Interaction of a conjugated polyaromatic molecule with a single dangling bond quantum dot on a hydrogenated semiconductor.
Controlling the strength of the coupling between organic molecules and single atoms provides a powerful tool for tuning electronic properties of single-molecule devices. Here, using scanning tunneling microscopy and spectroscopy (STM/STS) supported by theoretical modeling, we study the interaction of a planar organic molecule (trinaphthylene) with a hydrogen-passivated Ge(001):H substrate and a single dangling bond quantum dot on that surface. The electronic structure of the molecule adsorbed on the hydrogen-passivated surface is similar to the gas phase structure and the measurements show that HOMO and LUMO states contribute to the STM filled and empty state images, respectively. Furthermore, we show that the electronic properties are not significantly affected when the molecule is attached to the single dangling bond, which is in contrast with the strong interaction of the molecule with a dangling bond dimer. Our results show that the dangling bond quantum dots could stabilize organic molecules on a hydrogenated semiconductor without affecting their originally designed gas phase electronic properties. Together with the ability to laterally manipulate the molecules on the surface, this will be advantageous in the construction of single-molecule devices, where the coupling and positioning of the molecules on the substrate could be tuned by a proper design of the surface quantum dot arrays, comprising both single and dimerized dangling bonds.


Is homoeopathy a placebo response? Controlled trial of homoeopathic potency, with pollen in hayfever as model.
The hypothesis that homoeopathic potencies are placebos was tested in a randomised, double-blind, placebo-controlled trial. The study model chosen compared the effects of a homoeopathic preparation of mixed grass pollens with placebo in 144 patients with active hayfever. The homoeopathically treated patients showed a significant reduction in patient and doctor assessed symptom scores. The significance of this response was increased when results were corrected for pollen count and the response was associated with a halving of the need for antihistamines. An initial aggravation of symptoms was noted more often in patients receiving the potency and was followed by an improvement in that group. No evidence emerged to support the idea that placebo action fully explains the clinical responses to homoeopathic drugs.


Acupuncture in the emergency department: a systematic review of randomised controlled trials.
A comprehensive review of both English and Chinese language literature to inform acupuncture practice in emergency department (ED) settings is lacking. Accordingly, we aimed to conduct a systematic review of English and Chinese randomised controlled trials (RCTs) of acupuncture use in the ED. Four English databases (Embase, PubMed, AMED and CENTRAL) and two Chinese databases (CNKI and Wanfang) were systematically searched using the keywords 'acupuncture' and 'emergency department', followed by a bibliographic search of references. The data were extracted and assessed by two independent authors. RCTs were selected based on pre-defined criteria. Data were extracted and a risk of bias assessment was performed using the Cochrane risk of bias tool. The quality of evidence was rated using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. In total, 1461 articles were screened and six RCTs involving 651 patients were included. For various acute pain conditions, acupuncture was superior to sham acupuncture, more effective than intravenous morphine, comparable to conventional ED treatment, and superior to standard ED care alone when used on an adjuvant basis; however, the overall level of evidence was low. Studies that applied acupuncture in hypertension and cardiac arrest were deemed to be at high risk of bias, and the level of evidence for these outcomes was very low. No major adverse events were reported in the included studies. There is a lack of high-quality evidence to support the use of acupuncture in the ED. Multicentre RCTs with rigorous designs are warranted.


Genotypes of Japanese encephalitis virus isolated in three states in Malaysia.
Two hundred forty nucleotides from the pre-membrane gene region of 12 Japanese encephalitis virus (JEV) strains isolated from three different regions of Malaysia from 1993 to 1994 were sequenced and compared with each other and with the JEV strains from different geographic areas in Asia. These 12 Malaysian isolates were classified into two genotypes. The four JEV strains isolated from Sarawak in 1994 and the four JEV strains isolated from Sepang, Selangor in 1993 were classified into one genotype that included earlier isolated strains from Malaysia (JE-827 from Sarawak in 1968 and WTP/70/22 from Kuala Lumpur in 1970). The four JEV strains from Ipoh, Perak in 1994 were classified into another genotype that included JEV strains isolated from northern Thailand and Cambodia. In an earlier report, 10 JEV strains from Sabak Bernam, Selangor in 1992 were classified into the largest genotype that included strains isolated in temperate regions such as Japan, China, and Taiwan. The data indicate that at least three genotypes of JEV have been circulating in Malaysia.


