 27 studies because of design and data collection not matching the review requirements.


Allosteric Motions of the CRISPR-Cas9 HNH Nuclease Probed by NMR and Molecular Dynamics.
CRISPR-Cas9 is a widely employed genome-editing tool with functionality reliant on the ability of the Cas9 endonuclease to introduce site-specific breaks in double-stranded DNA. In this system, an intriguing allosteric communication has been suggested to control its DNA cleavage activity through flexibility of the catalytic HNH domain. Here, solution NMR experiments and a novel Gaussian-accelerated molecular dynamics (GaMD) simulation method are used to capture the structural and dynamic determinants of allosteric signaling within the HNH domain. We reveal the existence of a millisecond time scale dynamic pathway that spans HNH from the region interfacing the adjacent RuvC nuclease and propagates up to the DNA recognition lobe in full-length CRISPR-Cas9. These findings reveal a potential route of signal transduction within the CRISPR-Cas9 HNH nuclease, advancing our understanding of the allosteric pathway of activation. Further, considering the role of allosteric signaling in the specificity of CRISPR-Cas9, this work poses the mechanistic basis for novel engineering efforts aimed at improving its genome-editing capability.


Effect of continuous complement inhibition using soluble complement receptor type 1 on survival of pig-to-primate cardiac xenografts.
A single bolus of soluble complement (C) receptor type 1 (sCR1, TP-10) has been shown to delay hyperacute rejection (HAR) of porcine cardiac xenografts (Xgs) by primate recipients. In these recipients, C activity slowly returned and C deposition was noted in the Xgs at rejection. To evaluate the effect of sustained C inhibition using sCR1 on HAR, two additional cynomolgus monkeys received porcine cardiac Xgs and a continuous infusion of sCR1. In the first recipient, Xgs survival was 5 days (120+ hr), whereas in the second, Xg survival was 7 days (168+ hr). Serial biopsies of the Xgs were remarkable for an increasing cellular infiltrate composed predominantly of neutrophils and macrophages, and the development of edema, hemorrhage, and myocyte necrosis. These findings suggest that once C-mediated HAR has been inhibited, infiltration of the Xg by these cells may lead to accelerated acute rejection, which is an additional barrier to successful longer term Xg survival.


Precision Medicine in Targeted Therapies for Severe Asthma: Is There Any Place for "Omics" Technology?
According to the current guidelines, severe asthma still represents a controversial topic in terms of definition and management. The introduction of novel biological therapies as a treatment option for severe asthmatic patients paved the way to a personalized approach, which aims at matching the appropriate therapy with the different asthma phenotypes. Traditional asthma phenotypes have been decomposing by an increasing number of asthma subclasses based on functional and physiopathological mechanisms. This is possible thanks to the development and application of different omics technologies. The new asthma classification patterns, particularly concerning severe asthma, include an increasing number of endotypes that have been identified using new omics technologies. The identification of endotypes provides new opportunities for the management of asthma symptoms, but this implies that biological therapies which target inflammatory mediators in the frame of specific patterns of inflammation should be developed. However, the pathway leading to a precision approach in asthma treatment is still at its beginning. The aim of this review is providing a synthetic overview of the current asthma management, with a particular focus on severe asthma, in the light of phenotype and endotype approach, and summarizing the current knowledge about "omics" science and their therapeutic relevance in the field of bronchial asthma.


Tubulin polyglutamylase: isozymic variants and regulation during the cell cycle in HeLa cells.
Polyglutamylation is a posttranslational modification of tubulin that is very common in neurons and ciliated or flagellated cells. It was proposed to regulate the binding of microtubule associated proteins (MAPs) and molecular motors as a function of the length of the polyglutamyl side-chain. Though much less common, this modification of tubulin also occurs in proliferating cells like HeLa cells where it is associated with centrioles and with the mitotic spindle. Recently, we partially purified tubulin polyglutamylase from mouse brain and described its enzymatic properties. In this work, we focused on tubulin polyglutamylase activity from HeLa cells. Our results support the existence of a tubulin polyglutamylase family composed of several isozymic variants specific for alpha- or beta-tubulin subunits. In the latter case, the specificity probably also concerns the different beta-tubulin isotypes. Interestingly, we found that tubulin polyglutamylase activity is regulated in a cell cycle dependent manner and peaks in G(2)-phase while the level of glutamylated tubulin peaks in mitosis. Consistent results were obtained by treating the cells with hydroxyurea, nocodazole or taxotere. In particular, in mitotic cells, tubulin polyglutamylase activity was always low while glutamylation level was high. Finally, tubulin polyglutamylase activity and the level of glutamylated tubulin appeared to be inversely related. This paradox suggests a complex regulation of both tubulin polyglutamylase and the reverse deglutamylase activity.


Inflammatory cell response in bronchoalveolar lavage fluid after nitrogen dioxide exposure of healthy subjects: a dose-response study.
The combination of environmental chamber exposure and bronchoalveolar lavage (BAL) was used to study the effects of the common air pollutant nitrogen dioxide (NO2). Eighteen healthy nonsmokers were exposed to NO2 during 20 min in an exposure chamber during light bicycle ergometer work. All subjects were examined with BAL at least 3 wks before exposure, as a reference. The subjects were re-examined with BAL, in groups of eight, 24 h after exposure to 4, 7 and 10 mg NO2.m.3 (2.25, 4.0 and 5.5 ppm), respectively. An inflammatory cell response was found after exposure to all concentrations. An increase in the number of lymphocytes in BAL fluid was observed after 7 and 10 mg.m.3 (p less than 0.05 and 0.02, respectively). An increase in the number of mast cells, that appears to be dose-dependent, was found after exposure to all concentrations. The proportion of lysozyme positive alveolar macrophages was elevated after exposure to 7 mg.m.3. The inflammatory mediators fibronectin, hyaluronan, angiotensin converting enzyme (ACE) and beta 2-microglobulin were unchanged by exposure. Due to the findings of inflammatory cell changes far below the peak exposure limits for work places in industrialized countries, 9-18 mg.m.3, the safety of these limits is questioned. Studies are in progress in our laboratory using BAL to evaluate the effects of repeated NO2 exposure.


Group Velocity Engineering of Confined Ultrafast Magnons.
Quantum confinement permits the existence of multiple terahertz magnon modes in atomically engineered ultrathin magnetic films and multilayers. By means of spin-polarized high-resolution electron energy-loss spectroscopy, we report on the direct experimental detection of all exchange-dominated terahertz confined magnon modes in a 3 ML Co film. We demonstrate that, by tuning the structural and magnetic properties of the Co film, through its epitaxial growth on different surfaces, e.g., Ir(001), Cu(001), and Pt(111), one can achieve entirely different in-plane magnon dispersions, characterized by positive and negative group velocities. Our first-principles calculations show that spin-dependent many-body correlation effects in Co films play an important role in the determination of the energies of confined magnon modes. Our results suggest a pathway towards the engineering of the group velocity of confined ultrafast magnons.


A de novo protein binding pair by computational design and directed evolution.
The de novo design of protein-protein interfaces is a stringent test of our understanding of the principles underlying protein-protein interactions and would enable unique approaches to biological and medical challenges. Here we describe a motif-based method to computationally design protein-protein complexes with native-like interface composition and interaction density. Using this method we designed a pair of proteins, Prb and Pdar, that heterodimerize with a Kd of 130 nM, 1000-fold tighter than any previously designed de novo protein-protein complex. Directed evolution identified two point mutations that improve affinity to 180 pM. Crystal structures of an affinity-matured complex reveal binding is entirely through the designed interface residues. Surprisingly, in the in vitro evolved complex one of the partners is rotated 180° relative to the original design model, yet still maintains the central computationally designed hotspot interaction and preserves the character of many peripheral interactions. This work demonstrates that high-affinity protein interfaces can be created by designing complementary interaction surfaces on two noninteracting partners and underscores remaining challenges.


Sepiapterin reductase deficiency in a 2-year-old girl with incomplete response to treatment during short-term follow-up.
Sepiapterin reductase (SR) catalyses the last step in the tetrahydrobiopterin biosynthesis pathway; it converts 6-pyruvoyl-tetrahydropterin (6-PTP) to BH(4) in an NADPH-dependent reaction. SR deficiency is a very rare autosomal recessive disorder with normal phenylalanine (Phe) concentration in blood and diagnostic abnormalities are detected in CSF. We present a 16-month-old girl with SR deficiency. From the newborn period she presented with an adaptation regulatory disorder. At the age of 3 months, abnormal eye movements with dystonic signs and at 4.5 months psychomotor retardation were noticed. Since that time axial hypotonia with limb spasticity (or rather delayed reflex development), gastro-oesophageal reflux and fatigue at the end of the day has been observed. Brain MRI was normal; EEG was without epileptiform discharges. Analysis of biogenic amine metabolites in CSF at the age of 16 months showed very low HVA and 5-HIAA concentrations. Analysis of CSF pterins revealed strongly elevated dihydrobiopterin (BH(2)), slightly elevated neopterin and elevated sepiapterin levels. Plasma and CSF amino acids concentrations were normal. A phenylalanine loading test showed increased Phe after 1 h, 2 h and 4 h and very high Phe/Tyr ratios. SR deficiency was confirmed in fibroblasts and a novel homozygous g.1330C>G (p.N127K) SPR mutation was identified. On L-dopa and then additionally 5-hydroxytryptophan, the girl showed slow but remarkable progress in motor and intellectual ability. Now, at the age of 3 years, she is able to sit; expressive speech is delayed (to 1 1/2 years), passive speech is well developed. Her visual-motor skills, eye-hand coordination and social development correspond to the age of 2 1/2 years.


