The smoking cessation in pregnancy incentives trial (CPIT): study protocol for a phase III randomised controlled trial.
Eighty per cent of UK women have at least one baby, making pregnancy an opportunity to help women stop smoking before their health is irreparably compromised. Smoking cessation during pregnancy helps protect infants from miscarriage, still birth, low birth weight, asthma, attention deficit disorder and adult cardiovascular disease. UK national guidelines highlight lack of evidence for effectiveness of financial incentives to help pregnant smokers quit. This includes a research recommendation: within a UK context, are incentives an acceptable, effective and cost-effective way to help pregnant women who smoke to quit? The Cessation in Pregnancy Incentives Trial (CPIT) III is a pragmatic, 42-month, multi-centre, parallel-group, individually randomised controlled superiority trial of the effect on smoking status of adding to usual Stop Smoking Services (SSS) support, the offer of up to £400 of financial voucher incentives, compared with usual support alone, to quit smoking during pregnancy. Participants (n = 940) are pregnant smokers (age > 16 years, < 24 weeks pregnant, English speaking), who consent via telephone to take part and are willing to be followed-up in late pregnancy and 6 months after birth. The primary outcome is cotinine/anabasine-validated abstinence from smoking in late pregnancy. Secondary outcomes include engagement with SSS, quit rates at 4 weeks from agreed quit date and 6 months after birth, and birth weight. Outcomes will be analysed by intention to treat, and regression models will be used to compare treatment effects on outcomes. A meta-analysis will include data from the feasibility study in Glasgow. An economic evaluation will assess cost-effectiveness from a UK NHS perspective. Process evaluation using a case-study approach will identify opportunities to improve recruitment and learning for future implementation. Research questions include: what is the therapeutic efficacy of incentives; are incentives cost-effective; and what are the potential facilitators and barriers to implementing incentives in different parts of the UK? This phase III trial in Scotland, England and Northern Ireland follows a successful phase II trial in Glasgow, UK. The participating sites have diverse SSS that represent most cessation services in the UK and serve demographically varied populations. If found to be acceptable and cost-effective, this trial could demonstrate that financial incentives are effective and transferable to most UK SSS for pregnant women. Current Controlled Trials, ISRCTN15236311. Registered on 9 October 2017.


Spinal cord injury influences psychogenic as well as physical components of female sexual ability.
Secure, web-based survey. Elicit specific information about sexual function from women with spinal cord injuries (SCI). World-wide web. Individuals 18 years or older living with SCI obtained a pass code to enter a secure website and then answered survey questions. Bladder and/or bowel incontinence during sexual activity and/or sexual intercourse were significant concerns and prevented some women from seeking sexual activity. Autonomic dysreflexia (AD) during sexual activity was interpreted negatively by many and was found to interfere with sexual activity. Most subjects reported difficulty becoming psychologically aroused as well as physically aroused, which were both correlated with feeling that their SCI had altered their sexual sense of self. An inverse relationship existed between developing new areas of arousal above the level of lesion and not having sensation or movement below the lesion. The most commonly reported sexual stimulation leading to the best arousal involved stimulation of the head/neck and torso areas. The majority of subjects reported having experienced intercourse postinjury. Most participants reported difficulty with positioning during foreplay and intercourse, vaginal lubrication, and spasticity during intercourse. Almost half reported experiencing orgasm postinjury and this was positively associated with the presence of genital sensation. SCI significantly impairs psychological and physical aspects of female sexual arousal. In addition, bladder and bowel incontinence as well as AD negatively impact sexual activity and intercourse.


Hippocampal neurogenesis of Wistar Kyoto rats is congenitally impaired and correlated with stress resistance.
The hippocampus is thought to be an important region for depression. However, the relationship between hippocampal neurogenesis and depression is still controversial. Wistar Kyoto (WKY) rats are frequently used as a depression model. WKY rats are known to show physiologically abnormal features, and these features resemble abnormalities seen in depressed patients. However, the neurogenesis of WKY rats is still unknown. In this study, we first evaluated the neurogenesis of WKY rats and compared it to that of Wistar (WIS) rats. No strain effect was observed in the number of cells positive for 5-bromo-2'-deoxyuridine (BrdU) and BrdU/Doublecortin (Dcx) in the subventricular zone (SVZ). However, the number of BrdU- and BrdU/Dcx-positive cells in the dentate gyrus (DG) of the hippocampus was significantly lower in WKY rats than in WIS rats. Next, we evaluated the correlation between neurogenesis and behavior tests. Behavior tests did not affect neurogenesis in either strain. Hippocampal neurogenesis correlated negatively with the results of a forced swim test (FST) on day 2 in each strain. That is, rats with a lower level of native neurogenesis in the DG showed a higher level of learned helplessness induced by the inescapable stress of the FST on day 1. Our findings indicate that hippocampal neurogenesis in WKY rats is congenitally impaired in contrast to that in WIS rats. Native cell proliferation and neurogenesis in the DG are correlated with stress resistance. These findings may be useful for developing new targets for depression treatment.


Ion mobility mass spectrometry for extracting spectra of N-glycans directly from incubation mixtures following glycan release: application to glycans from engineered glycoforms of intact, folded HIV gp120.
The analysis of glycosylation from native biological sources is often frustrated by the low abundances of available material. Here, ion mobility combined with electrospray ionization mass spectrometry have been used to extract the spectra of N-glycans released with PNGase F from a serial titration of recombinantly expressed envelope glycoprotein, gp120, from the human immunodeficiency virus (HIV). Analysis was also performed on gp120 expressed in the α-mannosidase inhibitor, and in a matched mammalian cell line deficient in GlcNAc transferase I. Without ion mobility separation, ESI spectra frequently contained no observable ions from the glycans whereas ions from other compounds such as detergents and residual buffer salts were abundant. After ion mobility separation on a Waters T-wave ion mobility mass spectrometer, the N-glycans fell into a unique region of the ion mobility/m/z plot allowing their profiles to be extracted with good signal:noise ratios. This method allowed N-glycan profiles to be extracted from crude incubation mixtures with no clean-up even in the presence of surfactants such as NP40. Furthermore, this technique allowed clear profiles to be obtained from sub-microgram amounts of glycoprotein. Glycan profiles were similar to those generated by MALDI-TOF MS although they were more susceptible to double charging and fragmentation. Structural analysis could be accomplished by MS/MS experiments in either positive or negative ion mode but negative ion mode gave the most informative spectra and provided a reliable approach to the analysis of glycans from small amounts of glycoprotein.


Monitoring chemotherapeutic response by hyperpolarized 13C-fumarate MRS and diffusion MRI.
Targeted chemotherapeutic agents often do not result in tumor shrinkage, so new biomarkers that correlate with clinical efficacy are needed. In this study, we investigated noninvasive imaging protocols to monitor responses to sorafenib, a multikinase inhibitor approved for treatment of renal cell and hepatocellular carcinoma. Healthy cells are impermeable to fumarate, so conversion of this metabolite to malate as detected by (13)C-magnetic resonance spectroscopy (MRS) has been suggested as one marker for cell death and treatment response in tumors. Diffusion MRI also has been suggested as a measure of therapy-induced cytotoxic edema because viable cells act as a diffusion barrier in tissue. For these reasons, we assessed sorafenib responses using hyperpolarized (13)C-fumarate, diffusion-weighted MRI (DW-MRI) in a xenograft model of human breast cancer in which daily administration of sorafenib was sufficient to stabilize tumor growth. We detected signals from fumarate and malate following intravenous administration of hyperpolarized fumarate with a progressive increase in the malate-to-fumarate (MA/FA) ratio at days 2 to 5 after sorafenib infusion. The apparent diffusion coefficient (ADC) measured by DW-MRI increased in the treated group consistent with cytotoxic edema. However, the MA/FA ratio was a more sensitive marker of therapeutic response than ADC, with 2.8-fold versus 1.3-fold changes, respectively, by day 5 of drug treatment. Histologic analyses confirmed cell death in the sorafenib-treated cohort. Notably, (13)C-pyruvate-to-lactate conversion was not affected by sorafenib in the breast cancer model examined. Our results illustrate how combining hyperpolarized substrates with DW-MRI can allow noninvasive monitoring of targeted therapeutic responses at relatively early times after drug administration.


The notch ligand JAGGED1 as a target for anti-tumor therapy.
The Notch pathway is increasingly attracting attention as a source of therapeutic targets for cancer. Ligand-induced Notch signaling has been implicated in various aspects of cancer biology; as a consequence, pan-Notch inhibitors and therapeutic antibodies targeting one or more of the Notch receptors have been investigated for cancer therapy. Alternatively, Notch ligands provide attractive options for therapy in cancer treatment due to their more restricted expression and better-defined functions, as well as their low rate of mutations in cancer. One of the Notch ligands, Jagged1 (JAG1), is overexpressed in many cancer types, and plays an important role in several aspects of tumor biology. In fact, JAG1-stimulated Notch activation is directly implicated in tumor growth through maintaining cancer stem cell populations, promoting cell survival, inhibiting apoptosis, and driving cell proliferation and metastasis. In addition, JAG1 can indirectly affect cancer by influencing tumor microenvironment components such as tumor vasculature and immune cell infiltration. This article gives an overview of JAG1 and its role in tumor biology, and its potential as a therapeutic target.


Folate deficiency during pregnancy impacts on methyl metabolism without affecting global DNA methylation in the rat fetus.
The methionine cycle and methyl group metabolism are implicated in the long-term programming of metabolism. Diets deficient in folic acid, methionine and choline have been fed to pregnant rats to examine the effects on amino acid metabolism, choline reserves and DNA methylation in dam and fetuses. Animals were fed folate-deficient, folate-deficient with low methionine, folate-deficient with low choline and folate-deficient, low-methionine, low-choline diets starting 2 weeks before mating. The dams and their fetuses were subsequently killed on day 21 of gestation for analysis. Diets low in methionine reduced fetal and maternal weight. Folate deficiency increased the concentrations of homocysteine, glycine, serine and threonine in the maternal plasma, and this was exacerbated by the low-methionine diets. The changes in the amino acid profile in the fetal serum were similar but less pronounced. This result suggests that fetal metabolism was less perturbed. Folate deficiency increased free choline in the maternal liver at the expense of phosphocholine stores. It has been suggested that a deficiency in methyl donors in the diet during pregnancy may impact on key methylation reactions, including the methylation of DNA. Despite widespread changes in the metabolism of choline and amino acids, there was no change in the global methylation of cytosine in DNA from either maternal or fetal livers. This suggests a more indirect mechanism in which gene-nutrient interactions modify the process of differential methylation during development.