Oncogenomic Approaches in Exploring Gain of Function of Mutant p53.
Cancer is caused by the spatial and temporal accumulation of alterations in the genome of a given cell. This leads to the deregulation of key signalling pathways that play a pivotal role in the control of cell proliferation and cell fate. The p53 tumor suppressor gene is the most frequent target in genetic alterations in human cancers. The primary selective advantage of such mutations is the elimination of cellular wild type p53 activity. In addition, many evidences in vitro and in vivo have demonstrated that at least certain mutant forms of p53 may possess a gain of function, whereby they contribute positively to cancer progression. The fine mapping and deciphering of specific cancer phenotypes is taking advantage of molecular-profiling studies based on genome-wide approaches. Currently, high-throughput methods such as array-based comparative genomic hybridization (CGH array), single nucleotide polymorphism array (SNP array), expression arrays and ChIP-on-chip arrays are available to study mutant p53-associated alterations in human cancers. Here we will mainly focus on the integration of the results raised through oncogenomic platforms that aim to shed light on the molecular mechanisms underlying mutant p53 gain of function activities and to provide useful information on the molecular stratification of tumor patients.


IL-15 prevents apoptosis, reverses innate and adaptive immune dysfunction, and improves survival in sepsis.
IL-15 is a pluripotent antiapoptotic cytokine that signals to cells of both the innate and adaptive immune system and is regarded as a highly promising immunomodulatory agent in cancer therapy. Sepsis is a lethal condition in which apoptosis-induced depletion of immune cells and subsequent immunosuppression are thought to contribute to morbidity and mortality. This study tested the ability of IL-15 to block apoptosis, prevent immunosuppression, and improve survival in sepsis. Mice were made septic using cecal ligation and puncture or Pseudomonas aeruginosa pneumonia. The experiments comprised a 2 x 2 full factorial design with surgical sepsis versus sham and IL-15 versus vehicle. In addition to survival studies, splenic cellularity, canonical markers of activation and proliferation, intracellular pro- and antiapoptotic Bcl-2 family protein expression, and markers of immune cell apoptosis were evaluated by flow cytometry. Cytokine production was examined both in plasma of treated mice and splenocytes that were stimulated ex vivo. IL-15 blocked sepsis-induced apoptosis of NK cells, dendritic cells, and CD8 T cells. IL-15 also decreased sepsis-induced gut epithelial apoptosis. IL-15 therapy increased the abundance of antiapoptotic Bcl-2 while decreasing proapoptotic Bim and PUMA. IL-15 increased both circulating IFN-gamma, as well as the percentage of NK cells that produced IFN-gamma. Finally, IL-15 increased survival in both cecal ligation and puncture and P. aeruginosa pneumonia. In conclusion, IL-15 prevents two immunopathologic hallmarks of sepsis, namely, apoptosis and immunosuppression, and improves survival in two different models of sepsis. IL-15 represents a potentially novel therapy of this highly lethal disorder.


Ethical responsibilities toward indirect and collateral participants in pragmatic clinical trials.
Pragmatic clinical trials are designed to inform decision makers about the benefits, burdens, and risks of health interventions in real-world settings. Pragmatic clinical trials often use for research purposes data collected in the course of clinical practice. The distinctive features of pragmatic clinical trials demand fresh thinking about what is required to act properly toward people affected by their conduct, in ways that go beyond ensuring the protection of rights and welfare for "human research subjects" under conventional research ethics regulations. To stimulate such work, we propose to distinguish among categories of research participants in pragmatic clinical trials as follows: Direct participants: (1) individuals being directly intervened upon and/or (2) individuals from whom personal identifiable data are being collected for the purposes of the pragmatic clinical trial. Indirect participants: individuals who are (1) not identified as direct participants and (2) whose rights and welfare may be affected by the intervention through their routine exposure to the environment in which the intervention is being deployed. Collateral participants: patient groups and other stakeholder communities who may be otherwise affected by the occurrence and findings of the pragmatic clinical trial. We illustrate these distinctions with case examples and discuss the distinctive responsibilities of researchers and pragmatic clinical trial leadership toward each type of participant. We suggest that pragmatic clinical trial investigators, institutional review boards, health systems leaders, and others engaged in the research enterprise work together to identify these participants. For indirect participants, risks and benefits to which they are exposed should be weighed to ensure that their rights and welfare are protected accordingly, and communication strategies should be considered to help them make well-informed decisions. Collateral participants could provide input on the design, planning, and conduct of a pragmatic clinical trial and offer insights regarding the best way to communicate the trial's results to their constituencies.