The adaptor protein Cindr regulates JNK activity to maintain epithelial sheet integrity.
Epithelia are essential barrier tissues that must be appropriately maintained for their correct function. To achieve this a plethora of protein interactions regulate epithelial cell number, structure and adhesion, and differentiation. Here we show that Cindr (the Drosophila Cin85 and Cd2ap ortholog) is required to maintain epithelial integrity. Reducing Cindr triggered cell delamination and movement. Most delaminating cells died. These behaviors were consistent with JNK activation previously associated with loss of epithelial integrity in response to ectopic oncogene activity. We confirmed a novel interaction between Cindr and Drosophila JNK (dJNK), which when perturbed caused inappropriate JNK signaling. Genetically reducing JNK signaling activity suppressed the effects of reducing Cindr. Furthermore, ectopic JNK signaling phenocopied loss of Cindr and was partially rescued by concomitant cindr over-expression. Thus, correct Cindr-dJNK stoichiometry is essential to maintain epithelial integrity and disturbing this balance may contribute to the pathogenesis of disease states, including cancer.


Structural studies of calcium-binding proteins using nuclear magnetic resonance.
Lanthanide-shifted 1H nuclear magnetic resonance (NMR) spectroscopy has been used to compare the structure in solution of the EF-hand calcium-binding domains of four parvalbumins (isoelectric pH[pI] 3.95, 4.25, and 4.37 from carp, and pI from buffalo fish). These four parvalbumins are shown by NMR to have very similar structures at the level of resolution typical of x-ray structures. At the higher resolution possible by the lanthanide NMR technique, specific differences are noted between the pI 3.95 isoprotein from carp and the other two carp isoproteins, and the buffalo fish parvalbumin is shown to be different from all three carp isoproteins. The differences are estimated to correspond to changes of the order of 0.2 A in the positions of some of the nuclei surrounding the EF calcium site.


Suppression of toxin production in Clostridium difficile VPI 10463 by amino acids.
The impact of various growth conditions on the expression of toxins and other proteins by Clostridium difficile VPI 10463 was studied. During non-starved conditions, the rate of toxin synthesis paralleled that of total protein during both exponential growth and stationary phase, and in both defined and complex media. Biotin limitation reduced growth rate and bulk protein synthesis, whereas toxin expression continued, leading to a 50- to 200-fold increase in intracellular toxin levels. Concomitantly, several 22 kDa proteins were up-regulated as revealed by two-dimensional PAGE analysis. The toxin yield was 30-fold higher in peptone yeast extract (PY) than in PY containing glucose (PYG). By contrast, glucose limitation reduced toxin yields by 20- to 100-fold in defined media. By elevating the buffering capacity and bicarbonate concentration, toxin yields were increased by 10-fold in PY and PYG. The high toxin production by C. difficile during growth in PY was lowered 100-fold by adding a blend of nine amino acids and several 60-100 kDa proteins were concomitantly down-regulated. It was concluded that toxin expression in C. difficile VPI 10463 was not affected by growth rate, growth phase, catabolite repression or the stringent response. Instead the co-expression of toxins and a few specific additional proteins appeared to be influenced by metabolic pathways involving CO2 assimilation, carboxylation reactions and metabolism of certain amino acids.


Very Early Brain Damage Leads to Remodeling of the Working Memory System in Adulthood: A Combined fMRI/Tractography Study.
The human brain can adapt to overcome injury even years after an initial insult. One hypothesis states that early brain injury survivors, by taking advantage of critical periods of high plasticity during childhood, should recover more successfully than those who suffer injury later in life. This hypothesis has been challenged by recent studies showing worse cognitive outcome in individuals with early brain injury, compared with individuals with later brain injury, with working memory particularly affected. We invited individuals who suffered perinatal brain injury (PBI) for an fMRI/diffusion MRI tractography study of working memory and hypothesized that, 30 years after the initial injury, working memory deficits in the PBI group would remain, despite compensatory activation in areas outside the typical working memory network. Furthermore we hypothesized that the amount of functional reorganization would be related to the level of injury to the dorsal cingulum tract, which connects medial frontal and parietal working memory structures. We found that adults who suffered PBI did not significantly differ from controls in working memory performance. They exhibited less activation in classic frontoparietal working memory areas and a relative overactivation of bilateral perisylvian cortex compared with controls. Structurally, the dorsal cingulum volume and hindrance-modulated orientational anisotropy was significantly reduced in the PBI group. Furthermore there was uniquely in the PBI group a significant negative correlation between the volume of this tract and activation in the bilateral perisylvian cortex and a positive correlation between this activation and task performance. This provides the first evidence of compensatory plasticity of the working memory network following PBI.


Dipeptide repeat protein pathology in C9ORF72 mutation cases: clinico-pathological correlations.
Hexanucleotide repeat expansion in C9ORF72 is the most common genetic cause of frontotemporal dementia and motor neuron disease. Recently, unconventional non-ATG translation of the expanded hexanucleotide repeat, resulting in the production and aggregation of dipeptide repeat (DPR) proteins (poly-GA, -GR and GP), was identified as a potential pathomechanism of C9ORF72 mutations. Besides accumulation of DPR proteins, the second neuropathological hallmark lesion in C9ORF72 mutation cases is the accumulation of TDP-43. In this study, we characterized novel monoclonal antibodies against poly-GA and performed a detailed analysis of the neuroanatomical distribution of DPR and TDP-43 pathology in a cohort of 35 cases with the C9ORF72 mutation that included a broad spectrum of clinical phenotypes. We found the pattern of DPR pathology to be highly consistent among cases regardless of the phenotype with high DPR load in the cerebellum, all neocortical regions (frontal, motor cortex and occipital) and hippocampus, moderate pathology in subcortical areas and minimal pathology in lower motor neurons. No correlation between DPR pathology and the degree of neurodegeneration was observed, while a good association between TDP-43 pathology with clinical phenotype and degeneration in key anatomical regions was present. Our data confirm that the presence of DPR pathology is intimately related to C9ORF72 mutations. The observed dissociation between DPR inclusion body load and neurodegeneration might suggest inclusion body formation as a potentially protective response to cope with soluble toxic DPR species. Moreover, our data imply that alterations due to the C9ORF72 mutation resulting in TDP-43 accumulation and dysmetabolism as secondary downstream effects likely play a central role in the neurodegenerative process in C9ORF72 pathogenesis.


Gastrostomy feeding versus oral feeding alone for children with cerebral palsy.
Children with cerebral palsy can be significantly disabled in terms of their ability to suck, chew and swallow. This can lead to significant impairment in feeding and, eventually, to undernutrition. It can also result in aspiration of food into the lungs. Length of feeding time may be considerably increased and, instead of being an enjoyable experience, mealtimes may be distressing for both child and carer. For children unable to maintain a normal nutritional state feeding by mouth, gastrostomy or jejunostomy tubes are increasingly being used to provide the digestive system with nutrients. A gastrostomy tube is a feeding tube inserted surgically through the abdominal wall directly into the stomach. A jejunostomy feeding tube is inserted into the jejunum, part of the small intestine, either directly or via a previous gastrostomy. Although gastrostomy or jejunostomy placement may greatly facilitate the feeding of children with cerebral palsy, many carers find it very emotionally difficult to accept this intervention. Moreover, the intervention is costly and there is the possibility of complications. The effectiveness and safety of the treatment requires further assessment. This review is an update of one previously published in 2004. To assess the effects of nutritional supplementation given via gastrostomy or jejunostomy to children with feeding difficulties due to cerebral palsy. For this update, we searched the following databases in July 2012: CENTRAL, MEDLINE , Embase, CINAHL, Science Citation Index, Conference Proceedings Citation Index, LILACS and Zetoc. We searched for trials in ICTRP and Clinicaltrials.gov, and for theses in WorldCat and Proquest Index to Theses. We also contacted other researchers and experts in this field. We looked for randomised controlled trials that compared delivery of nutrition via a gastrostomy or jejunostomy tube compared with oral feeding alone for children up to the age of 16 years. Screening of search results was undertaken independently by two review authors. No data extraction was possible as there were no included studies. No trials were identified that met the inclusion criteria for this review. Considerable uncertainty about the effects of gastrostomy for children with cerebral palsy remains. A well designed and conducted randomised controlled trial should be undertaken to resolve the current uncertainties about medical management for children with cerebral palsy and physical difficulties in eating.


Vision Loss in Older Adults.
Vision loss affects 37 million Americans older than 50 years and one in four who are older than 80 years. The U.S. Preventive Services Task Force concludes that current evidence is insufficient to assess the balance of benefits and harms of screening for impaired visual acuity in adults older than 65 years. However, family physicians play a critical role in identifying persons who are at risk of vision loss, counseling patients, and referring patients for disease-specific treatment. The conditions that cause most cases of vision loss in older patients are age-related macular degeneration, glaucoma, ocular complications of diabetes mellitus, and age-related cataracts. Vitamin supplements can delay the progression of age-related macular degeneration. Intravitreal injection of a vascular endothelial growth factor inhibitor can preserve vision in the neovascular form of macular degeneration. Medicated eye drops reduce intraocular pressure and can delay the progression of vision loss in patients with glaucoma, but adherence to treatment is poor. Laser trabeculoplasty also lowers intraocular pressure and preserves vision in patients with primary open-angle glaucoma, but long-term studies are needed to identify who is most likely to benefit from surgery. Tight glycemic control in adults with diabetes slows the progression of diabetic retinopathy, but must be balanced against the risks of hypoglycemia and death in older adults. Fenofibrate also slows progression of diabetic retinopathy. Panretinal photocoagulation is the mainstay of treatment for diabetic retinopathy, whereas vascular endothelial growth factor inhibitors slow vision loss resulting from diabetic macular edema. Preoperative testing before cataract surgery does not improve outcomes and is not recommended.