The immune response to coitus and conception.
It is well recognized that cells or tissues exchanged between genetically dissimilar members of the same species will be destroyed by a specific immune response. This process of destruction is initiated by the expression of histocompatibility antigens on the surface of the donor cells which provoke a reaction by the immune system of the recipient. Successful reproduction even through a fundamental process is thought to expose the female to significant antigenic challenge. Numerous hypotheses have been proposed to account for the survival of the semiallogeneic conceptus, although the immunological consequences of coitus are frequently ignored. The possible immunosuppressive role of seminal plasma in normal reproduction is clearly of great clinical importance. Its exclusion from the in vitro fertilization techniques of human reproduction may partially account for the high failure rates associated with this form of assisted reproduction. Its presence in the normal ejaculate may explain the vulnerability of the female reproductive tract to virally inducted neoplasms and be a relevant factor in the etiology of the acquired immune deficiency syndrome.


4th Annual Predictive Toxicology Summit 2012.
This meeting report presents a brief summary on the 4th Annual Predictive Toxicology Summit 2012, which was held on 15 - 16 February 2012 in London. The majority of presentations came from global pharmaceutical companies, although small and medium enterprise (SME) and academic researchers were represented too. Major regulatory bodies were also present. The article highlights the summit, which was considered a good learning opportunity to catch up on the recent advances in predictive toxicology. Predictive toxicology has become more and more important due to social and economic pressure and scientific reasons. Technological developments are rapid, but there is a gulf between the technology developers and the pharmaceutical end users; hence, early engagement is desirable. Stem cell-derived cell-based assays as well as three-dimensional in vitro tissue/organ model development are within the reach now, but a lot needs to be done to optimise and validate the developed protocols and products. The field of predictive toxicology needs fundamental research of interdisciplinary nature, which requires much needed trained personnel and funding.


The peripheral clock regulates human pigmentation.
Although the regulation of pigmentation is well characterized, it remains unclear whether cell-autonomous controls regulate the cyclic on-off switching of pigmentation in the hair follicle (HF). As human HFs and epidermal melanocytes express clock genes and proteins, and given that core clock genes (PER1, BMAL1) modulate human HF cycling, we investigated whether peripheral clock activity influences human HF pigmentation. We found that silencing BMAL1 or PER1 in human HFs increased HF melanin content. Furthermore, tyrosinase expression and activity, as well as TYRP1 and TYRP2 mRNA levels, gp100 protein expression, melanocyte dendricity, and the number gp100+ HF melanocytes, were all significantly increased in BMAL1 and/or PER1-silenced HFs. BMAL1 or PER1 silencing also increased epidermal melanin content, gp100 protein expression, and tyrosinase activity in human skin. These effects reflect direct modulation of melanocytes, as BMAL1 and/or PER1 silencing in isolated melanocytes increased tyrosinase activity and TYRP1/2 expression. Mechanistically, BMAL1 knockdown reduces PER1 transcription, and PER1 silencing induces phosphorylation of the master regulator of melanogenesis, microphthalmia-associated transcription factor, thus stimulating human melanogenesis and melanocyte activity in situ and in vitro. Therefore, the molecular clock operates as a cell-autonomous modulator of human pigmentation and may be targeted for future therapeutic strategies.


Origin and spread of human mitochondrial DNA haplogroup U7.
Human mitochondrial DNA haplogroup U is among the initial maternal founders in Southwest Asia and Europe and one that best indicates matrilineal genetic continuity between late Pleistocene hunter-gatherer groups and present-day populations of Europe. While most haplogroup U subclades are older than 30 thousand years, the comparatively recent coalescence time of the extant variation of haplogroup U7 (~16-19 thousand years ago) suggests that its current distribution is the consequence of more recent dispersal events, despite its wide geographical range across Europe, the Near East and South Asia. Here we report 267 new U7 mitogenomes that - analysed alongside 100 published ones - enable us to discern at least two distinct temporal phases of dispersal, both of which most likely emanated from the Near East. The earlier one began prior to the Holocene (~11.5 thousand years ago) towards South Asia, while the later dispersal took place more recently towards Mediterranean Europe during the Neolithic (~8 thousand years ago). These findings imply that the carriers of haplogroup U7 spread to South Asia and Europe before the suggested Bronze Age expansion of Indo-European languages from the Pontic-Caspian Steppe region.


[Metabolic limitation of DNA-polymerase I synthesis by Escherichia coli strain CM5199].
The work was aimed at studying DNA polymerase I synthesis after induction of the vector prophage lambda polA (NM 964) in lysogenic Escherichia coli CM 5199 in the course of batch cultivation in different media and at various growth phases as well as upon "nutrient shifts" caused by adding organic compounds to the minimal medium. The enzyme activity was highest when the phage was induced at the exponential phase of growth and in media richer in their composition. The enzyme synthesis, the dynamics of protein and RNA content were studied after induction of the phage and enrichment of the medium; the studies have shown that synthesis of DNA polymerase I is influenced by limitation at two levels: (1) biosynthesis of amino acids and (2) biosynthesis of components of the protein-synthesizing apparatus. There is a direct correlation between DNA polymerase I biosynthesis under the control of vector DNA and the growth rate of the culture.


Antiretroviral therapy adherence and drug-drug interactions in the aging HIV population.
It is estimated that by 2015 more than half of all HIV-infected individuals in the United States will be 50 years of age or older. As this population ages, the frequency of non-AIDS related comorbidities increases, which includes cardiovascular, metabolic, gastrointestinal, genitourinary and psychiatric disorders. As a result, medical management of the aging HIV population can be complicated by polypharmacy and higher pill burden, leading to poorer antiretroviral therapy (ART) adherence. Adherence to ART is generally better in older populations when compared to younger populations; however, cognitive impairment in elderly patients can impair adherence, leading to worse treatment outcomes. Practical monitoring tools can improve adherence and increase rates of viral load suppression. Several antiretroviral drugs exhibit inhibitory and/or inducing effects on cytochrome P450 isoenzymes, which are responsible for the metabolism of many medications used for the treatment of comorbidities in the aging HIV population. The combination of ART with polypharmacy significantly increases the chance of potentially serious drug-drug interactions (DDIs), which can lead to drug toxicity, poorer ART adherence, loss of efficacy of the coadministered medication, or virologic breakthrough. Increasing clinicians awareness of common DDIs and the use of DDI programs can prevent coadministration of potentially harmful combinations in elderly HIV-infected individuals. Well designed ART adherence interventions and DDI studies are needed in the elderly HIV population.


Control of gene expression by CRISPR-Cas systems.
Clustered regularly interspaced short palindromic repeats (CRISPR) loci and their associated cas (CRISPR-associated) genes provide adaptive immunity against viruses (phages) and other mobile genetic elements in bacteria and archaea. While most of the early work has largely been dominated by examples of CRISPR-Cas systems directing the cleavage of phage or plasmid DNA, recent studies have revealed a more complex landscape where CRISPR-Cas loci might be involved in gene regulation. In this review, we summarize the role of these loci in the regulation of gene expression as well as the recent development of synthetic gene regulation using engineered CRISPR-Cas systems.


12-Methyltetradecanoic acid, a branched-chain fatty acid, represses the extracellular production of surfactants required for swarming motility in Pseudomonas aeruginosa PAO1.
Pseudomonas aeruginosa is known to produce surfactants that are involved in its swarming motility behavior, such as rhamnolipids and their precursors-3-(3-hydroxyalkanoyloxy)-alkanoic acids (HAAs). In P. aeruginosa PAO1, swarming motility is inhibited by some fatty acids, including branched-chain fatty acids and unsaturated fatty acids. In the present study, addition of 12-methyltetradecanoic acid (12-MTA, anteiso-C15:0) to an agar medium markedly repressed surfactant activity in the extracellular fraction of a P. aeruginosa culture in a drop collapse assay. Further, an extracellular fraction of a culture of rhlA mutant P. aeruginosa, which did not produce both rhamnolipids and HAAs, showed a complete loss of surfactant activity and markedly reduced swarming activity. In contrast, an extracellular fraction of a culture of rhlB mutant P. aeruginosa, which produced HAAs but not rhamnolipids, showed moderate swarming activity and weak extracellular surfactant activity that was lost on the addition of 12-MTA to the agar medium. Expression of the rhlAB operon from the plasmid pMR2 restored normal swarming motility on 12-MTA-containing agar medium. Taken together, these findings indicate that 12-MTA reduced extracellular surfactant activity, thus resulting in a swarming defect in P. aeruginosa PAO1.


Rapid Attentional Selection of Non-native Stimuli despite Perceptual Narrowing.
Visual experiences increase our ability to discriminate environmentally relevant stimuli (native stimuli, e.g., human faces) at the cost of a reduced sensitivity to irrelevant or infrequent stimuli (non-native stimuli, e.g., monkey/ape faces)-a developmental progression known as perceptual narrowing. One possible source of the reduced sensitivity in distinguishing non-native stimuli (e.g., one ape face vs. another ape face) could be underspecified attentional search templates (i.e., working memory representations). To determine whether perceptual narrowing stems from underspecified attentional templates for non-native exemplars, this study used ERP (the N2pc component) and behavioral measures in a visual search task, where the target was either an exemplar (e.g., a specific ape face) or a category (e.g., any ape face). The N2pc component, an ERP marker of early attentional selection emerging at 200 msec poststimulus, is typically modulated by the specificity of the target and, therefore, by the attentional template-the N2pc is larger for specific items versus categories. In two experiments using both human and ape faces (i.e., native and non-native stimuli), we found that perceptual narrowing affects later response selection (i.e., manual RT and accuracy), but not early attentional selection relying on attentional templates (i.e., the N2pc component). Our ERP results show that adults deploy exemplar level attentional templates for non-native stimuli (as well as native stimuli), despite poor downstream behavioral performance. Our findings suggest that long-term previous experience with reduced exemplar level judgments (i.e., perceptual narrowing) does not appear to eliminate early attentional selection of non-native exemplars.