Immune dysregulation of pemphigus in humans and mice.
Pemphigus vulgaris is an autoimmune blistering disease of the skin and mucous membranes that is caused by immunoglobulin (Ig)G autoantibodies against the cadherin-type adhesion molecule desmoglein (Dsg)3 expressed on stratified epithelial cells. Interaction between antigen-specific T and B cells, which is selectively achieved through T-cell receptor/major histocompatibility complex-peptide complex association and subsequently corroborated by co-stimulatory molecules such as CD40/CD154, is required for production of pathological anti-desmoglein 3 antibody. Some genetically and environmentally susceptible individuals harbor desmoglein reactive B and T cells, and anti-desmoglein antibodies were detected in their serum. Analysis of the anti-desmoglein antibody clones derived from pemphigus patients or pemphigus model mice revealed that pathogenic antibodies mostly react with conformational epitopes on mature form desmogleins, whereas non-pathogenic ones tend to react with non-conformational epitopes. Surprisingly, antibodies to the Dsg1 precursor pro-protein are also cloned from individuals without pemphigus. These observations suggest that active suppression by regulatory cell subsets is dominant in these susceptible individuals. In fact, Dsg-reactive T-inducible regulatory type 1 (Tr1) cells are readily detected in healthy carriers of pemphigus-related human leukocyte antigen haplotypes, but rarely in pemphigus patients. These Tr1 cells can be functionally converted to T-helper 2-like cells which secrete interleukin-2 by inactivation of Foxp3 through antisense oligonucleotides. Thus, delicate balance between self-reactive lymphocytes and regulatory T cells may be a key element in determining whether individuals produce pathogenic antibodies and develop pemphigus phenotypes or not.


In vitro inhibition of ETEC K88 adhesion by pea hulls and of LT enterotoxin binding by faba bean hulls.
Enterotoxigenic Escherichia coli (ETEC) expressing K88 (F4) adhesins are associated with post-weaning diarrhoea in piglets. Different grain fractions from pea (Pisum sativum) and faba bean (Vicia faba) were tested in vitro for their capacity to counteract aetiological factors, which contribute to the development of diarrhoea. In detail, adhesion of E. coli O149:K91:K88ac (ETEC K88ac) to grain legume products, intended to impair the colonization of the host, was studied as well as interference with receptor binding of the pathogen's heat-labile enterotoxin LT, intended to reduce toxin-inflicted gut cell damage. When comparing different pea and faba bean products tested for their binding capacity of ETEC K88ac, especially pea hulls, but also whole pea meal, starch-enriched and protein-enriched pea meal, and digestion-resistant pea hull and meal fractions showed a higher binding of ETEC K88ac than faba bean products. In contrast to the ETEC K88ac adhesion results, bean hulls proved more effective than pea hulls in preventing GM1 receptor binding of LT. Previous small intestinal segment perfusion experiments we performed with ETEC K88ac-challenged piglets indicated that both pea and bean hulls have the potential for successful application in diarrhoea prophylaxis and treatment, which is in agreement with and refined by our detection of their different modes of functioning.


Recent Positive Selection in Genes of the Mammalian Epidermal Differentiation Complex Locus.
The epidermal differentiation complex (EDC) is the most rapidly evolving locus in the human genome compared to that of the chimpanzee. Yet the EDC genes that are undergoing positive selection across mammals and in humans are not known. We sought to identify the positively selected genetic variants and determine the evolutionary events of the EDC using mammalian-wide and clade-specific branch- and branch-site likelihood ratio tests and a genetic algorithm (GA) branch test. Significant non-synonymous substitutions were found in filaggrin, SPRR4, LELP1, and S100A2 genes across 14 mammals. By contrast, we identified recent positive selection in SPRR4 in primates. Additionally, the GA branch test discovered lineage-specific evolution for distinct EDC genes occurring in each of the nodes in the 14-mammal phylogenetic tree. Multiple instances of positive selection for FLG, TCHHL1, SPRR4, LELP1, and S100A2 were noted among the primate branch nodes. Branch-site likelihood ratio tests further revealed positive selection in specific sites in SPRR4, LELP1, filaggrin, and repetin across 14 mammals. However, in addition to continuous evolution of SPRR4, site-specific positive selection was also found in S100A11, KPRP, SPRR1A, S100A7L2, and S100A3 in primates and filaggrin, filaggrin2, and S100A8 in great apes. Very recent human positive selection was identified in the filaggrin2 L41 site that was present in Neanderthal. Together, our results identifying recent positive selection in distinct EDC genes reveal an underappreciated evolution of epidermal skin barrier function in primates and humans.