Solidarity and care as relational practices.
Many working in bioethics today are engaging in forms of normative interpretation concerning the meaningful contexts of relational agency and institutional structures of power. Using the framework of relational bioethics, this article focuses on two significant social practices that are significant for health policy and public health: the practices of solidarity and the practices of care. The main argument is that the affirming recognition of, and caring attention paid to, persons as moral subjects can politically motivate a society in three respects. The recognition of solidarity and the attention of care can prompt progressive change toward a democratic willingness: (a) to provide for equal respect for rights and dignity; (b) to provide the social resources and services needed for just health and well-being; and (c) to focus its creativity and wealth on the actualization of potential flourishing of each and all. Solidarity is discussed as a morally developmental stance that moves from standing up for another, standing up with another, and standing up as another. Care is discussed as a morally developmental stance that moves from the attentive rehabilitation of another, attentive companionship with and for another, and attentive commitment to another.


A reproducing kernel hilbert space approach for q-ball imaging.
Diffusion magnetic resonance (MR) imaging has enabled us to reveal the white matter geometry in the living human brain. The Q-ball technique is widely used nowadays to recover the orientational heterogeneity of the intra-voxel fiber architecture. This article proposes to employ the Funk-Radon transform in a Hilbert space with a reproducing kernel derived from the spherical Laplace-Beltrami operator, thus generalizing previous approaches that assume a bandlimited diffusion signal. The function estimation problem is solved within a Tikhonov regularization framework, while a Gaussian process model allows for the selection of the smoothing parameter and the specification of confidence bands. Shortcomings of Q-ball imaging are discussed.


Implementation of the 21-gene recurrence score test in the United States in 2011.
We examined hospital use of the 21-gene breast cancer test in the United States. We report state-level differences in utilization and propose a model for predicting implementation of guideline-recommended genomic testing. Genomic Health provided test orders for calendar year 2011.We summarized utilization at the hospital and state levels. Using logistic regression, we analyzed the association between the likelihood to order the test and the hospital's institutional and regional characteristics. In 2011, 45% of 4,712 acute-care hospitals ordered the test, which suggests that 25% of newly diagnosed invasive female breast cancer cases were tested. Significant predictors of testing included participation in National Cancer Institute (NCI) clinical research cooperative groups (odds ratio (OR) 3.73; 95% confidence interval, 2.96-4.70), advanced imaging (OR, 2.19; CI, 1.78-2.68), high-complexity laboratory (OR, 2.15; CI, 1.24-3.70), affiliation with a medical school (OR, 1.57; CI, 1.31-1.88), and reconstructive surgery (OR, 1.23; CI, 1.01-1.50). Significant regional predictors included metropolitan county (OR, 3.77; CI, 2.83-5.03), above-mean income (OR, 1.37; CI, 1.11-1.69), and education (OR, 1.26; CI, 1.03-1.54). Negative predictors included designation as a critical-access hospital (OR, 0.10; CI, 0.07-0.14) and distance from an NCI cancer center (OR, 0.998; CI, 0.997-0.999), with a 15% decrease in likelihood for every 100 miles. Despite considerable market penetration of the test, there are significant regional and site-of-care differences in implementation, particularly in rural states.Genet Med 18 10, 982-990.


Post-doctoral research fellowship as a health policy and systems research capacity development intervention: a case of the CHESAI initiative.
Building capacity in health policy and systems research (HPSR), especially in low- and middle-income countries, remains a challenge. Various approaches have been suggested and implemented by scholars and institutions using various forms of capacity building to address challenges regarding HPSR development. The Collaboration for Health Systems Analysis and Innovation (CHESAI) - a collaborative effort between the Universities of Cape Town and the Western Cape Schools of Public Health - has employed a non-research based post-doctoral research fellowship (PDRF) as a way of building African capacity in the field of HPSR by recruiting four post-docs. In this paper, we (the four post-docs) explore whether a PDRF is a useful approach for capacity building for the field of HPSR using our CHESAI PDRF experiences. We used personal reflections of our written narratives providing detailed information regarding our engagement with CHESAI. The narratives were based on a question guide around our experiences through various activities and their impacts on our professional development. The data analysis process was highly iterative in nature, involving repeated meetings among the four post-docs to reflect, discuss and create themes that evolved from the discussions. The CHESAI PDRF provided multiple spaces for our engagement and capacity development in the field of HPSR. These spaces provided us with a wide range of learning experiences, including teaching and research, policy networking, skills for academic writing, engaging practitioners, co-production and community dialogue. Our reflections suggest that institutions providing PDRF such as this are valuable if they provide environments endowed with adequate resources, good leadership and spaces for innovation. Further, the PDRFs need to be grounded in a community of HPSR practice, and provide opportunities for the post-docs to gain an in-depth understanding of the broader theoretical and methodological underpinnings of the field. The study concludes that PDRF is a useful approach to capacity building in HPSR, but it needs be embedded in a community of practice for fellows to benefit. More academic institutions in Africa need to adopt innovative and flexible support for emerging leaders, researchers and practitioners to strengthen our health systems.


Chemotherapy of malaria and resistance to antimalarial drugs in Guayana area, Venezuela.
Resistance to antimalarial chemotherapy is one of the greatest difficulties for the control of malaria transmission. Seventy patients with Plasmodium falciparum malaria were included in a study of resistance to chloroquine and sulfadoxine-pyrimethamine therapy. Resistance levels RI, RII, and RIII were established. Eighteen infections (51%) cleared after chloroquine treatment and did not recur within 28 days of follow-up; these were classified as sensitive. Ten infections (29%) were resistant at the RI level. Resistance at level RII was observed in 5 (14%) cases, and RIII resistance was demonstrated in 2 infections (6%). With sulfadoxine-pyrimethamine, 28 (80%) infections were classified as sensitive. Six infections (17%) showed resistance at level RII, and 1 (3%) infection was resistant at the RI level. Resistance at level RIII was not observed. In a microtest for chloroquine and sulfadoxine-pyrimethamine sensitivity in vitro, schizont development was accomplished successfully in 70 blood samples. In vitro resistance to chloroquine was demonstrated in 15 of 70 (21%) of all isolates. Eight of 70 (11%) of all isolates showed resistance to sulfadoxine-pyrimethamine. Diversity of response of P. falciparum to the studied antimalarial drugs in the Guayana area of Venezuela is considered a problem restricting the control of malaria in this geographical area. A constant evaluation program monitoring P. falciparum drug sensitivity is necessary for preserving the efficacy of the established treatment.


Coherent perfect absorption, transmission, and synthesis in a double-cavity optomechanical system.
We study a double-cavity optomechanical system in which a movable mirror with perfect reflection is inserted between two fixed mirrors with partial transmission. This optomechanical system is driven from both fixed end mirrors in a symmetric scheme by two strong coupling fields and two weak probe fields. We find that three interesting phenomena: coherent perfect absorption (CPA), coherent perfect transmission (CPT), and coherent perfect synthesis (CPS) can be attained within different parameter regimes. That is, we can make two input probe fields totally absorbed by the movable mirror without yielding any energy output from either end mirror (CPA); make an input probe field transmitted from one end mirror to the other end mirror without suffering any energy loss in the two cavities (CPT); make two input probe fields synthesized into one output probe field after undergoing either a perfect transmission or a perfect reflection (CPS). These interesting phenomena originate from the efficient hybrid coupling of optical and mechanical modes and may be all-optically controlled to realize novel photonic devices in quantum information networks.


Characterization of the parasite-host cell interactions involved in Theileria parva sporozoite invasion of bovine lymphocytes.
Sporozoite invasion of bovine lymphocytes by Theileria parva is a pH-dependent process that occurs without the need for de novo protein synthesis. The process was inhibited by RGD(S) peptides, fibronectin and, in the presence of serum, by antibodies reactive with fibronectin. Invasion was also blocked by a range of sulphated glycoconjugates, but treatment of lymphocytes with heparitinase did not inhibit entry. Enzymic modifications of the lymphocyte surface demonstrated that trypsin-insensitive glycoproteins containing O- and N-linked carbohydrates as well as phospholipase-sensitive molecules on the host cell surface were critical to sporozoite entry. Modification of the lymphocyte surface with NEM and DTT had only marginal effects on sporozoite binding but blocked parasite internalization. Invasion was also blocked by several antibodies which cross-reacted with sporozoite surface molecules. While only a few experimental conditions specifically blocked sporozoite binding, a wider range of reagents and treatments inhibited parasite entry. The reasons for this are discussed in terms of the nature of the zippering process that facilitates sporozoite internalization.


Design, fabrication, and characterization of thermoplastic microlenses for fiber-optic probe imaging.
Microlens-ended fibers could find great usefulness in future biomedical applications, particularly in endoscopic imaging applications. In this context, this paper focuses on microlens-attached specialty optical fibers such as imaging fiber that can be used for probe imaging applications. Stand-alone self-aligned polymer microlenses have been fabricated by microcompression molding. The fabrication parameters have been optimized for different materials, such as poly(methyl methacrylate) (PMMA), polycarbonate (PC Lexan 123R), Zeonor 1060R (ZNR), and Topas COC. A comparison study of the focusing and spatial resolution of the fabricated lenses is performed prior to employing them for fiber-optic fluorescence imaging applications.