The formation of the superior and jugular ganglia: insights into the generation of sensory neurons by the neural crest.
The superior and jugular ganglia (S/JG) are the proximal ganglia of the IXth and Xth cranial nerves and the sensory neurons of these ganglia are neural crest derived. However, it has been unclear the extent to which their differentiation resembles that of the Dorsal Root Ganglia (DRGs). In the DRGs, neural crest cells undergo neuronal differentiation just after the onset of migration and there is evidence suggesting that these cells are pre-specified towards a sensory fate. We have analysed sensory neuronal differentiation in the S/JG. We show, in keeping with previous studies, that neuronal differentiation initiates long after the cessation of neural crest migration. We also find no evidence for the existence of migratory neural crest cells pre-specified towards a sensory phenotype prior to ganglion formation. Rather our results suggest that sensory neuronal differentiation in the S/JG is the result of localised spatiotemporal cues.


Bioengineering of noncoding RNAs for research agents and therapeutics.
The discovery of functional small noncoding RNAs (ncRNAs), such as microRNAs and small interfering RNAs, in the control of human cellular processes has opened new avenues to develop RNA-based therapies for various diseases including viral infections and cancers. However, studying ncRNA functions and developing RNA-based therapeutics relies on access to large quantities of affordable ncRNA agents. Currently, synthetic RNAs account for the major source of agents for RNA research and development, yet carry artificial modifications on the ribose ring and phosphate backbone in sharp contrast to posttranscriptional modifications present on the nucleobases or unmodified natural RNA molecules produced within cells. Therefore, large efforts have been made in recent years to develop recombinant RNA techniques to cost-effectively produce biological RNA agents that may better capture the structure, function, and safety properties of natural RNAs. In this article, we summarize and compare current in vitro and in vivo methods for the production of RNA agents including chemical synthesis, in vitro transcription, and bioengineering approaches. We highlight the latest recombinant RNA approaches using transfer RNA (tRNA), ribosomal RNA (rRNA), and optimal ncRNA scaffold (OnRS), and discuss the applications of bioengineered ncRNA agents (BERAs) that should facilitate RNA research and development.


Thermally induced convective movements in a standard experimental model for characterization of lesions prior to radiofrequency functional neurosurgery.
Experimental exploration of equipment for stereotactic functional neurosurgery based on heating induced by radio-frequency current is most often carried out prior to surgery in order to secure a correct function of the equipment. The experiments are normally conducted in an experimental model including an albumin solution in which the treatment electrode is submerged, followed by a heating session during which a protein clot is generated around the electrode tip. The clot is believed to reflect the lesion generated in the brain during treatment. It is thereby presupposed that both the thermal and electric properties of the model are similar to brain tissue. This study investigates the presence of convective movements in the albumin solution using laser Doppler velocimetry. The result clearly shows that convective movements that depend on the time dependent heating characteristics of the equipment arise in the solution upon heating. The convective movements detected show a clear discrepancy compared with the in vivo situation that the experimental model tries to mimic; both the velocity (maximum velocity of about 5 mms) and mass flux are greater in this experimental setting. Furthermore the flow geometry is completely different since only a small fraction of the tissue surrounding the electrode in vivo consists of moving blood, whereas the entire surrounding given by the albumin solution in the experimental model is moving. Earlier investigations by our group (Eriksson et al., 1999, Med. Biol. Eng. Comput. 37, pp. 737-741; Wren, 2001, Ph.D. thesis; and Wren et al., 2001, Med. Biol. Eng. Comput. 39, pp. 255-262) indicate that the heat flux is an essential parameter for the lesion growth and final size, and that presence of convective movements in the model might substantially increase the heat flux. Thus, convective movements of the magnitude presented here will very likely underestimate the size of the brain lesion, a finding that definitely should be taken into consideration when using the model prior to patient treatment.


Child Caries Management: A Randomized Controlled Trial in Dental Practice.
This multicenter 3-arm, parallel-group, patient-randomized controlled trial compared clinical effectiveness of 3 treatment strategies over 3 y for managing dental caries in primary teeth in UK primary dental care. Participants aged 3 to 7 y with at least 1 primary molar with dentinal carious lesion were randomized across 3 arms (1:1:1 via centrally administered system with variable-length random permuted blocks): C+P, conventional carious lesion management (complete carious tooth tissue removal and restoration placement) with prevention; B+P, biological management (sealing in carious tooth tissue restoratively) with prevention; and PA, prevention alone (diet, plaque removal, fluorides, and fissure sealants). Parents, children, and dentists were not blind to allocated arm. Co-primary outcomes were 1) the proportion of participants with at least 1 episode of dental pain and/or infection and 2) the number of episodes of dental pain and/or infection during follow-up (minimum, 23 mo). In sum, 1,144 participants were randomized (C+P, n = 386; B+P, n = 381; PA, n = 377) by 72 general dental practitioners, of whom 1,058 (C+P, n = 352; B+P, n = 352; PA, n = 354) attended at least 1 study visit and were included in the primary analysis. The median follow-up was 33.8 mo (interquartile range, 23.8 to 36.7). Proportions of participants with at least 1 episode of dental pain and/or infection were as follows: C+P, 42%; B+P, 40%; PA, 45%. There was no evidence of a difference in incidence of dental pain and/or infection when B+P (adjusted risk difference [97.5% CI]: -2% [-10% to 6%]) or PA (4% [-4% to 12%]) was compared with C+P. The mean (SD) number of episodes of dental pain and/or infection were as follows: C+P, 0.62 (0.95); B+P, 0.58 (0.87); and PA, 0.72 (0.98). Superiority could not be concluded for number of episodes between B+P (adjusted incident rate ratio (97.5% CI): 0.95 [0.75 to 1.21]) or PA (1.18 [0.94 to 1.48]) and C+P. In conclusion, there was no evidence of a difference among the 3 treatment approaches for incidence or number of episodes of dental pain and/or infection experienced by these participants with high caries risk and established disease (trial registration: ISRCTN77044005).


Vitamin D and Risk of Neuroimaging Abnormalities.
Vitamin D deficiency has been linked with an increased risk of incident all-cause dementia and Alzheimer's disease. The aim of the current study was to explore the potential mechanisms underlying these associations by determining whether low vitamin D concentrations are associated with the development of incident cerebrovascular and neurodegenerative neuroimaging abnormalities. The population consisted of 1,658 participants aged ≥65 years from the US-based Cardiovascular Health Study who were free from prevalent cardiovascular disease, stroke and dementia at baseline in 1992-93. Serum 25-hydroxyvitamin D (25(OH)D) concentrations were determined by liquid chromatography-tandem mass spectrometry from blood samples collected at baseline. The first MRI scan was conducted between 1991-1994 and the second MRI scan was conducted between 1997-1999. Change in white matter grade, ventricular grade and presence of infarcts between MRI scan one and two were used to define neuroimaging abnormalities. During a mean follow-up of 5.0 years, serum 25(OH)D status was not significantly associated with the development of any neuroimaging abnormalities. Using logistic regression models, the multivariate adjusted odds ratios (95% confidence interval) for worsening white matter grade in participants who were severely 25(OH)D deficient (<25 nmol/L) and deficient (≥25-50 nmol/L) were 0.76 (0.35-1.66) and 1.09 (0.76-1.55) compared to participants with sufficient concentrations (≥50 nmol/L). The multivariate adjusted odds ratios for ventricular grade in participants who were severely 25(OH)D deficient and deficient were 0.49 (0.20-1.19) and 1.12 (0.79-1.59) compared to those sufficient. The multivariate adjusted odds ratios for incident infarcts in participants who were severely 25(OH)D deficient and deficient were 1.95 (0.84-4.54) and 0.73 (0.47-1.95) compared to those sufficient. Overall, serum vitamin D concentrations could not be shown to be associated with the development of cerebrovascular or neurodegenerative neuroimaging abnormalities in Cardiovascular Health Study participants.


A retrospective study of the eligibility for tonsillectomy.
The criteria for tonsillectomy for recurrent tonsillitis were established by prospective studies in the pediatric population and are applied to adults as well. No studies have been conducted to assess whether these guidelines are followed. To examine the eligibility for tonsillectomy of tonsillectomized patients who were referred because of recurrent acute tonsillitis. A retrospective case series in an ambulatory military otolaryngology clinic was conducted, and the medical records of 44 tonsillectomized patients who suffered from throat infections during the year before surgery were analyzed. The number of tonsillar infections that met the referral criteria was counted. The average number of throat infections that met the referral criteria was 1.89 per year. The average number of visits to the clinic due to upper respiratory tract infection was 12.92 (range 2-36) per year. The average number of visits for any cause was 45.13 (range 6-64) per year. One patient with eight documented throat infections met the criterion of more than six infections in the last year. Although the referral criteria were not strictly met, we speculate that surgery was probably beneficial. This study shows that the indications for tonsillectomy referral are not strictly followed, and that new criteria for referral of adults for tonsillectomy need to be established.


Access to patients' health records for drug therapy problem determination by pharmacists.
To evaluate differences in the number and type of drug therapy problems (DTPs) identified by pharmacists with and without access to patients' primary care health records; determine the confidence level of pharmacists in their assessment of DTPs with and without access to health records; and determine the type of information pharmacists need to confirm their assessment. The study design was an exploratory and comparative evaluation of comprehensive medication management assessments. Pharmacists initially completed patient assessments without access to the patient's primary care health record. Pharmacists documented the visit according to the standard of care and documented the assessment in a standardized study form. Pharmacists then reviewed the patient's primary care health record and documented a revised assessment in the standardized study form. The standardized form included sections about the number of DTPs, the classification of DTPs, the pharmacist's confidence level in identifying DTPs, and the information needed to increase the pharmacist's confidence level in identifying DTPs. Pharmacists evaluated 24 patients and identified 132 DTPs. After reviewing patients' primary care health records, 31 DTPs were deemed "false DTPs," 3 DTPs were recategorized, and 9 new DTPs were identified. Practitioner confidence levels in DTP determination improved after reviewing patients' primary care health records. The health information most frequently identified as desirable after the initial review was laboratory tests. Pharmacists identified more DTPs with lower confidence levels without access to patients' primary care health records. Fewer DTPs were deemed "confirmed DTPs" and confidence in the practitioners' assessments improved after review of the primary care health records. Access to primary care health records can help community pharmacists build an efficient and comprehensive medication management practice.