Polyproline tetramer organizing peptides in fetal bovine serum acetylcholinesterase.
Acetylcholinesterase (AChE) in the serum of fetal cow is a tetramer. The related enzyme, butyrylcholinesterase (BChE), in the sera of humans and horse requires polyproline peptides for assembly into tetramers. Our goal was to determine whether soluble tetrameric AChE includes tetramer organizing peptides in its structure. Fetal bovine serum AChE was denatured by boiling to release non-covalently bound peptides. Bulk protein was separated from peptides by filtration and by high performance liquid chromatography. Peptide mass and amino acid sequence of the released peptides were determined by MALDI-TOF-TOF and LTQ-Orbitrap mass spectrometry. Twenty polyproline peptides, divided into 5 families, were identified. The longest peptide contained 25 consecutive prolines and no other amino acid. Other polyproline peptides included one non-proline amino acid, for example serine at the C-terminus of 20 prolines. A search of the mammalian proteome database suggested that this assortment of polyproline peptides originated from at least 5 different precursor proteins, none of which were the ColQ or PRiMA of membrane-anchored AChE. To date, AChE and BChE are the only proteins known that include polyproline tetramer organizing peptides in their tetrameric structure.


Similar mitochondrial signaling responses to a single bout of continuous or small-sided-games-based exercise in sedentary men.
This study assessed the mitochondrial related signaling responses to a single bout of noncontact, modified football (touch rugby), played as small-sided games (SSG), or cycling (CYC) exercise in sedentary, obese, middle-aged men. In a randomized, crossover design, nine middle-aged, sedentary, obese men completed two, 40-min exercise conditions (CYC and SSG) separated by a 21-day recovery period. Heart rate (HR) and ratings of perceived exertion (RPE) were collected during each bout. Needle biopsies from the vastus lateralis muscle were collected at rest and 30 and 240 min postexercise for analysis of protein content and phosphorylation (PGC-1α, SIRT1, p53, p53Ser15, AMPK, AMPKThr172, CAMKII, CAMKIIThr286, p38MAPK, and p38MAPKThr180/Tyr182) and mRNA expression (PGC-1α, p53, NRF1, NRF2, Tfam, and cytochrome c). A main effect of time effect for both conditions was evident for HR, RPE, and blood lactate (P < 0.05), with no condition by time interaction (P > 0.05). Both conditions increased PGC1-α protein and mRNA expression at 240 min (P < 0.05). AMPKThr172 increased 30 min post CYC (P < 0.05), with no change in SSG (P > 0.05). CYC increased p53 protein content at 240 min to a greater extent than SSG (P < 0.05). mRNA expression of NRF2 decreased in both conditions (P < 0.05). No condition by time interactions were evident for mRNA expression of Tfam, NRF1, cytochrome c, and p53. The similar PGC-1α response between intensity-matched conditions suggests both conditions are of similar benefit for stimulating mitochondrial biogenesis. Differences between conditions regarding fluctuation in exercise intensity and type of muscle contraction may explain the increase of p53 and AMPK within CYC and not SSG (noncontact, modified football).


Selective activation of Fas/Fas ligand-mediated cytotoxicity by a self peptide.
To study how MHC-associated self antigens may regulate the function of T cells in the periphery, we generated CD8+ T cell lines specific for a single residue variant of a self peptide. The self peptide (GAYEFTTL) was isolated from H-2-Kb class I MHC molecules immunopurified from tumor cells. CD8+ CTL lines from H-2b mice were generated against a variant peptide, pE4R, (arginine for glutamic acid at the TCR contact position 4). In short-term 51Cr-release assays, these CTL lysed H-2Kb targets that were pulsed with picomolar levels of pE4R but did not lyse target cells coated with the self peptide at micromolar levels. However, in overnight assays the CTL lysed Fas-positive target cells in the presence of nanomolar levels of the self peptide. This killing was shown to be entirely Fas/Fas ligand mediated by blocking with anti-Fas antibody and Fas-Fc chimeric molecules. While the self peptide was unable to induce serine esterase release from the CTL, it did induce secretion of IFN-gamma. By these criteria then, the unmodified self ligand served as a partial agonist for the CTL raised against a single-residue variant. CD8+ T cell lines raised by in vitro stimulation with the self peptide were likewise unable to kill self peptide-coated targets via the perforin pathway but did lyse targets via Fas. These and similar data from other groups show that self antigens (i.e., MHC/peptide complexes) may be recognized by mature peripheral T cells. The T cell population is tolerant of the self antigen in the sense that they do not respond to physiological levels of the MHC/peptide complex. However, when the level of self antigen is increased (by using synthetic peptide loading) CD8+ T cells may respond by proliferation, IFN-gamma secretion, Fas ligand upregulation, and Fas-mediated cytolysis but are still unable to respond by perforin-mediated cytolysis or granzyme release. The physiological significance of such partial activation in regulation of the immune system remains to be demonstrated.