Phase I/II study of topical imiquimod and intralesional interleukin-2 in the treatment of accessible metastases in malignant melanoma.
Patients with metastatic skin disease in malignant melanoma can be difficult to treat effectively, often requiring repeated treatments with different modalities in an attempt to control their disease. Treatment of nonsurgically resectable melanoma deposits is unsatisfactory, as they are often multiple and recurring. Anecdotal evidence from individual use of imiquimod in superficial metastases and intralesional interleukin (IL)-2 in subcutaneous deposits suggests that the combination may be more effective in bulky subcutaneous disease. To investigate the combination of topical imiquimod and, for selected lesions, intralesional IL-2, to treat a small cohort of patients with accessible melanoma metastases resistant to other treatments. Thirteen patients were recruited: all had evidence of multiple cutaneous and/or subcutaneous metastases. Imiquimod was applied to the metastases on a daily basis for 4 weeks, before the introduction of intralesional IL-2. This was injected up to three times a week, into selected lesions, with 0.1 mL injected per lesion at a concentration of 3.6 MIU mL(-1), a total of 1 mL being given at each session. The treated lesions were assessed individually at intervals of 3 months. Thirteen patients were treated, with 10 being eligible for assessment. In total, 182 lesions were treated: 137 purely cutaneous lesions and 41 subcutaneous lesions. Overall, a clinical response was seen in 92 lesions (50.5%) with 74 (40.7%) of these being a complete response (CR) with 91% of the CRs being in the cutaneous lesions. New lesions did appear during the treatment course; however, patients with cutaneous disease experienced a marked slowing of the appearance of new cutaneous lesions. No cutaneous lesions that responded reappeared on cessation of treatment. The combination of imiquimod and IL-2 is effective in controlling this mixed cutaneous and subcutaneous disease, and is well tolerated. Imiquimod alone is often enough to elicit a response in purely cutaneous lesions. The addition of intralesional IL-2 increases the response rates in subcutaneous lesions, and in otherwise refractory cutaneous lesions.


Biogeography of Amazon birds: rivers limit species composition, but not areas of endemism.
Amazonian rivers are usually suggested as dispersal barriers, limiting biogeographic units. This is evident in a widely accepted Areas of Endemism (AoEs) hypothesis proposed for Amazonian birds. We empirically test this hypothesis based on quantitative analyses of species distribution. We compiled a database of bird species and subspecies distribution records, and used this dataset to identify AoEs through three different methods. Our results show that the currently accepted Amazonian AoEs are not consistent with areas identified, which were generally congruent among datasets and methods. Some Amazonian rivers represent limits of AoEs, but these areas are not congruent with those previously proposed. However, spatial variation in species composition is correlated with largest Amazonian rivers. Overall, the previously proposed Amazonian AoEs are not consistent with the evidence from bird distribution. However, the fact that major rivers coincide with breaks in species composition suggest they can act as dispersal barriers, though not necessarily for all bird taxa. This scenario indicates a more complex picture of the Amazonian bird distribution than previously imagined.


Teenage recommendations to improve physical activity for their age group: a qualitative study.
It is recommended that young people should engage in 60 min of moderate-to-vigorous activity (MVPA) a day for health benefits, but few teenagers actually meet this recommendation. Policy-makers play a vital role in designing physical activity initiatives, but they generally do this with little or no input from the intervention recipients. This study explores the recommendations made by teenagers to improve activity provision, uptake and sustainability of physical activity engagement for both themselves and their peers. Thirteen focus groups were carried out in seven secondary schools in South Wales, United Kingdom. Participants (n = 78) were recruited from a larger mixed-method randomised control trial, which involved the implementation of a voucher scheme to promote physical activity in teenagers (aged 13-14). Thematic analysis was undertaken to identify key issues from the perspective of the teenage participants. Six key recommendations were identified following analysis of the focus groups: i) Lower/remove the cost of activities without sacrificing the quality, ii) Make physical activity opportunities more locally accessible, iii) Improve the standards of existing facilities, iv) Make activities more specific to teenagers v) Give teenagers a choice of activities/increase variety of activity and vi) Provide activities that teenage girls enjoy (e.g., fun, sociable and not competitive sport). Throughout the focus groups, the increased opportunity to participate in unstructured activity was a key recommendation echoed by both boys and girls in all themes. There is a disconnect between what is available and what teenagers want to do. Policy-makers and those involved in physical activity delivery (e.g., schools, local council and local activity providers) should include young people in designing interventions and facilities to ensure they are meeting the needs of this age group and providing the right opportunities for teenagers to be active. That is unstructured, local, low cost, fun, sociable opportunities and the right facilities to be active.


Long-Term Field Study Reveals Subtle Effects of the Invasive Alga Sargassum muticum upon the Epibiota of Zostera marina.
Invasive species can alter coastal ecosystems both directly, e.g. through competition for substratum and nutrients, and indirectly. Indirect effects may be mediated by creation of dissimilar or inimical habitats, changes in predator and/or prey assemblages, alterations in associated biota, and perturbations of water movement and thermal regimes. Previous studies have shown that invasive algae can modify native habitat architecture, disrupt intricately linked food webs and alter epibiotic assemblages. In the UK, the seagrass Zostera marina supports a diverse epibiotic assemblage, influencing key factors such as sediment dynamics, depositional regime and trophic linkages. Increasing encroachment of the invasive alga Sargassum muticum into seagrass meadows changes the physical and chemical characteristics of the local environment and creates the potential for changes in the epibionts associated with the seagrass blades, threatening the integrity of the seagrass ecosystem. We investigated the effects of S. muticum invasion upon the epibiota of Z. marina in a drowned river valley in SW England seasonally from spring to autumn over four years in an in-situ manipulative experiment, comparing permanent quadrats with and without artificially introduced S. muticum. Epibiota were weighed, identified to the most detailed operational taxonomic unit (OTU) possible, and unitary organisms were enumerated. Multivariate PERMANOVA+ analysis revealed significant differences in epibiont assemblages between Sargassum treatments. Linear mixed effects models indicated that differences in epibiota assemblage composition were not reflected as significant differences in mean biomass per sample, or number of epibiont OTUs per sample. We conclude that S. muticum invasion into Z. marina meadows may significantly alter the species composition and abundance distribution of epibiotic assemblages found on the blades of the seagrass. Thus S. muticum invasion could have more wide-reaching effects on processes within coastal ecosystems than predicted purely by direct effects.


Natural language processing and machine learning to assist radiation oncology incident learning.
To develop a Natural Language Processing (NLP) and Machine Learning (ML) pipeline that can be integrated into an Incident Learning System (ILS) to assist radiation oncology incident learning by semi-automating incident classification. Our goal was to develop ML models that can generate label recommendations, arranged according to their likelihoods, for three data elements in Canadian NSIR-RT taxonomy. Over 6000 incident reports were gathered from the Canadian national ILS as well as our local ILS database. Incident descriptions from these reports were processed using various NLP techniques. The processed data with the expert-generated labels were used to train and evaluate over 500 multi-output ML algorithms. The top three models were identified and tuned for each of three different taxonomy data elements, namely: (1) process step where the incident occurred, (2) problem type of the incident and (3) the contributing factors of the incident. The best-performing model after tuning was identified for each data element and tested on unseen data. The MultiOutputRegressor extended Linear SVR models performed best on the three data elements. On testing, our models ranked the most appropriate label 1.48 ± 0.03, 1.73 ± 0.05 and 2.66 ± 0.08 for process-step, problem-type and contributing factors respectively. We developed NLP-ML models that can perform incident classification. These models will be integrated into our ILS to generate a drop-down menu. This semi-automated feature has the potential to improve the usability, accuracy and efficiency of our radiation oncology ILS.


A linear-time algorithm for computing inversion distance between signed permutations with an experimental study.
Hannenhalli and Pevzner gave the first polynomial-time algorithm for computing the inversion distance between two signed permutations, as part of the larger task of determining the shortest sequence of inversions needed to transform one permutation into the other. Their algorithm (restricted to distance calculation) proceeds in two stages: in the first stage, the overlap graph induced by the permutation is decomposed into connected components; then, in the second stage, certain graph structures (hurdles and others) are identified. Berman and Hannenhalli avoided the explicit computation of the overlap graph and gave an O(nalpha(n)) algorithm, based on a Union-Find structure, to find its connected components, where alpha is the inverse Ackerman function. Since for all practical purposes alpha(n) is a constant no larger than four, this algorithm has been the fastest practical algorithm to date. In this paper, we present a new linear-time algorithm for computing the connected components, which is more efficient than that of Berman and Hannenhalli in both theory and practice. Our algorithm uses only a stack and is very easy to implement. We give the results of computational experiments over a large range of permutation pairs produced through simulated evolution; our experiments show a speed-up by a factor of 2 to 5 in the computation of the connected components and by a factor of 1.3 to 2 in the overall distance computation.