Differential dopamine receptor D4 allele association with ADHD dependent of proband season of birth.
Season of birth (SOB) has been associated with attention deficit hyperactivity disorder (ADHD) in two existing studies. One further study reported an interaction between SOB and genotypes of the dopamine D4 receptor (DRD4) gene. It is important that these findings are further investigated to confirm or refute the findings. In this study, we investigated the SOB association with ADHD in four independent samples collected for molecular genetic studies of ADHD and found a small but significant increase in summer births compared to a large population control dataset. We also observed a significant association with the 7-repeat allele of the DRD4 gene variable number tandem repeat polymorphism in exon three with probands born in the winter season, with no significant differential transmission of this allele between summer and winter seasons. Preferential transmission of the 2-repeat allele to ADHD probands occurred in those who were born during the summer season, but did not surpass significance for association, even though the difference in transmission between the two seasons was nominally significant. However, following adjustment for multiple testing of alleles none of the SOB effects remained significant. We conclude that the DRD4 7-repeat allele is associated with ADHD but there is no association or interaction with SOB for increased risk for ADHD. Our findings suggest that we can refute a possible effect of SOB for ADHD.


Transcriptome analysis reveals putative genes involved in iridoid biosynthesis in Rehmannia glutinosa.
Rehmannia glutinosa, one of the most widely used herbal medicines in the Orient, is rich in biologically active iridoids. Despite their medicinal importance, no molecular information about the iridoid biosynthesis in this plant is presently available. To explore the transcriptome of R. glutinosa and investigate genes involved in iridoid biosynthesis, we used massively parallel pyrosequencing on the 454 GS FLX Titanium platform to generate a substantial EST dataset. Based on sequence similarity searches against the public sequence databases, the sequences were first annotated and then subjected to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) based analysis. Bioinformatic analysis indicated that the 454 assembly contained a set of genes putatively involved in iridoid biosynthesis. Significantly, homologues of the secoiridoid pathway genes that were only identified in terpenoid indole alkaloid producing plants were also identified, whose presence implied that route II iridoids and route I iridoids share common enzyme steps in the early stage of biosynthesis. The gene expression patterns of four prenyltransferase transcripts were analyzed using qRT-PCR, which shed light on their putative functions in tissues of R. glutinosa. The data explored in this study will provide valuable information for further studies concerning iridoid biosynthesis.


Microsimulation Modeling for Health Decision Sciences Using R: A Tutorial.
Microsimulation models are becoming increasingly common in the field of decision modeling for health. Because microsimulation models are computationally more demanding than traditional Markov cohort models, the use of computer programming languages in their development has become more common. R is a programming language that has gained recognition within the field of decision modeling. It has the capacity to perform microsimulation models more efficiently than software commonly used for decision modeling, incorporate statistical analyses within decision models, and produce more transparent models and reproducible results. However, no clear guidance for the implementation of microsimulation models in R exists. In this tutorial, we provide a step-by-step guide to build microsimulation models in R and illustrate the use of this guide on a simple, but transferable, hypothetical decision problem. We guide the reader through the necessary steps and provide generic R code that is flexible and can be adapted for other models. We also show how this code can be extended to address more complex model structures and provide an efficient microsimulation approach that relies on vectorization solutions.


Mechanosensitive Vaginal Epithelial Adenosine Triphosphate Release and Pannexin 1 Channels in Healthy, in Type 1 Diabetic, and in Surgically Castrated Female Mice.
Distension of hollow organs is known to release adenosine triphosphate (ATP) from the lining epithelium, which triggers local responses and activates sensory nerves to convey information to the central nervous system. However, little is known regarding participation of ATP and mediators of ATP release, such as Pannexin 1 (Panx1) channels, in mechanisms of vaginal mechanosensory transduction and of changes imposed by diabetes and menopause, conditions associated with vaginal dysfunction and risk for impaired genital arousal. To investigate if intravaginal mechanical stimulation triggers vaginal ATP release and if (a) this response involves Panx1 channels and (b) this response is altered in animal models of diabetes and menopause. Diabetic Akita female mice were used as a type 1 diabetes (T1D) model and surgical castration (ovariectomy [OVX]) as a menopause model. Panx1-null mice were used to evaluate Panx1 participation in mechanosensitive vaginal ATP release. Vaginal washes were collected from anesthetized mice at baseline (non-stimulated) and at 5 minutes after intravaginal stimulation. For the OVX and Sham groups, samples were collected before surgery and at 4, 12, 22, 24, and 28 weeks after surgery. ATP levels in vaginal washes were measured using the luciferin-luciferase assay. Panx1 mRNA levels in vaginal epithelium were quantified by quantitative polymerase chain reaction. The main outcome measures are quantification of mechanosensitive vaginal ATP release and evaluation of impact of Panx1 deletion, OVX, and T1D on this response. Intravaginal mechanical stimulation-induced vaginal ATP release was 84% lower in Panx1-null (P < .001) and 76% lower in diabetic (P < .0001) mice compared with controls and was reduced in a progressive and significant manner in OVX mice when compared with Sham. Panx1 mRNA expression in vaginal epithelium was 44% lower in diabetics than that in controls (P < .05) and 40% lower in OVX than that in the Sham (P < .05) group. Panx1 downregulation and consequent attenuation of mechanosensitive vaginal responses may be implicated in mechanisms of female genital arousal disorder, thereby providing potential targets for novel therapies to manage this condition. Using animal models, we demonstrated Panx1 involvement in mechanosensitive vaginal ATP release and effects of T1D and menopause on this response and on Panx1 expression. A limitation is that sex steroid hormone levels were not measured, precluding correlations and insights into mechanisms that may regulate Panx1 expression in the vaginal epithelium. Panx1 channel is a component of the vaginal epithelial mechanosensory transduction system that is essential for proper vaginal response to mechanical stimulation and is targeted in T1D and menopause. Harroche J, Urban-Maldonado M, Thi MM, et al. Mechanosensitive Vaginal Epithelial Adenosine Triphosphate Release and Pannexin 1 Channels in Healthy, in Type 1 Diabetic, and in Surgically Castrated Female Mice. J Sex Med 2020;17:870-880.


Do pharmacological approaches that prevent opioid tolerance target different elements in the same regulatory machinery?
In the nervous system, the interaction of opioids like heroin and morphine with the G protein-coupled Mu-opioid receptor (MOR) provokes the development of tolerance to these opioids, as well as physical dependence. Tolerance implies that higher doses of these drugs must be consumed in order to obtain an equivalent sensation, a situation that contributes notably to the social problems surrounding recreational opioid abuse. The mechanisms that promote opioid tolerance involve a series of adaptive changes in the MOR and in the post-receptor signalling elements. Pharmacological studies have consistently identified a number of signalling proteins relevant to morphine-induced tolerance, including the delta-opioid receptor (DOR), protein kinase C (PKC), protein kinase A (PKA), calcium/calmodulin-dependent kinase II (CaMKII), nitric oxide synthase (NOS), N-methyl-D-aspartate acid glutamate receptors (NMDAR), and regulators of G-signalling (RGS) proteins. Thus, it is feasible that these treatments which diminish morphine tolerance target distinct elements within the same regulatory machinery. In this scheme, the signals originated at the agonist-activated MORs would be recognised by elements such as the NMDARs, which in turn exert a negative feedback on MOR-evoked signalling. This process involves DOR regulation of MORs, MOR-induced activation of NMDARs (probably via the regulation of Src, recruiting PKC and Galpha subunits) and the NMDAR-mediated activation of CaMKII. The active CaMKII promotes the sequestering of morphine-activated Gbetagamma dimers by phosducin-like proteins (PhLP) and of Galpha subunits by RGS proteins and tolerance to opioids like morphine develops. Future efforts to study these phenomena should focus on fitting additional pieces into this puzzle in order to fully define the mechanism underlying the desensitization of MORs in neural cells.


Three-Year Outcomes of Neovascular Age-Related Macular Degeneration in Eyes That Do Not Develop Macular Atrophy or Subretinal Fibrosis.
To report the 36-month treatment outcomes of eyes with neovascular age-related macular degeneration (nAMD) receiving vascular endothelial growth factor (VEGF) inhibitors in daily practice who did not develop either subretinal fibrosis (SRFi) or macular atrophy (MA). This is a retrospective analysis of data from the Fight Retinal Blindness registry. Treatment-naïve eyes starting intravitreal injection of VEGF inhibitors for nAMD from January 1, 2010, to September 1, 2017, and did not have SRFI and MA at baseline were tracked. We identified 2478 eligible eyes, of which 1712 eyes did not develop SRFi or MA, 291 developed extrafoveal SRFI or MA, and 475 developed subfoveal SRFi or MA over 36 months. The estimated visual acuity stabilized from 6 months to 36 months in eyes that did not develop SRFI or MA with a mean (95% confidence interval [CI]) change in VA of -1 (-2, 0) letters, whereas eyes that developed extrafoveal (-3 [-5, -2] letters) or subfoveal (-10 [-11, -8] letters) SRFi or MA declined in vision in the same period. Eyes with no or extrafoveal SRFi or MA over 36 months were more likely to maintain their visual improvement from six months to 36 months (odds ratio [OR; 95% CI] = 2.3 [1.5, 3.3] for absence vs. subfoveal SRFi or MA, P ≤ 0.01 and OR = 2.0 [1.2, 3.4] for extrafoveal vs. subfoveal MA or SRFi, P = 0.01). Treatment-naïve nAMD eyes receiving VEGF inhibitors maintain their initial six-month visual improvement over three years if they do not develop SRFI or MA. The nAMD is still a major cause of blindness despite antiangiogenic treatments. We found that eyes that did not develop subretinal fibrosis or macular atrophy maintained their initial vision improvement for at least three years, suggesting that identifying treatments for these complications is the final barrier to achieving excellent outcomes in nAMD.


Neuropathic features of joint pain: a community-based study.
Quantitative sensory testing (QST) and questionnaire-based assessments have been used to demonstrate features of neuropathic pain in subjects with musculoskeletal pain. However, their direct relationship has not been investigated in the community. The purpose of this study was to conduct an observational study to describe the characteristics of joint pain and to examine the relationship between QST measures and the PainDETECT Questionnaire (PD-Q). Warm detection, heat pain, and mechanical pain thresholds as well as mechanical pain sensitivity over the sternum were determined and the PD-Q scores were calculated in a cross-sectional study of 462 participants in the Chingford Study. Comparisons were made between subjects with and those without joint pain. Logistic regression modeling was used to describe the association between neuropathic pain features, as determined by the PD-Q score, and each of the QST measures individually, adjusting for age, body mass index, and use of pain-modifying medications. A total of 66.2% of the subjects reported recent joint pain, with a median average pain severity of 5 of 10. There was increased sensitivity to painful stimuli in the group with pain as compared to the pain-free group, and this persisted after stratification by pain-modifying medication use. While only 6.7% of subjects had possible neuropathic pain features and 1.9% likely neuropathic pain features according to the standard PD-Q thresholds, features of neuropathic pain were common and were present in >50% of those reporting pain of at least moderate severity. Heat pain thresholds and mechanical pain sensitivity were significantly associated with features of neuropathic pain identified using the PD-Q, with an odds ratio (OR) of 0.88 (95% confidence interval [95% CI] 0.79-0.97; P = 0.011) and an OR of 1.24 (95% CI 1.04-1.48; P = 0.018), respectively. QST measures and the PD-Q identified features of neuropathic pain in subjects in this community-based study, with significant overlap between the findings of the two techniques.


A Digital Health Innovation to Prevent Relapse and Support Recovery in Youth Receiving Specialized Services for First-Episode Psychosis: Protocol for a Pilot Pre-Post, Mixed Methods Study of Horyzons-Canada (Phase 2).
Psychotic disorders are among the most disabling of all mental disorders. The first-episode psychosis (FEP) often occurs during adolescence or young adulthood. Young people experiencing FEP often face multiple barriers in accessing a comprehensive range of psychosocial services, which have predominantly been delivered in person. New models of service delivery that are accessible, sustainable, and engaging are needed to support recovery in youth diagnosed with FEP. In this paper, we describe a protocol to implement and evaluate the acceptability, safety, and potential efficacy of an online psychosocial therapeutic intervention designed to sustain recovery and prevent relapses in young adults diagnosed with FEP. This intervention was originally developed and tested in Australia and has been adapted for implementation and evaluation in Canada and is called Horyzons-Canada (HoryzonsCa). This cohort study is implemented in a single-center and applies a pre-post mixed methods (qualitative-quantitative convergent) design. The study involves recruiting 20 participants from a specialized early intervention program for psychosis located in Montreal, Canada and providing them with access to the HoryzonsCa intervention for 8 weeks. Data collection includes interview-based psychometric measures, self-reports, focus groups, and interviews. This study received funding from the Brain and Behavior Research Foundation (United States), the Quebec Health Research Funding Agency (Canada), and the Canada Research Chairs Program. The study was approved by the Research Ethics Board of the Centre intégré universitaire de santé et de services sociaux de l'Ouest-de-l'Île-de-Montréal on April 11, 2018 (#IUSMD 17-54). Data were collected from August 16, 2018, to April 29, 2019, and a final sample of 20 individuals participated in the baseline and follow-up interviews, among which 9 participated in the focus groups. Data analysis and reporting are in process. The results of the study will be submitted for publication in 2021. This study will provide preliminary evidence on the acceptability, safety, and potential efficacy of using a digital health innovation adapted for the Canadian context to deliver specialized mental health services to youth diagnosed with FEP. ISRCTN Registry ISRCTN43182105; https://www.isrctn.com/ISRCTN43182105. RR1-10.2196/28141.


Mitochondrial aging: open questions.
Interest in the role of mitochondria in aging has intensified in recent years. This focus on mitochondria originated in part from the free radical theory of aging, which argues that oxidative damage plays a key role in degenerative senescence. Among the numerous mechanisms known to generate oxidants, leakage of the superoxide anion and hydrogen peroxide from the mitochondrial electron transport chain are of particular interest, due to the correlation between species-specific metabolic rate ("rate of living") and life span. Phenomenological studies of mitochondrial function long ago noted a decline in mitochondrial function with age, and on-going research continues to add to this body of knowledge. The extranuclear somatic mutation theory of aging proposes that the accumulation of mutations in the mitochondrial genome may be responsible in part for the mitochondrial phenomenology of aging. Recent studies of mitochondrial DNA (mtDNA) deletions have shown that they increase with age in humans and other mammals. Currently, there exist numerous important and fundamental questions surrounding mitochondria and aging. Among these are (1) How important are mitochondrial oxidants in determining overall cellular oxidative stress? (2) What are the mechanisms of mitochondrial oxidant generation? (3) How are lesions and mutations in mtDNA formed? (4) How important are mtDNA lesions and mutations in causing mitochondrial dysfunction? (5) How are mitochondria regulated, and how does this regulation change during aging? (6) What are the dynamics of mitochondrial turnover? (7) What is the relationship between mitochondrial damage and lipofuscinogenesis? (8) What are the relationships among mitochondria, apopotosis, and aging? and (9) How can mitochondrial function (ATP generation and the establishment of a membrane potential) and dysfunction (oxidant generation) be modulated and degenerative senescence thereby treated?


Axons provide the secretory machinery for trafficking of voltage-gated sodium channels in peripheral nerve.
The regulation of the axonal proteome is key to generate and maintain neural function. Fast and slow axoplasmic waves have been known for decades, but alternative mechanisms to control the abundance of axonal proteins based on local synthesis have also been identified. The presence of the endoplasmic reticulum has been documented in peripheral axons, but it is still unknown whether this localized organelle participates in the delivery of axonal membrane proteins. Voltage-gated sodium channels are responsible for action potentials and are mostly concentrated in the axon initial segment and nodes of Ranvier. Despite their fundamental role, little is known about the intracellular trafficking mechanisms that govern their availability in mature axons. Here we describe the secretory machinery in axons and its contribution to plasma membrane delivery of sodium channels. The distribution of axonal secretory components was evaluated in axons of the sciatic nerve and in spinal nerve axons after in vivo electroporation. Intracellular protein trafficking was pharmacologically blocked in vivo and in vitro. Axonal voltage-gated sodium channel mRNA and local trafficking were examined by RT-PCR and a retention-release methodology. We demonstrate that mature axons contain components of the endoplasmic reticulum and other biosynthetic organelles. Axonal organelles and sodium channel localization are sensitive to local blockade of the endoplasmic reticulum to Golgi transport. More importantly, secretory organelles are capable of delivering sodium channels to the plasma membrane in isolated axons, demonstrating an intrinsic capacity of the axonal biosynthetic route in regulating the axonal proteome in mammalian axons.


Engineering therapeutic antibodies targeting G-protein-coupled receptors.
G-protein-coupled receptors (GPCRs) are one of the most attractive therapeutic target classes because of their critical roles in intracellular signaling and their clinical relevance to a variety of diseases, including cancer, infection and inflammation. However, high conformational variability, the small exposed area of extracellular epitopes and difficulty in the preparation of GPCR antigens have delayed both the isolation of therapeutic anti-GPCR antibodies as well as studies on the structure, function and biochemical mechanisms of GPCRs. To overcome the challenges in generating highly specific anti-GPCR antibodies with enhanced efficacy and safety, various forms of antigens have been successfully designed and employed for screening with newly emerged systems based on laboratory animal immunization and high-throughput-directed evolution.


Initial and Progressive Gray Matter Abnormalities in Insular Gyrus and Temporal Pole in First-Episode Schizophrenia Contrasted With First-Episode Affective Psychosis.
Although the insula and temporal pole (TP) of paralimbic regions are important in both affective and cognitive processing, it is not well known whether gray matter volume (GMV) abnormalities in these regions show post-onset progression and differentially affect first-episode schizophrenia (FESZ) and first-episode affective psychosis (FEAFF) patients. To determine whether there are initial and progressive GMV deficits in insula and TP in FESZ and FEAFF (mainly manic) patients, their relative specificity to FESZ or FEAFF, and relationship to symptoms, we conducted a naturalistic study at first hospitalization for psychosis and follow-up ~1.5 years later. Initial 1.5T magnetic resonance imaging (MRI) scans and follow-up scans were on the same scanner. Twenty-two FESZ, 23 FEAFF, and 23 healthy control (HC) subjects were group matched for age, gender, parental socioeconomic status, and handedness. At first hospitalization, FESZ showed significantly smaller bilateral insular GMV compared with FEAFF, and smaller left TP GMV compared with FEAFF and HC. Moreover, on 1.5 years follow-up, FESZ showed progressive GMV decreases in bilateral insula compared with FEAFF and HC, and in TP GMV compared with HC. In contrast, FEAFF showed no progression. Progression of FESZ GMV in both insula and TP was inversely associated with changes in the overall Brief Psychiatric Rating Scale symptom score, indicating less improvement or worsening of symptoms.


The Non-Profit Sector: Leveraging Resources and Strengths to Promote More Physically Active Lifestyles.
Many Americans do not meet current minimum physical activity recommendations. Although the choice to be physically active is made by individuals, that choice is affected by the social and physical environments in which people live, work, play and learn. Creating environments that are more supportive of physical activity will require policies, practices and programs that individuals may not be able to influence on their own; such changes will require comprehensive, coordinated and collaborative action by a variety of organizational sectors at national, state and local levels. Because of their core-and frequently unique-competencies, many non-profit organizations are poised to be active players in promoting important changes in policy and community environments that can facilitate lifelong physical activity for all Americans. Review of mission statements and strategic plans of a variety of non-profit organizations reveal key characteristics and competencies that can be leveraged, frequently across multiple levels and sectors, to promote physical activity. Nonprofit organizations should leverage their unique capabilities, particularly in the areas of advocacy, strategic collaborations and outreach to their membership, volunteer and/or constituent bases to promote policy and environmental changes in support of physical activity.