Identification of genetic variants influencing the human plasma proteome.
Genetic variants influencing the transcriptome have been extensively studied. However, the impact of the genetic factors on the human proteome is largely unexplored, mainly due to lack of suitable high-throughput methods. Here we present unique and comprehensive identification of genetic variants affecting the human plasma protein profile by combining high-throughput and high-resolution mass spectrometry (MS) with genome-wide SNP data. We identified and quantified the abundance of 1,056 tryptic-digested peptides, representing 163 proteins in the plasma of 1,060 individuals from two population-based cohorts. The abundance level of almost one-fifth (19%) of the peptides was found to be heritable, with heritability ranging from 0.08 to 0.43. The levels of 60 peptides from 25 proteins, 15% of the proteins studied, were influenced by cis-acting SNPs. We identified and replicated individual cis-acting SNPs (combined P value ranging from 3.1 × 10(-52) to 2.9 × 10(-12)) influencing 11 peptides from 5 individual proteins. These SNPs represent both regulatory SNPs and nonsynonymous changes defining well-studied disease alleles such as the ε4 allele of apolipoprotein E (APOE), which has been shown to increase risk of Alzheimer's disease. Our results show that high-throughput mass spectrometry represents a promising method for large-scale characterization of the human proteome, allowing for both quantification and sequencing of individual proteins. Abundance and peptide composition of a protein plays an important role in the etiology, diagnosis, and treatment of a number of diseases. A better understanding of the genetic impact on the plasma proteome is therefore important for evaluating potential biomarkers and therapeutic agents for common diseases.


Genetic polymorphisms of CYP2C8, CYP2C9 and CYP2C19 in Ecuadorian Mestizo and Spaniard populations: a comparative study.
This study was designed to investigate the potential differences between Spaniards and Ecuadorian Mestizo people regarding CYP2C8, CYP2C9, and CYP2C19 genetic polymorphisms. DNA from 282 Spaniard and 297 Ecuadorian subjects were analyzed by either a previously reported pyrosequencing method (CY2C8*3, CYP2C9*2, CYP2C9*3, CYP2C19*2 and CYP2C19*3) or a nested PCR technique (CYP2C19*17). Whereas CYP2C19*17 allele distribution was higher in Ecuadorians than in Spaniards (P < 0.001) and the frequency of CYP2C19*3 was similar in these two populations (P > 0.05), the other allelic variants were detected at significantly lower frequencies in Ecuadorians than in Spaniards (P < 0.05). According to the diplotype distributions, the prevalence of the presumed CYP2C9 and CYP2C8 extensive metabolizers was higher in Ecuadorians than in Spaniards (P < 0.05). Individuals genotyped CYP2C19*1/*17 and *17/*17 who were considered as ultrarapid metabolizers were overrepresented in Ecuadorians in relation to Spaniards (P < 0.001). By contrast, among Ecuadorians no poor metabolizers (PMs) of either CYP2C8 or CYP2C9 were found and only two individuals were CYP2C19 PMs. These data are compatible with a higher CYP2C8, CYP2C9, and CYP2C19 activity in Mestizo Ecuadorians as opposed to Spaniards, which could imply differences in dosage requirements for drugs metabolized by these cytochromes and should also be considered in allele-disease association studies.


Novel approach for identification of influenza virus host range and zoonotic transmissible sequences by determination of host-related associative positions in viral genome segments.
Recent (2013 and 2009) zoonotic transmission of avian or porcine influenza to humans highlights an increase in host range by evading species barriers. Gene reassortment or antigenic shift between viruses from two or more hosts can generate a new life-threatening virus when the new shuffled virus is no longer recognized by antibodies existing within human populations. There is no large scale study to help understand the underlying mechanisms of host transmission. Furthermore, there is no clear understanding of how different segments of the influenza genome contribute in the final determination of host range. To obtain insight into the rules underpinning host range determination, various supervised machine learning algorithms were employed to mine reassortment changes in different viral segments in a range of hosts. Our multi-host dataset contained whole segments of 674 influenza strains organized into three host categories: avian, human, and swine. Some of the sequences were assigned to multiple hosts. In point of fact, the datasets are a form of multi-labeled dataset and we utilized a multi-label learning method to identify discriminative sequence sites. Then algorithms such as CBA, Ripper, and decision tree were applied to extract informative and descriptive association rules for each viral protein segment. We found informative rules in all segments that are common within the same host class but varied between different hosts. For example, for infection of an avian host, HA14V and NS1230S were the most important discriminative and combinatorial positions. Host range identification is facilitated by high support combined rules in this study. Our major goal was to detect discriminative genomic positions that were able to identify multi host viruses, because such viruses are likely to cause pandemic or disastrous epidemics.


[Self-perception and oral health conditions in an elderly population].
This study assessed oral health conditions through clinical examination and self-perception. The sample consisted of 112 subjects 60 years of age or older in Rio Claro, São Paulo, Brazil, divided into two groups: G1, with dental insurance (n = 55) and G2, without dental insurance (n = 57). Clinical examinations were conducted according to WHO guidelines. Data on self-perceived oral health were collected using the GOHAI (Geriatric Oral Health Assessment Index). DMFT was 29.13, higher in G1 (p = 0.0091). Mean number of teeth currently present in both groups was 7.63, higher in G2 (p = 0.0131). Periodontal conditions showed a high percentage of null sextants (70.3%), where CPI revealed higher prevalence for calculus and PIP for pockets up to 3mm. The percentage of edentulous subjects was 45.5%, higher in G1 (p = 0.0142). Among edentulous subjects, 69.6% wore complete upper dentures and 42.9% complete lower dentures. Mean GOHAI was 33.61, qualifying self-perceived oral health status as positive, and the only difference was in the physical dimension, where G2 showed higher values (p = 0.0154). Self-perceived oral health was considered satisfactory, but this was not confirmed by clinical data from the two groups.


Effect of surface treatments to remove temporary cement remnants on the bond strength between the core composite and resin cement.
There was no enough data about the appropriate surface cleaning of core composite material after temporary cementation. To evaluate the effects of surface cleaning techniques on initial shear bond strength (SBS) between core composite material and resin nanoceramic crown materials after temporary cementation. Cubic specimens were prepared from prosthetic materials, including Lava Ultimate. Cylinder-shaped composites were cemented to glass slides with eugenol-free temporary cement, resulting in a total of 44 cylinders (n = 11). The surfaces of composite cylinders were then cleaned with an Er, Cr:YSGG laser, 37% orthophosphoric acid, yellow tape diamond bur, or dental explorer. Cleaned cylinders were bonded to cubic specimens with resin cement. Initial SBS tests were performed with a universal testing machine at 0.5 mm/min crosshead speed. One-way ANOVA and post hoc Tukey tests were used to analyze the obtained data (P =0.05). Initial SBS values were significantly affected by the different surface cleaning methods (P <.05). The highest SBS value was obtained with the laser group (SBS = 17.14), while the lowest was obtained with dental explorer group (SBS = 5.95). There was no significant difference between the diamond bur group and the laser group (P =0.982). Laser irradiation or yellow tape diamond bur cleaning of the core composite surface could be recommended to strengthen bond strength between the resin luting cement and the core composite. Before adhesive or conventional cementation of prosthetic restoration, the core composite surface should be cleaned.


Role of Components in the Formation of Self-microemulsifying Drug Delivery Systems.
Pharmaceutical research is focused in designing novel drug delivery systems to improve the bioavailability of poorly water soluble drugs. Self-microemulsifying drug delivery systems, one among the lipid-based dosage forms were proven to be promising in improving the oral bioavailability of such drugs by enhancing solubility, permeability and avoiding first-pass metabolism via enhanced lymphatic transport. Further, they have been successful in avoiding both inter and intra individual variations as well as the dose disproportionality. Aqueous insoluble drugs, in general, show greater solubility in lipid based excipients, and hence they are formulated as lipid based drug delivery systems. The extent of solubility of a hydrophobic drug in lipid excipients i.e. oil, surfactant and co-surfactant (components of self-microemulsifying drug delivery systems) greatly affects the drug loading and in producing stable self-microemulsifying drug delivery systems. The present review highlighted the influence of physicochemical factors and structural features of the hydrophobic drug on its solubility in lipid excipients and an attempt was made to explore the role of each component of self-microemulsifying drug delivery systems in the formation of stable microemulsion upon dilution.


Training, credentialing, proctoring and medicolegal risks of robotic urological surgery: recommendations of the society of urologic robotic surgeons.
With the exponential growth of robotic urological surgery, particularly with robot assisted radical prostatectomy, guidelines for safe initiation of this technology are a necessity. Currently no standardized credentialing system exists to our knowledge to evaluate surgeon competency and safety with robotic urological surgery performance. Although proctoring is a modality by which such competency can be evaluated, other training tools and guidelines are needed to ensure that the requisite knowledge and technical skills to perform this procedure have been acquired. We evaluated the current status of proctoring and credentialing in other surgical specialties to discuss and recommend its application and implementation specifically for robot assisted radical prostatectomy. We reviewed the literature on safety and medicolegal implications of proctoring and the safe introduction of surgical procedures to develop recommendations for robot assisted radical prostatectomy proctoring and credentialing. Proctoring is an essential mechanism for robot assisted radical prostatectomy institutional credentialing and should be a prerequisite for granting unrestricted privileges on the robot. This should be differentiated from preceptoring, wherein the expert is directly involved in hands-on training. Advanced technology has opened new avenues for long-distance observation through teleproctoring. Although the medicolegal implications of an active surgical intervention by a proctor are not clearly defined, the role as an observer should grant immunity from malpractice liability. The implementation of guidelines and proctoring recommendations is necessary to protect surgeons, proctors, institutions and, above all, the patients who are associated with the institutional introduction of a robot assisted radical prostatectomy program. With no current guidelines we anticipate this article will serve as a catalyst of interorganizational discussion to initiate regulatory oversight of surgeon certification and proctorship.