Updated US Public Health Service guidelines for the management of occupational exposures to human immunodeficiency virus and recommendations for postexposure prophylaxis.
This report updates US Public Health Service recommendations for the management of healthcare personnel (HCP) who experience occupational exposure to blood and/or other body fluids that might contain human immunodeficiency virus (HIV). Although the principles of exposure management remain unchanged, recommended HIV postexposure prophylaxis (PEP) regimens and the duration of HIV follow-up testing for exposed personnel have been updated. This report emphasizes the importance of primary prevention strategies, the prompt reporting and management of occupational exposures, adherence to recommended HIV PEP regimens when indicated for an exposure, expert consultation in management of exposures, follow-up of exposed HCP to improve adherence to PEP, and careful monitoring for adverse events related to treatment, as well as for virologic, immunologic, and serologic signs of infection. To ensure timely postexposure management and administration of HIV PEP, clinicians should consider occupational exposures as urgent medical concerns, and institutions should take steps to ensure that staff are aware of both the importance of and the institutional mechanisms available for reporting and seeking care for such exposures. The following is a summary of recommendations: (1) PEP is recommended when occupational exposures to HIV occur; (2) the HIV status of the exposure source patient should be determined, if possible, to guide need for HIV PEP; (3) PEP medication regimens should be started as soon as possible after occupational exposure to HIV, and they should be continued for a 4-week duration; (4) new recommendation-PEP medication regimens should contain 3 (or more) antiretroviral drugs (listed in Appendix A ) for all occupational exposures to HIV; (5) expert consultation is recommended for any occupational exposures to HIV and at a minimum for situations described in Box 1 ; (6) close follow-up for exposed personnel ( Box 2 ) should be provided that includes counseling, baseline and follow-up HIV testing, and monitoring for drug toxicity; follow-up appointments should begin within 72 hours of an HIV exposure; and (7) new recommendation-if a newer fourth-generation combination HIV p24 antigen-HIV antibody test is utilized for follow-up HIV testing of exposed HCP, HIV testing may be concluded 4 months after exposure ( Box 2 ); if a newer testing platform is not available, follow-up HIV testing is typically concluded 6 months after an HIV exposure.


Cognitive therapy and pharmacotherapy for depression. Sustained improvement over one year.
Seventy patients with nonbipolar affective disorder who completed a 12-week course of either cognitive therapy (CT), pharmacotherapy, CT plus active placebo, or CT plus pharmacotherapy were assessed one month, six months, and one year after termination of active treatment. Of the 44 patients who had originally responded to treatment, 16 relapsed as defined by reentry into treatment or by self-reported depression scores in the moderately depressed range. Twenty-eight patients remained well during the one-year follow-up. Patients with relatively high levels of remaining depressive symptoms on completion of treatment relapsed more often than those who had little or no residual depression. Further, at treatment termination, patients who relapsed had significantly higher scores on a measure of dysfunctional attitudes. Patients who had received CT (with or without tricyclic antidepressants) were less likely to relapse in the one-year follow-up period than patients who received pharmacotherapy.


Arterial reconstructions associated with the resection of malignant tumors.
When trunk arteries are affected by malignant neoplasia, and surgical treatment involving tumor and arterial resection is used, the vascular reconstruction must be performed immediately to avoid ischemia in the brain and large tissue masses. The objective of this study was to analyze the results obtained with the treatment of patients with malignant neoplasia who underwent tumor and vascular resection associated with arterial reconstruction. The primary patency of reconstructions, the occurrence arterial complications, and patient survival were assessed. Thirty-six patients with cervical, abdominal, or lower limb neoplasias were followed up. These patients underwent elective operations at Hospital do Câncer A.C. Camargo, São Paulo, between September 1997 and September 2004. They were divided into 3 groups according to tumor location: Cervical (14), lower limbs (13), and Abdomen (9). Thirty-eight arterial reconstructions were performed in these 36 patients. There were 5 arterial complications: 2 early- and 3 late-stage. The early complications consisted of 1 symptomatic carotid occlusion with sequelae and 1 femoral graft rupture without sequelae. The late-stage complications consisted of 1 symptomatic carotid occlusion, 1 occlusion of an axillary-carotid graft, and 1 occlusion of a branch of the aortobifemoral graft, all without sequelae. There was no difference between the primary arterial patency rates. All the deaths (22) resulted from progression of neoplasic disease. Arterial reconstructions associated with resection of malignant neoplasia in cervical, abdominal, or lower limbs can be carried out with low rates of morbidity and mortality. There was no difference in the primary arterial patency rates among the groups studied.


The paradox of excellence.
Why is it that so many smart, ambitious professionals are less productive and satisfied than they could be? Thomas DeLong, an academic and consultant to executives, and Sara DeLong, a psychiatrist, argue that it's often because they're afraid to demonstrate any sign of weakness. They're reluctant to ask important questions or try new approaches that push them outside their comfort zones. For high achievers, looking stupid or incompetent is anathema. So they stick to the tasks they're good at, even while the rest of the organization may be passing them by. In short, they'd rather do the wrong thing well than do the right thing poorly. They get stuck in this unproductive and unfulfilling pattern and can't break free. Of course, leaders in organizations bear some of the blame for this type of play-it-safe mind-set. They don't always want to hear that a person is struggling, nor do they necessarily reward risk taking, even though they might pay lip service to innovative initiative. The authors outline several steps that individuals can take to shake off fear and paralysis, including looking at past negative experiences from somebody else's point of view and seeking out safe ways to allow themselves to become vulnerable.


Lewis-Acid Doping of Triphenylamine-Based Hole Transport Materials Improves the Performance and Stability of Perovskite Solar Cells.
Highly efficient perovskite solar cells (PSCs) fabricated in the classic n-i-p configuration generally employ triphenylamine-based hole-transport layers (HTLs) such as spiro-OMeTAD, PTAA, and poly-TPD. Controllable doping of such layers has been critical to achieve increased conductivity and high device performance. To this end, LiTFSI/tBP doping and subsequent air exposure is widely utilized. However, this approach often leads to low device stability and reproducibility. Departing from this point, we introduce the Lewis acid tris(pentafluorophenyl)borane (TPFB) as an effective dopant, resulting in a significantly improved conductivity and lowered surface potential for triphenylamine-based HTLs. Here, we specifically investigated spiro-OMeTAD, which is the most widely used HTL for n-i-p devices, and revealed improved power conversion efficiency (PCE) and stability of the PSCs. Further, we demonstrated the applicability of TPFB doping to other triphenylamine-based HTLs. Spectroscopic characterizations reveal that TPFB doping results in significantly improved charge transport and reduced recombination losses. Importantly, the TPFB-doped perovskite devices retained near 85% of the initial PCE after 1000 h of storage in the air, while the conventional LiTFSI-doped device dropped to 75%. Finally, we give insight into utilizing other similar molecular dopants such as fluorine-free triphenylborane and phosphorus-centered tris(pentafluorophenyl)phosphine (TPFP) by density functional theory analysis underscoring the significance of the central boron atom and fluorination in TPFB for the formation of Lewis acid-base adducts.


Smoking and polymorphisms of genes encoding mannose-binding lectin and surfactant protein-D in patients with rheumatoid arthritis.
To investigate whether polymorphisms in genes coding for mannose-binding lectin (MBL) and surfactant protein-D (SP-D) are associated directly or by interaction with smoking with rheumatoid arthritis (RA), anti-citrullinated peptide antibody (ACPA) positive RA, and erosive RA. MBL2 genotypes, SFTPD genotype at codon 11, and HLA-shared epitope were determined in 456 patients with rheumatoid arthritis and 533 sex- and age-matched controls. Patients were grouped according to the presence of ACPA antibodies and RA-associated bone erosions and sub-stratified according to smoking status as never or ever smokers. Odds ratios with 95% confidence interval (OR, 95% CI) were calculated using multiple logistic regression analyses controlling for shared epitope. The low-producing SFTPD genotype was not associated with risk of RA or ACPA positive RA, but with erosive disease in the RA patients (OR = 1.8; 95% CI 1.1-3.0) particularly in RA ever smokers (OR = 2.4; 95% CI 1.3-4.3). The high-producing MBL2 genotype YA/YA was associated with ACPA positive RA (OR = 1.4; 95% CI 1.0-1.9) and erosive joint disease in RA ever smokers (OR = 1.8; 95% CI 1.1-3.0). Genetic disposition for low SP-D was not associated with RA but with erosive RA by interaction with smoking. The genetic disposition for high MBL production was associated with ACPA positive RA irrespective of shared epitope. The findings need to be replicated but do as such offer further explanations for the clinical heterogeneity of RA.


Reduction of stimulus artifact in somatosensory evoked potentials: segmented versus subthreshold training.
A new approach to stimulus artifact cancellation is introduced, which attempts to model the process of stimulus artifact generation. This is done by training an estimator with multiple exemplars of the stimulus artifact at levels below the threshold of evoked response stimulation. Two estimators are formulated: one using a dynamic neural network and another using a linear estimator. The performance of these new approaches is compared to the segmented training approach, which has been previously demonstrated to be one of the most capable methods available. Performance assessment is carried out using a novel metric introduced in this paper, which focuses upon the relevant portion of the recorded waveform. The new cancellation schemes show distinct performance advantages over the segmented training approach.


Parasitological surveillance in a rat (Rattus norvegicus) colony in São Paulo Zoo animal house
Rattus norvegicus (Mammalia: Rodentia) is a widespread and synanthropic rodent, broadly used in medical experiments. It can also be used for feeding captive animals in zoos. Parasitological surveys are important to guarantee the health of both the animals and the staff responsible for their management. The aim of this study was to identify intestinal parasites of Rattus norvegicus offered as food to captive animals from São Paulo Zoo, and demonstrate the importance of sanitary hurdling, disease control and biosecurity. The identified protozoan parasites were Eimeria sp., Entamoeba sp., Spironucleus sp., Giardia sp., Tritrichomonas sp., Chilomastix sp., unidentified cysts and non-sporulated coccidians oocysts (Isospora/Eimeria). The following helminths were found: Syphacia muris, Rodentolepis nana and Aspiculuris tetraptera.


A pair of centromeric proteins mediates reproductive isolation in Drosophila species.
Speciation involves the reproductive isolation of natural populations due to the sterility or lethality of their hybrids. However, the molecular basis of hybrid lethality and the evolutionary driving forces that provoke it remain largely elusive. The hybrid male rescue (Hmr) and the lethal hybrid rescue (Lhr) genes serve as a model to study speciation in Drosophilids because their interaction causes lethality in male hybrid offspring. Here, we show that HMR and LHR form a centromeric complex necessary for proper chromosome segregation. We find that the Hmr expression level is substantially higher in Drosophila melanogaster, whereas Lhr expression levels are increased in Drosophila simulans. The resulting elevated amount of HMR/LHR complex in hybrids results in an extensive mislocalization of the complex, an interference with the regulation of transposable elements, and an impairment of cell proliferation. Our findings provide evidence for a major role of centromere divergence in the generation of biodiversity.


Antibody response to sheep red blood cells in major histocompatibility (B) complex aneuploid line of chickens.
An integral part of the immune response is the production of antibodies specific for different antigenic challenges. Genes of the MHC encode products that regulate immunity. This study utilized the FCT-15 line of chickens, which is aneuploid for the chromosome containing the ribosomal RNA genes (rDNA) and the MHC or B complex to determine whether an antibody response to SRBC would vary as a function of B complex gene dose. Mating of trisomic parents (B15B15B15) animals produced progeny having either a disomic (B15B15), trisomic (B15B15B15), or tetrasomic (B15B15B15B15) B complex dosage. The number of B/rDNA chromosomes, and thus the B complex dosage was determined by feather pulp nucleolar typing of chicks at hatch. A 5% SRBC antigenic challenge, which induces a T cell-dependent antibody response, was injected at 6 wk of age. Samples taken prior to SRBC injection as well as 5, 8, and 12 d postinjection were assayed for total and mercaptoethanol-resistant antibody. Peak antibody titers (log2), day of peak titer and rate of titer decline were calculated using a quadratic equation for each bird. Differences among the three B complex dosages were evaluated by analysis of variance. Antibody titers rose from 5 to 8 d postinjection and declined thereafter without significant differences among the three B complex doses. Calculations from the quadratic equations showed that B complex dose affected neither peak antibody titer nor day of peak titer. However, trisomic and tetrasomic animals had significantly more rapid rates of decline from the maximum titer. In aneuploid chickens, changes in antigen processing, antigen presentation, or persistence of processed antigen may maintain levels of antibody production found in disomic chickens and explain the more rapid decline of titer.


Effect of accelerated aging of MSWI bottom ash on the leaching mechanisms of copper and molybdenum.
The effect of accelerated aging of Municipal Solid Waste Incinerator (MSWI) bottom ash on the leaching of Cu and Mo was studied using a "multisurface" modeling approach, based on surface complexation to iron/aluminum (hydr)oxides, mineral dissolution/precipitation, and metal complexation by humic substances. A novel experimental method allowed us to identify that the solid/liquid partitioning of fulvic acids (FA) quantitatively explains the observed beneficial effect of accelerated aging on the leaching of Cu. Our results suggestthat iron/aluminum (hydr)oxides are the major reactive surfaces that retain fulvic acid in the bottom ash matrix, of which the aluminum (hydr)oxides were found to increase after aging. A new modeling approach, based on the surface complexation of FA on iron/aluminum (hydr)oxides is developed to describe the pH-dependent leaching of FA from MSWI bottom ash. Accelerated aging results in enhanced adsorption of FA to (neoformed) iron/aluminum (hydr)oxides, leading to a significant decrease in the leaching of FA and associated Cu. Accelerated aging was also found to reduce the leaching of Mo, which is also attributed to enhanced adsorption to (neoformed) iron/aluminum (hydr)oxides. These findings provide important new insights that may help to improve accelerated aging technology.


Survival and prognostic factors in patients with connective tissue disease-associated pulmonary hypertension diagnosed by echocardiography: results from a Korean nationwide registry.
Pulmonary arterial hypertension (PAH) is a major cause of mortality in connective tissue disease (CTD). The survival rates and mortality-predictive factors of a nationwide registry of Korean patients with CTD-PH measured by echocardiography were determined. Patients with CTD-PH were enrolled between April 2008 and December 2012. Hemodynamic parameters and clinical data (WHO-functional class [FC], organ involvement, laboratory tests and treatment agents) were recorded. Survival rates were calculated by using the Kaplan-Meier method. Mortality-associated factors were examined by Cox proportional hazards regression analysis. In total, 174 incident PH cases (61 with systemic lupus erythematosus, 50 with systemic sclerosis, 10 with mixed CTD, 22 with rheumatoid arthritis (RA) and 31 with other CTDs) were diagnosed by Doppler echocardiography. Of these, 25 (14%) died during the 3.8 ± 2.7 year follow-up period after PH diagnosis. The 1- and 3-year survival rates were 90.7% and 87.3%, respectively. Compared to the other CTD-PHs, RA-PH had the lowest survival rates (56% 3 year survival; P = 0.022). Multiple regression analysis revealed that low diffusion capacity of carbon monoxide (DLCO), pleural effusion and diabetes mellitus were poor prognostic factors (P = 0.008, 0.04 and 0.009, respectively). Anti-UI-RNP (ribonucleoprotein) antibody positivity was protective (P = 0.022). In patients with WHO-FC III/IV, patients who received vasodilators had lower mortality than those who did not (P = 0.038). In Korean patients with CTD-PH, the 3-year survival rate was 87%. Low diffusion capacity of carbon monoxide (DLCO), pleural effusion and diabetes mellitus were independent poor prognostic factors. Anti-UI-RNP antibody was protective. Prompt PAH-specific vasodilator therapy may improve the survival of patients with severe CTD-PH.


Simultaneous detection of ultraviolet B-induced DNA damage using capillary electrophoresis with laser-induced fluorescence.
An immunoassay based on CE-LIF was developed for the simultaneous detection of cyclobutane pyrimidine dimers (CPDs) and pyrimidine 6-4 pyrimidone photoproducts (6-4PPs) in genomic DNA irradiated with UVB or natural sunlight. Human cells were first exposed to varying amounts of UVB or natural sunlight to induce DNA damage. Genomic DNA was extracted and incubated with anti-CPD and anti-6-4PP primary antibodies attached to secondary antibodies with a fluorescent quantum dot (QD) reporter that emitted either red or yellow fluorescence. CE was used to separate the unbound antibodies from those bound to the photoproducts, and LIF with appropriate optical filters was used to separate the fluorescence signals from each QD to individual photomultiplier tubes for simultaneous photoproduct detection. Using this strategy, photoproducts were detected from ∼6 ng (200 ng μL(-1)) of DNA under a low UVB fluence of 65 J m(-2) for CPDs or 195 J m(-2) for 6-4PPs. This assay was also the first to demonstrate the detection of CPDs in human cells after only 15 min of irradiation under natural sunlight.


A comprehensive map coupling histone modifications with gene regulation in adult dopaminergic and serotonergic neurons.
The brain is composed of hundreds of different neuronal subtypes, which largely retain their identity throughout the lifespan of the organism. The mechanisms governing this stability are not fully understood, partly due to the diversity and limited size of clinically relevant neuronal populations, which constitute a technical challenge for analysis. Here, using a strategy that allows for ChIP-seq combined with RNA-seq in small neuronal populations in vivo, we present a comparative analysis of permissive and repressive histone modifications in adult midbrain dopaminergic neurons, raphe nuclei serotonergic neurons, and embryonic neural progenitors. Furthermore, we utilize the map generated by our analysis to show that the transcriptional response of midbrain dopaminergic neurons following 6-OHDA or methamphetamine injection is characterized by increased expression of genes with promoters dually marked by H3K4me3/H3K27me3. Our study provides an in vivo genome-wide analysis of permissive/repressive histone modifications coupled to gene expression in these rare neuronal subtypes.


Recent advances in nitric oxide delivery for antimicrobial applications using polymer-based systems.
The nitric oxide (NO) molecule has gained increasing attention in biological applications to combat biofilm-associated bacterial infections. However, limited NO loading, relatively short half-lives of low molecular weight NO donor compounds, and difficulties in targeted delivery of NO have hindered their practical clinical administration. To overcome these drawbacks, the combination of NO and scaffolds based on biocompatible polymers is an effective way towards realizing the practical utility of NO in biomedical applications. In this regard, the present overview highlights the recent developments in NO-releasing polymeric biomaterials for antimicrobial applications, focusing on antibiofilm treatments and the challenges that need to be overcome.


JASS: command line and web interface for the joint analysis of GWAS results.
Genome-wide association study (GWAS) has been the driving force for identifying association between genetic variants and human phenotypes. Thousands of GWAS summary statistics covering a broad range of human traits and diseases are now publicly available. These GWAS have proven their utility for a range of secondary analyses, including in particular the joint analysis of multiple phenotypes to identify new associated genetic variants. However, although several methods have been proposed, there are very few large-scale applications published so far because of challenges in implementing these methods on real data. Here, we present JASS (Joint Analysis of Summary Statistics), a polyvalent Python package that addresses this need. Our package incorporates recently developed joint tests such as the omnibus approach and various weighted sum of Z-score tests while solving all practical and computational barriers for large-scale multivariate analysis of GWAS summary statistics. This includes data cleaning and harmonization tools, an efficient algorithm for fast derivation of joint statistics, an optimized data management process and a web interface for exploration purposes. Both benchmark analyses and real data applications demonstrated the robustness and strong potential of JASS for the detection of new associated genetic variants. Our package is freely available at https://gitlab.pasteur.fr/statistical-genetics/jass.


The collaborative care project: A practice-based approach to interprofessional education in a primary healthcare setting in South Africa.
There is global evidence that primary healthcare (PHC) leads to improved health outcomes. In the South Africa PHC model, the PHC team identifies healthcare needs through community visits. For health professional students to learn this PHC model requires an immersed, interprofessional community experience. A select number of final year undergraduate health science students from Stellenbosch University, South Africa spend six weeks to one full year working at a rural clinical school with the focus on contextualised, transformative and interprofessional clinical training. The collaborative care project is one of the opportunities aimed at exposing students to contextual interprofessional training in a resource constrained community. Students are challenged to collaboratively find potential solutions to problems patients face using local resources, with the aim of improving patient outcomes and transforming students into collaborative change agents. Students, under the supervision of local community health workers, are tasked with conducting interprofessional home visits for discharged patients or patients identified by community members. Possible environmental, personal and health risk factors are identified and referrals made to existing community or state facilities for further management. The collaborative care project has resulted in improved patient identification, accessibility to available resources and referral. Students recognise the value of contextualised collaborative clinical training to shape them as clinicians. Challenges and successes are shared to encourage more practical, community based opportunities for collaborative care. Reciprocal teaching and learning take place and students express a change in self-perception, team identity and improved role clarification. This project creates an opportunity for students and community to improve their understanding of precipitating factors to illness, which are not often considered as routine health care and to find local solutions to problems identified.