Actions Speak Louder than Words: A Behavioral Analysis of 183 Individuals Convicted for Terrorist Offenses in the United States from 1995 to 2012.
Involvement in terrorism has traditionally been discussed in relatively simplistic ways with little effort spent on developing a deeper understanding of what involvement actually entails, and how it differs from person to person. In this paper, we present the results of a three-year project focused on 183 individuals associated with the global jihadist movement who were convicted in the United States, for terrorist offenses, between 1995 and 2012. These data were developed by a large-scale, open-source data collection activity that involved a coding dictionary of more than 120 variables. We identify and explore the diversity of behaviors that constitute involvement in terrorism. We also compare lone actors and those who acted as part of a group, finding that lone actors differed from group-based actors in key demographic attributes and were more likely to be involved in attack execution behaviors. Implications for counterterrorism are then discussed.


Meeting the challenge to improve the treatment of hypertension in blacks.
Hypertension is more prevalent and severe in African descendent populations living outside Africa than in any other population. Given this greater burden of hypertension in blacks, it is increasingly necessary to refine strategies to prevent the disorder as well as improve its treatment and control. This review assesses results from clinical trials on lifestyle and pharmacologic interventions to identify which approaches most effectively prevent adverse hypertension-related outcomes in African descendent populations. The Dietary Approaches to Stop Hypertension (DASH) study provided evidence that a carefully controlled diet rich in fruits, vegetables, low-fat dairy foods, and reduced in saturated fat, total fat, and cholesterol (i.e., the DASH diet) reduces blood pressure in blacks and is well accepted. The combination of the DASH diet with reduction in dietary sodium below 100 mmol/d may provide a reduction in blood pressure beyond that reached by the DASH diet alone. Physical exercise and interventions to reduce psychological stress may also reduce blood pressure in blacks. Strong evidence from numerous studies is a compelling argument for continuing to recommend diuretics and beta blockers as first-line antihypertensive therapy for persons of all races. Some new studies also favor angiotensin-converting enzyme inhibitors as first-line antihypertensive drugs. The African American Study of Kidney Disease and Hypertension provided evidence that an angiotensin-converting enzyme inhibitor-based treatment program is more beneficial than calcium channel blockers and beta blockers in reducing the progression of renal failure in blacks with hypertensive nephropathy. Studies in patients with diabetes have also shown evidence that both angiotensin-converting enzyme inhibitors and angiotensin receptor antagonists are more effective than other classes of antihypertensives in reducing adverse renal events. Studies to evaluate the effects of the new antihypertensives in improving outcomes in blacks living outside the United States are needed.


Sensitivity of freshwater pulmonate snail Lymnaea luteola L., to silver nanoparticles.
Toxicity of nanoparticles depends on many factors including size, shape, chemical composition, surface area and surface charge. Silver nanoparticles (AgNPs) are likely to enter the aquatic ecosystems because of their multiple applications and pose a health concern for humans and aquatic species. Therefore, we used a freshwater snail Lymnaea luteola L (L. luteola) to investigate the acute toxicity and genotoxicity of AgNPs in a static-renewal system for 96 h. AgNPs caused molluscicidal activity in L. luteola, with 96-h median lethal concentrations (LC50) (48.10 μg L(-1)). We have observed that AgNPs (36 μg L(-1)) elicited a significant (p<0.01) reduction in glutathione, glutathione-s-transferase and glutathione peroxidase with a concomitant increase in malondialdehyde level and catalase in digestive gland of L. luteola. However, a significant (p<0.01) induction in DNA damage was observed by the alkaline single cell gel electrophoresis in digestive gland cells treated with AgNPs for 24 and 96 h. These results demonstrate that silver nanoparticles are lethal to freshwater snail L. luteola. The oxidative stress biomarkers and comet assay can successfully be used as sensitive tools of aquatic pollution biomonitoring.


A new role for the mitotic RAD21/SCC1 cohesin in meiotic chromosome cohesion and segregation in the mouse.
The evolutionarily conserved cohesin complex is required for the establishment and maintenance of sister chromatid cohesion, in turn essential for proper chromosome segregation. RAD21/SCC1 is a regulatory subunit of the mitotic cohesin complex, as it links together all other subunits of the complex. The destruction of RAD21/SCC1 along chromosomal arms and later at centromeres results in the dissociation of the cohesin complex, facilitating chromosome segregation. Here, we report for the first time that mammalian RAD21/SCC1 associates with the axial/lateral elements of the synaptonemal complex along chromosome arms and on centromeres of mouse spermatocytes. Importantly, RAD21/SCC1 is lost from chromosome arms in late prophase I but persists on centromeres. The loss of centromeric RAD21/SCC1 coincides with the separation of sister chromatids at anaphase II. These findings support a role for mammalian RAD21/SCC1 in maintaining sister chromatid cohesion in meiosis.


The evolutionary origins of pesticide resistance.
Durable crop protection is an essential component of current and future food security. However, the effectiveness of pesticides is threatened by the evolution of resistant pathogens, weeds and insect pests. Pesticides are mostly novel synthetic compounds, and yet target species are often able to evolve resistance soon after a new compound is introduced. Therefore, pesticide resistance provides an interesting case of rapid evolution under strong selective pressures, which can be used to address fundamental questions concerning the evolutionary origins of adaptations to novel conditions. We ask: (i) whether this adaptive potential originates mainly from de novo mutations or from standing variation; (ii) which pre-existing traits could form the basis of resistance adaptations; and (iii) whether recurrence of resistance mechanisms among species results from interbreeding and horizontal gene transfer or from independent parallel evolution. We compare and contrast the three major pesticide groups: insecticides, herbicides and fungicides. Whilst resistance to these three agrochemical classes is to some extent united by the common evolutionary forces at play, there are also important differences. Fungicide resistance appears to evolve, in most cases, by de novo point mutations in the target-site encoding genes; herbicide resistance often evolves through selection of polygenic metabolic resistance from standing variation; and insecticide resistance evolves through a combination of standing variation and de novo mutations in the target site or major metabolic resistance genes. This has practical implications for resistance risk assessment and management, and lessons learnt from pesticide resistance should be applied in the deployment of novel, non-chemical pest-control methods.


Twenty years of ecosystem response after clearcutting and slashburning in conifer forests of central British Columbia, Canada.
Forests are being clearcut over extensive areas of western North America, but plant community response to harvesting and slashburning under varying climatic conditions in central British Columbia, Canada is still largely unknown. Evaluation of resilience is hampered by the short history of logging, lack of long-term experiments and methodological limitations. To test the effect of clearcut logging, prescribed burning and reforestation on forest resilience, we recorded vascular plant cover repeatedly after treatment between 1981 and 2008 in 16 permanent research installations in three biogeoclimatic zones: Engelmann Spruce-Subalpine Fir, Interior Cedar-Hemlock and Sub-Boreal Spruce. We created a plant-trait dataset for the 181 recorded species to define plant functional types representing groups of plants that behave in similar ways and/or produce similar ecological outcomes. These plant functional types, along with taxonomic analysis of diagnostic and indicator species, were then used to evaluate plant community response to disturbance. Twenty years post-treatment, species diversity increased in all zones and plant abundance was greatest in the Interior Cedar-Hemlock. Cover of understory plant functional types associated with mature conifer forests increased in all zones, constituting a significant proportion (> 40%) of the vegetation community by year 20. Response patterns varied by zone and with time. Understory species diagnostic of mature forests were present in all zones by year 20, but we identified indicator species sensitive to slashburning or requiring more time for recovery, including white-flowered rhododendron (Rhododendron albiflorum) and devil's club (Oplopanax horridus). Overall, loss of compositional or functional diversity following harvest and site remediation was not detected, suggesting that montane and subalpine forests in British Columbia are resilient to this treatment. However, because these forests can be slow to recover from disturbance, the post-disturbance assessment window of this study may not have been long enough to detect diminishment of ecosystem resilience.


Epilepsy and Neurodevelopmental Comorbidities in Tuberous Sclerosis Complex: A Natural History Study.
We studied the natural history, genotype influence, and inter-relationship of epilepsy and neuropsychiatric disorders in tuberous sclerosis complex. Patients were identified using the TSC Natural History Database, the largest repository of longitudinally studied patients enrolled by the TSC Clinics Consortium. A cohort of 1657 TSC Natural History Database patients was analyzed. Eighty-eight percent patients (91% TSC2 vs 82% TSC1; P = 0.002) had epilepsy; TSC2 was more frequent with epilepsy onset at age less than two years (TSC2 82% vs TSC1 54%; P < 0.001) and infantile spasms (TSC2 56% vs TSC1 27%; P < 0.001). Frequency of intellectual disability (intelligence quotient less than 70) was higher when epilepsy coexisted (P < 0.001), but was not impacted by genotype (P = 0.08). Severe intellectual disability (intelligence quotient less than 50) was associated with epilepsy onset at age less than two years (P = 0.007), but not with the epilepsy duration (P = 0.45). Autism was diagnosed in 23% and was associated with epilepsy (P < 0.001), particularly with epilepsy onset at age less than two years (P = 0.02) but not with genotype (P = 0.06). Attention-deficit/hyperactivity disorder (age greater than four years) was diagnosed in 18% and was associated with epilepsy (P < 0.001), but genotype made no difference. Nine percent had anxiety (age greater than seven years) and 6% had depression (age greater than nine years), but neither showed association with epilepsy or genotype. Epilepsy is associated with intellectual disability, and when epilepsy begins before age two years the frequency and severity of intellectual disability is much higher. Epilepsy is also associated with autism and attention-deficit/hyperactivity disorder but not with anxiety and depression. Additional trials, blinded, prospective, and adequately powered, will help clarify if early and effective treatment of epilepsy may also mitigate intellectual disability, autism, and attention-deficit/hyperactivity disorder.