Docking and Linking of Fragments To Discover Jumonji Histone Demethylase Inhibitors.
Development of tool molecules that inhibit Jumonji demethylases allows for the investigation of cancer-associated transcription. While scaffolds such as 2,4-pyridinedicarboxylic acid (2,4-PDCA) are potent inhibitors, they exhibit limited selectivity. To discover new inhibitors for the KDM4 demethylases, enzymes overexpressed in several cancers, we docked a library of 600,000 fragments into the high-resolution structure of KDM4A. Among the most interesting chemotypes were the 5-aminosalicylates, which docked in two distinct but overlapping orientations. Docking poses informed the design of covalently linked fragment compounds, which were further derivatized. This combined approach improved affinity by ∼ 3 log-orders to yield compound 35 (Ki = 43 nM). Several hybrid inhibitors were selective for KDM4C over the related enzymes FIH, KDM2A, and KDM6B while lacking selectivity against the KDM3 and KDM5 subfamilies. Cocrystal structures corroborated the docking predictions. This study extends the use of structure-based docking from fragment discovery to fragment linking optimization, yielding novel KDM4 inhibitors.


Genomic and Ecogenomic Characterization of Proteus mirabilis Bacteriophages.
Proteus mirabilis often complicates the care of catheterized patients through the formation of crystalline biofilms which block urine flow. Bacteriophage therapy has been highlighted as a promising approach to control this problem, but relatively few phages infecting P. mirabilis have been characterized. Here we characterize five phages capable of infecting P. mirabilis, including those shown to reduce biofilm formation, and provide insights regarding the wider ecological and evolutionary relationships of these phages. Transmission electron microscopy (TEM) imaging of phages vB_PmiP_RS1pmA, vB_PmiP_RS1pmB, vB_PmiP_RS3pmA, and vB_PmiP_RS8pmA showed that all share morphologies characteristic of the Podoviridae family. The genome sequences of vB_PmiP_RS1pmA, vB_PmiP_RS1pmB, and vB_PmiP_RS3pmA showed these are species of the same phage differing only by point mutations, and are closely related to vB_PmiP_RS8pmA. Podophages characterized in this study were also found to share similarity in genome architecture and composition to other previously described P. mirabilis podophages (PM16 and PM75). In contrast, vB_PimP_RS51pmB showed morphology characteristic of the Myoviridae family, with no notable similarity to other phage genomes examined. Ecogenomic profiling of all phages revealed no association with human urinary tract viromes, but sequences similar to vB_PimP_RS51pmB were found within human gut, and human oral microbiomes. Investigation of wider host-phage evolutionary relationships through tetranucleotide profiling of phage genomes and bacterial chromosomes, indicated vB_PimP_RS51pmB has a relatively recent association with Morganella morganii and other non-Proteus members of the Morganellaceae family. Subsequent host range assays confirmed vB_PimP_RS51pmB can infect M. morganii.


A review of creatine supplementation in age-related diseases: more than a supplement for athletes.
Creatine is an endogenous compound synthesized from arginine, glycine and methionine. This dietary supplement can be acquired from food sources such as meat and fish, along with athlete supplement powders. Since the majority of creatine is stored in skeletal muscle, dietary creatine supplementation has traditionally been important for athletes and bodybuilders to increase the power, strength, and mass of the skeletal muscle. However, new uses for creatine have emerged suggesting that it may be important in preventing or delaying the onset of neurodegenerative diseases associated with aging. On average, 30% of muscle mass is lost by age 80, while muscular weakness remains a vital cause for loss of independence in the elderly population. In light of these new roles of creatine, the dietary supplement's usage has been studied to determine its efficacy in treating congestive heart failure, gyrate atrophy, insulin insensitivity, cancer, and high cholesterol. In relation to the brain, creatine has been shown to have antioxidant properties, reduce mental fatigue, protect the brain from neurotoxicity, and improve facets/components of neurological disorders like depression and bipolar disorder. The combination of these benefits has made creatine a leading candidate in the fight against age-related diseases, such as Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, long-term memory impairments associated with the progression of Alzheimer's disease, and stroke. In this review, we explore the normal mechanisms by which creatine is produced and its necessary physiology, while paying special attention to the importance of creatine supplementation in improving diseases and disorders associated with brain aging and outlining the clinical trials involving creatine to treat these diseases.


Food web persistence is enhanced by non-trophic interactions.
The strength of interspecific interactions is often proposed to affect food web stability, with weaker interactions increasing the persistence of species, and food webs as a whole. However, the mechanisms that modify interaction strengths, and their effects on food web persistence are not fully understood. Using food webs containing different combinations of predator, prey, and nonprey species, we investigated how predation risk of susceptible prey is affected by the presence of species not directly trophically linked to either predators or prey. We predicted that indirect alterations to the strength of trophic interactions translate to changes in persistence time of extinction-prone species. We assembled interaction webs of protist consumers and turbellarian predators with eight different combinations of prey, predators and nonprey species, and recorded abundances for over 130 prey generations. Persistence of predation-susceptible species was increased by the presence of nonprey. Furthermore, multiple nonprey species acted synergistically to increase prey persistence, such that persistence was greater than would be predicted from the dynamics of simpler food webs. We also found evidence suggesting increased food web complexity may weaken interspecific competition, increasing persistence of poorer competitors. Our results demonstrate that persistence times in complex food webs cannot be predicted from the dynamics of simplified systems, and that species not directly involved in consumptive interactions likely play key roles in maintaining persistence. Global species diversity is currently declining at an unprecedented rate and our findings reveal that concurrent loss of species that modify trophic interactions may have unpredictable consequences for food web stability.


High and low dietary potassium effects on rat vascular sodium pump activity.
Studies of renal and other tissues suggest that chronic elevation or reduction of dietary potassium intake could affect vascular smooth muscle sodium pump (Na-pump) activity. To examine this possibility, the effects of 3 weeks of low (LK: 4 mmole KCl/kg chow), normal (NK; 162 mmole/kg), and high (HK; 1350 mmole/kg) dietary potassium intake on Na-pump activity, the Na-pump activity response to changes in extracellular potassium concentration, and Na-pump site density were determined in tail arteries of rats. Plasma potassium concentration was elevated by 21% in HK rats and reduced by 45% in LK rats. When incubated in autologous plasma, compared to arteries from NK rats, Na-pump activity was decreased in the tail arteries from LK rats but not altered in those from HK rats. When arteries from NK and LK rats were incubated in autologous plasma with the potassium concentration increased to equal that of the HK rats, Na-pump activity exceeded that of HK rat arteries: Na-pump activity of arteries incubated in autologous plasma did not differ from that of arteries incubated in Krebs-Henseleit buffer with the potassium concentration adjusted to equal that of the plasma. Tail artery Na-pump activity for all three dietary potassium groups increased as potassium concentration of the incubation medium was increased from 1 to 12 mM; Na-pump activity was similar for the NK and LK rats at all potassium concentrations, but Na-pump activity of HK rat arteries was less than that of NK arteries at high extracellular potassium concentrations. Na-pump site density was not altered by either HK or LK diet. It is concluded that in tail arteries of rats fed the LK diet, chronically decreased extracellular potassium results in chronically decreased Na-pump activity. In contrast, an adaptive change occurs in tail arteries of rats fed HK diet, such that Na-pump activity remains at normal levels despite elevated extracellular potassium; this adaptive response to chronically increased dietary potassium does not appear to be the result of decreased Na-pump site density.


Enhancing Patient Experience With Internet Protocol Addressable Digital Light-Emitting Diode Lighting in Imaging Environments: A Phase I Study.
Conventional approaches to improve the quality of clinical patient imaging studies focus predominantly on updating or replacing imaging equipment; however, it is often not considered that patients can also highly influence the diagnostic quality of clinical imaging studies. Patient-specific artifacts can limit the diagnostic image quality, especially when patients are uncomfortable, anxious, or agitated. Imaging facility or environmental conditions can also influence the patient's comfort and willingness to participate in diagnostic imaging studies, especially when performed in visually unesthetic, anxiety-inducing, and technology-intensive imaging centers. When given the opportunity to change a single aspect of the environmental or imaging facility experience, patients feel much more in control of the otherwise unfamiliar and uncomfortable setting. Incorporating commercial, easily adaptable, ambient lighting products within clinical imaging environments allows patients to individually customize their environment for a more personalized and comfortable experience. The aim of this pilot study was to use a customizable colored light-emitting diode (LED) lighting system within a clinical imaging environment and demonstrate the feasibility and initial findings of enabling healthy subjects to customize the ambient lighting and color. Improving the patient experience within clinical imaging environments with patient-preferred ambient lighting and color may improve overall patient comfort, compliance, and participation in the imaging study and indirectly contribute to improving diagnostic image quality. We installed consumer-based internet protocol addressable LED lights using the ZigBee standard in different imaging rooms within a clinical imaging environment. We recruited healthy volunteers (n=35) to generate pilot data in order to develop a subsequent clinical trial. The visual perception assessment procedure utilized questionnaires with preprogrammed light/color settings and further assessed how subjects preferred ambient light and color within a clinical imaging setting. Technical implementation using programmable LED lights was performed without any hardware or electrical modifications to the existing clinical imaging environment. Subject testing revealed substantial variabilities in color perception; however, clear trends in subject color preference were noted. In terms of the color hue of the imaging environment, 43% (15/35) found blue and 31% (11/35) found yellow to be the most relaxing. Conversely, 69% (24/35) found red, 17% (6/35) found yellow, and 11% (4/35) found green to be the least relaxing. With the majority of subjects indicating that colored lighting within a clinical imaging environment would contribute to an improved patient experience, we predict that enabling patients to customize environmental factors like lighting and color to individual preferences will improve patient comfort and patient satisfaction. Improved patient comfort in clinical imaging environments may also help to minimize patient-specific imaging artifacts that can otherwise limit diagnostic image quality. ClinicalTrials.gov NCT03456895; https://clinicaltrials.gov/ct2/show/NCT03456895.