Grief Reactions of Potential Organ Donors' Bereaved Relatives: An Observational Study.
Most family members of potential organ donors experience the death of their relative in an intensive care unit. While under an emotional burden, bereaved relatives must make a decision that will affect the life of other patients. A better understanding of grief within the context of organ donation will help intensive care unit staff better support families during this process. To empirically describe the emotional reactions of potential organ donors' family members facing a loved one's death and analyze the relationship of these reactions to factors that occur in the process of illness and death. A prospective observational study was conducted in 16 Spanish hospitals for 36 months. Data of 421 relatives of potential organ donors, collected through a previously validated instrument, included relatives' emotional responses, deceased's and relatives' characteristics, circumstances of death, and behavior of health care staff. Unexpected deaths were linked to more intense emotional reactions and less acceptance of death than were anticipated deaths. Additional stressors, such as perception of poor treatment by hospital staff, perception of deficient medical care, and poor relationships among family members, were associated with stronger reactions. Observation and analysis of the factors studied may help hospital staff members anticipate bereaved relatives' emotional reactions and provide better support during the grieving process, increasing family members' well-being and facilitating a better-informed organ donation decision.


Nanomaterial translocation--the biokinetics, tissue accumulation, toxicity and fate of materials in secondary organs--a review.
Engineered nanomaterials (NMs) offer great technological advantages but their risks to human health are still not fully understood. An increasing body of evidence suggests that some NMs are capable of distributing from the site of exposure to a number of secondary organs. The research into the toxicity posed by the NMs in these secondary organs is expanding due to the realisation that some materials may reach and accumulate in these target sites. The translocation to secondary organs includes, but is not limited to, the hepatic, central nervous, cardiovascular and renal systems. Current data indicates that pulmonary exposure is associated with low (inhalation route-0.00001-1% of total applied dose-24 h) translocation of virtually insoluble NMs such as iridium, carbon black, gold and polystyrene, while slightly higher translocation has been observed for NMs with either slow (e.g., silver, cerium dioxide and quantum dots) or fast (e.g., zinc oxide) solubility. The translocation of NMs following intratracheal, intranasal and pharyngeal aspiration is higher (up to 10% of administered dose), however the relevance of these routes for risk assessment is questionable. Uptake of the materials from the gastrointestinal tract seems to follow the same pattern as inhalation translocation, whereas the dermal uptake of NMs is generally reported to be low. The toxicological effects in secondary organs include oxidative stress, inflammation, cytotoxicity and dysfunction of cellular and physiological processes. For toxicological and risk evaluation, further information on the toxicokinetics and persistence of NMs is crucial. The overall aim of this review is to outline the data currently available in the literature on the biokinetics, accumulation, toxicity and eventual fate of NMs in order to assess the potential risks posed by NMs to secondary organs.


Ozone production chemistry in the presence of urban plumes.
Ozone pollution affects human health, especially in urban areas on hot sunny days. Its basic photochemistry has been known for decades and yet it is still not possible to correctly predict the high ozone levels that are the greatest threat. The CalNex_SJV study in Bakersfield CA in May/June 2010 provided an opportunity to examine ozone photochemistry in an urban area surrounded by agriculture. The measurement suite included hydroxyl (OH), hydroperoxyl (HO2), and OH reactivity, which are compared with the output of a photochemical box model. While the agreement is generally within combined uncertainties, measured HO2 far exceeds modeled HO2 in NOx-rich plumes. OH production and loss do not balance as they should in the morning, and the ozone production calculated with measured HO2 is a decade greater than that calculated with modeled HO2 when NO levels are high. Calculated ozone production using measured HO2 is twice that using modeled HO2, but this difference in calculated ozone production has minimal impact on the assessment of NOx-sensitivity or VOC-sensitivity for midday ozone production. Evidence from this study indicates that this important discrepancy is not due to the HO2 measurement or to the sampling of transported plumes but instead to either emissions of unknown organic species that accompany the NO emissions or unknown photochemistry involving nitrogen oxides and hydrogen oxides, possibly the hypothesized reaction OH + NO + O2 → HO2 + NO2.


Telephone care coordination for smokers in VA mental health clinics: protocol for a hybrid type-2 effectiveness-implementation trial.
This paper describes an innovative protocol for a type-II hybrid effectiveness-implementation trial that is evaluating a smoking cessation telephone care coordination program for Veterans Health Administration (VA) mental-health clinic patients. As a hybrid trial, the protocol combines implementation science and clinical trial methods and outcomes that can inform future cessation studies and the implementation of tobacco cessation programs into routine care. The primary objectives of the trial are (1) to evaluate the process of adapting, implementing, and sustaining a smoking cessation telephone care coordination program in VA mental health clinics, (2) to determine the effectiveness of the program in promoting long-term abstinence from smoking among mental health patients, and (3) to compare the effectiveness of telephone counseling delivered by VA staff with that delivered by state quitlines. The care coordination program is being implemented at six VA facilities. VA mental health providers refer patients to the program via an electronic medical record consult. Program staff call referred patients to offer enrollment. All patients who enroll receive a self-help booklet, mailed smoking cessation medications, and proactive multi-call telephone counseling. Participants are randomized to receive this counseling from VA staff or their state's quitline. Four primary implementation strategies are being used to optimize program implementation and sustainability: blended facilitation, provider training, informatics support, and provider feedback. A three-phase formative evaluation is being conducted to identify barriers to, and facilitators for, program implementation and sustainability. A mixed-methods approach is being used to collect quantitative clinical effectiveness data (e.g., self-reported abstinence at six months) and both quantitative and qualitative implementation data (e.g., provider referral rates, coded interviews with providers). Summative data will be analyzed using the Reach Effectiveness Adoption Implementation Maintenance (RE-AIM) framework. This paper describes the rationale and methods of a trial designed to simultaneously study the clinical effectiveness and implementation of a telephone smoking cessation program for smokers using VA mental health clinics. Such hybrid designs are an important methodological design that can shorten the time between the development of an intervention and its translation into routine clinical care.


Codeine misuse and dependence in South Africa--learning from substance abuse treatment admissions.
Misuse of prescription and over-the-counter codeine-containing products is a global public health issue. To investigate the extent of treatment demand related to the misuse of codeine or codeine dependence in South Africa (SA) and the profile of patients seeking treatment, so as to understand the nature and extent of the problem. Data were collected from centres participating in the South African Community Epidemiology Network on Drug Use in 2014. A total of 17 260 admissions were recorded. There were 435 recorded treatment admissions for codeine misuse or dependence as a primary or secondary substance of abuse (2.5% of all admissions). Of treatment admissions, 137 (0.8%) involved codeine as the primary substance of abuse; 74.9% of patients were males, with an even spread across population groups. Ages ranged from 11 to 70 years, with the highest proportion aged 20 - 29 years; >40% were referred by self, family and/or friends, and 26.7% by health professionals; and 36.8% had received treatment previously. The majority reported misuse of tablets/capsules, with 17.6% reporting misuse of syrups. Oral use comprised 96.6% and daily use 63.1%. Data from treatment admissions related to codeine misuse and dependence are informative, but provide an incomplete picture of the nature and extent of codeine-related problems in SA. Other data sources must be considered before further regulatory/policy changes regarding codeine are implemented.


Optical closure in marine waters from in situ inherent optical property measurements.
Optical closure using radiative transfer simulations can be used to determine the consistency of in situ measurements of inherent optical properties (IOPs) and radiometry. Three scattering corrections are applied to in situ absorption and attenuation profile data for a range of coastal and oceanic waters, but are found to have only very limited impact on subsequent closure attempts for these stations. Best-fit regressions on log-transformed measured and modelled downwards irradiance, Ed, and upwards radiance, Lu, profiles have median slopes between 0.92 - 1.24, revealing a tendency to underestimate Ed and Lu with depth. This is only partly explained by non-inclusion of fluorescence emission from CDOM and chlorophyll in the simulations. There are several stations where multiple volume scattering function related data processing steps perform poorly which suggests the potential existence of unresolved features in the modelling of the angular distribution of scattered photons. General optical closure therefore remains problematic, even though there are many cases in the data set where the match between measured and modelled radiometric data is within 25% RMS%E. These results are significant for applications that rely on optical closure e.g. assimilating ocean colour data into coupled physical-ecosystem models.


Co-morbidity in an elderly inpatient population: are the risks of co-existing conditions differentially distributed?
This study examines the distribution of co-morbidity among 167,738 inpatients, aged 65 or more, who experienced an episode of hospitalization during 1999 in short-term institutions that are located in Oklahoma. The analysis was conducted in two phases. In the first, logistic regression analysis was used to examine covariates that separate inpatients who presented at least one secondary diagnosis from those who were not co-morbid. Limited to those whose condition was complicated by at least one secondary diagnosis, Probit analysis was used to assess the covariates of the number of co-existing conditions. The covariates examined were the individual's racial status, demographic attributes, primary diagnosis, source of admission and discharge destination. Results indicate that the oldest of the elderly, African Americans and, to a lesser extent, Native Americans presented more complex cases than other members of the study population. The paper concludes with the policy implications that are associated with the differential distribution of co-morbidity.


Higher-Order-Aberrations Following Hyperopia Treatment: Small Incision Lenticule Extraction, Laser-Assisted In Situ Keratomileusis and Lenticule Implantation.
To compare the postoperative higher-order-aberrations (HOAs) after hyperopic small incision lenticule extraction (SMILE), hyperopic laser-assisted in situ keratomileusis (LASIK), and lenticule implantation for correction of hyperopia. Eighteen monkeys were divided to six groups: +2.00 D and +4.00 D hyperopic SMILE, +2.00 D and +4.00 D hyperopic LASIK (n = 6 eyes for each), and lenticule implantation with a -2.00 D and -4.00 D lenticule (n = 3 eyes for each). The corneal HOAs were evaluated preoperatively and 3-month postoperatively. At 3-month postoperatively, the spherical aberrations significantly increased toward negative direction in all +4.00 D groups (all P < 0.05). There was a significant change toward more negative values in the third-order vertical coma in the SMILE +4.00 D and LASIK +4.00 D groups (P = 0.026 and P = 0.036, respectively). There were also significant changes in the third-order horizontal trefoil (P = 0.034) and oblique secondary astigmatism (P = 0.012) in the LASIK +4.00 D group. In the eyes that underwent +4.00 D lenticule implantation, the fourth-order horizontal quatrefoil significantly increased (P = 0.029). In low hyperopia correction (+2.00 D), treatment with lenticule implantation tended to have less changes in HOAs, compared to the other two groups. In hyperopic SMILE, hyperopic LASIK or lenticule implantation surgery, significant induction of third- and fourth-order HOAs were seen in moderate hyperopia correction but not in low hyperopia correction. In low hyperopia treatment, lenticule implantation might offer a favorable trend in the aspect of HOAs. The results provided the knowledge of surgically induced HOAs and understanding of the effects of surgery in different types of hyperopic correction.


PaCO2 in surfactant, positive pressure, and oxygenation randomised trial (SUPPORT).
To determine the association of arterial partial pressure of carbon dioxide PaCO2 with severe intraventricular haemorrhage (sIVH), bronchopulmonary dysplasia (BPD), and neurodevelopmental impairment (NDI) at 18-22 months in premature infants. Secondary exploratory data analysis of Surfactant, Positive Pressure, and Oxygenation Randomised Trial (SUPPORT). Multiple referral neonatal intensive care units. 1316 infants 24 0/7 to 27 6/7 weeks gestation randomised to different oxygenation (SpO2 target 85-89% vs 91-95%) and ventilation strategies. Blood gases from postnatal day 0 to day14 were analysed. Five PaCO2 variables were defined: minimum (Min), maximum (Max), SD, average (time-weighted), and a four level categorical variable (hypercapnic (highest quartile of Max PaCO2), hypocapnic (lowest quartile of Min PaCO2), fluctuators (hypercapnia and hypocapnia), and normocapnic (middle two quartiles of Max and Min PaCO2)). PaCO2 variables were compared for infants with and without sIVH, BPD and NDI (±death). Multivariable logistic regression models were developed for adjusted results. sIVH, BPD and NDI (±death) were associated with hypercapnic infants and fluctuators. Association of Max PaCO2 and outcomes persisted after adjustment (per 10 mm Hg increase: sIVH/death: OR 1.27 (1.13 to 1.41); BPD/death: OR 1.27 (1.12 to 1.44); NDI/death: OR 1.23 (1.10 to 1.38), death: OR 1.27 (1.12 to 1.44), all p<0.001). No interaction was found between PaCO2 category and SpO2 treatment group for sIVH/death, NDI/death or death. Max PaCO2 was positively correlated with maximum FiO2 (rs0.55, p<0.0001) and ventilator days (rs0.61, p<0.0001). Higher PaCO2 was an independent predictor of sIVH/death, BPD/death and NDI/death. Further trials are needed to evaluate optimal PaCO2 targets for high-risk infants.


E-mail or snail mail? Randomized controlled trial on which works better for surveys.
To compare e-mail with regular mail for conducting surveys of physicians. Randomized controlled trial. Ontario, Canada. A random sample of physicians listed in the College of Family Physicians of Canada's membership database. Survey delivered by e-mail and by post. Response rates and times, and completeness and characteristics of responses to the survey. Overall response rate was 44.7% (33.6% of e-mail recipients, 52.7% of post recipients who have e-mail, and 47.8% of post recipients without e-mail). While the e-mail rate was significantly lower than for both post groups, e-mail responses were received much faster. There was no significant difference among groups as to completeness of responses, but e-mail responses had more frequent and longer comments. E-mail provides faster but fewer responses to surveys. Content of structured-response questions was similar in all groups, but e-mail provided more and longer responses to open-ended questions. Where a quick response to a survey is required, e-mail is superior.


RNAi-mediated immunity provides strong protection against the negative-strand RNA vesicular stomatitis virus in Drosophila.
Activation of innate antiviral responses in multicellular organisms relies on the recognition of structural differences between viral and cellular RNAs. Double-stranded (ds)RNA, produced during viral replication, is a well-known activator of antiviral defenses and triggers interferon production in vertebrates and RNAi in invertebrates and plants. Previous work in mammalian cells indicates that negative-strand RNA viruses do not appear to generate dsRNA, and that activation of innate immunity is triggered by the recognition of the uncapped 5' ends of viral RNA. This finding raises the question whether antiviral RNAi, which is triggered by the presence of dsRNA in insects, represents an effective host-defense mechanism against negative-strand RNA viruses. Here, we show that the negative-strand RNA virus vesicular stomatitis virus (VSV) does not produce easily detectable amounts of dsRNA in Drosophila cells. Nevertheless, RNAi represents a potent response to VSV infection, as illustrated by the high susceptibility of RNAi-defective mutant flies to this virus. VSV-derived small RNAs produced in infected cells or flies uniformly cover the viral genome, and equally map the genome and antigenome RNAs, indicating that they derive from dsRNA. Our findings reveal that RNAi is not restricted to the defense against positive-strand or dsRNA viruses but can also be highly efficient against a negative-strand RNA virus. This result is of particular interest in view of the frequent transmission of medically relevant negative-strand RNA viruses to humans by insect vectors.


Unraveling the processes shaping mammalian gut microbiomes over evolutionary time.
Whether mammal-microbiome interactions are persistent and specific over evolutionary time is controversial. Here we show that host phylogeny and major dietary shifts have affected the distribution of different gut bacterial lineages and did so on vastly different bacterial phylogenetic resolutions. Diet mostly influences the acquisition of ancient and large microbial lineages. Conversely, correlation with host phylogeny is mostly seen among more recently diverged bacterial lineages, consistent with processes operating at similar timescales to host evolution. Considering microbiomes at appropriate phylogenetic scales allows us to model their evolution along the mammalian tree and to infer ancient diets from the predicted microbiomes of mammalian ancestors. Phylogenetic analyses support co-speciation as having a significant role in the evolution of mammalian gut microbiome compositions. Highly co-speciating bacterial genera are also associated with immune diseases in humans, laying a path for future studies that probe these co-speciating bacteria for signs of co-evolution.


Noncolligative properties of intravenous fluids.
Currently available crystalloids were designed over a century ago for dehydration and not for the treatment of hemorrhagic shock. Information regarding fluids used for resuscitation has grown and thus resuscitation has changed radically in the last two decades. Artificial fluids such as crystalloids and other solutions typically used for resuscitation are now recognized to be inflammatory when infused at high volumes to replace blood. Recent studies have shown that the crystalloids and artificial colloids cause inflammation. Prehospital fluid use has not shown to be of benefit and permissive hypotension may be useful. Careful titration of fluids with minimizing crystalloids and early use of blood products have improved outcome after traumatic hemorrhagic shock. Seemingly innocuous fluids have a dose effect and can be detrimental. Crystalloids can create inflammation when used at high volumes and may be the reason for the sequelae seen after massive resuscitation. This has led to the recognition that whole blood is extremely complex and does much more than carry oxygen. Resuscitation has changed recently with the adoption of damage control resuscitation which is the practice of allowing permissive hypotension, minimizing crystalloids and early aggressive use of blood products. This has led to a decrease in multiple organ dysfunction syndrome and acute respiratory distress syndrome.


Computational identification of variables in neonatal vocalizations predictive for postpubertal social behaviors in a mouse model of 16p11.2 deletion.
Autism spectrum disorder (ASD) is often signaled by atypical cries during infancy. Copy number variants (CNVs) provide genetically identifiable cases of ASD, but how early atypical cries predict a later onset of ASD among CNV carriers is not understood in humans. Genetic mouse models of CNVs have provided a reliable tool to experimentally isolate the impact of CNVs and identify early predictors for later abnormalities in behaviors relevant to ASD. However, many technical issues have confounded the phenotypic characterization of such mouse models, including systematically biased genetic backgrounds and weak or absent behavioral phenotypes. To address these issues, we developed a coisogenic mouse model of human proximal 16p11.2 hemizygous deletion and applied computational approaches to identify hidden variables within neonatal vocalizations that have predictive power for postpubertal dimensions relevant to ASD. After variables of neonatal vocalizations were selected by least absolute shrinkage and selection operator (Lasso), random forest, and Markov model, regression models were constructed to predict postpubertal dimensions relevant to ASD. While the average scores of many standard behavioral assays designed to model dimensions did not differentiate a model of 16p11.2 hemizygous deletion and wild-type littermates, specific call types and call sequences of neonatal vocalizations predicted individual variability of postpubertal reciprocal social interaction and olfactory responses to a social cue in a genotype-specific manner. Deep-phenotyping and computational analyses identified hidden variables within neonatal social communication that are predictive of postpubertal behaviors.