Nuclear transportation of exogenous epidermal growth factor receptor and androgen receptor via extracellular vesicles.
Epidermal growth factor receptor (EGFR) plays a central role in the progression of several human malignancies. Although EGFR is a membrane receptor, it undergoes nuclear translocation, where it has a distinct signalling pathway. Herein, we report a novel mechanism by which cancer cells can directly transport EGFR to the nucleus of other cells via extracellular vesicles (EVs). The transported receptor is active and stimulates the nuclear EGFR pathways. Interestingly, the translocation of EGFR via EVs occurs independently of the nuclear localisation sequence that is required for nuclear translocation of endogenous EGFR. Also, we found that the mutant receptor EGFRvIII could be transported to the nucleus of other cells via EVs. To assess the role of EVs in the regulation of an actual nuclear receptor, we studied the regulation of androgen receptor (AR). We found that full-length AR and mutant variant ARv7 are secreted in EVs derived from prostate cancer cell lines and could be transported to the nucleus of AR-null cells. The EV-derived AR was able to bind the androgen-responsive promoter region of prostate specific antigen, and recruit RNA Pol II, an indication of active transcription. The nuclear-translocated AR via EVs enhanced the proliferation of acceptor cells in the absence of androgen. Finally, we provide evidence that nuclear localisation of AR could occur in vivo via orthotopically-injected EVs in male SCID mice prostate glands. To our knowledge, this is the first study showing the nuclear translocation of nuclear receptors via EVs, which significantly extends the role of EVs as paracrine transcriptional regulators.


Role of interleukin 12 in experimental neonatal sepsis caused by group B streptococci.
Cytokines are suspected to play an important role in systemic infections by group B streptococci (GBS), an important cause of neonatal sepsis. This work was undertaken to determine if interleukin 12 (IL-12) is produced in mouse pups infected with GBS and has a role in this sepsis model. IL-12 elevations were measured by both an enzyme-linked immunosorbent assay and a bioassay in plasma samples obtained from 12 to 72 h after GBS challenge. Pretreatment with neutralizing anti-IL-12 antibodies significantly increased lethality and blood CFU (P < 0.05). Conversely, either prophylactically or therapeutically administered recombinant IL-12 (rIL-12) significantly improved survival time and decreased blood CFU. Since these beneficial effects were associated with increased spleen gamma interferon (IFN-gamma) production, we examined whether the latter cytokine mediated the observed rIL-12 effects. Pretreatment with neutralizing anti-IFN-gamma monoclonal antibodies significantly counteracted the beneficial effects of rIL-12 on lethality. Our data indicate that rIL-12 is a possible candidate for treatment of GBS sepsis and that its activities in this model are at least partially mediated by IFN-gamma.


PknG senses amino acid availability to control metabolism and virulence of Mycobacterium tuberculosis.
Sensing and response to changes in nutrient availability are essential for the lifestyle of environmental and pathogenic bacteria. Serine/threonine protein kinase G (PknG) is required for virulence of the human pathogen Mycobacterium tuberculosis, and its putative substrate GarA regulates the tricarboxylic acid cycle in M. tuberculosis and other Actinobacteria by protein-protein binding. We sought to understand the stimuli that lead to phosphorylation of GarA, and the roles of this regulatory system in pathogenic and non-pathogenic bacteria. We discovered that M. tuberculosis lacking garA was severely attenuated in mice and macrophages and furthermore that GarA lacking phosphorylation sites failed to restore the growth of garA deficient M. tuberculosis in macrophages. Additionally we examined the impact of genetic disruption of pknG or garA upon protein phosphorylation, nutrient utilization and the intracellular metabolome. We found that phosphorylation of GarA requires PknG and depends on nutrient availability, with glutamate and aspartate being the main stimuli. Disruption of pknG or garA caused opposing effects on metabolism: a defect in glutamate catabolism or depletion of intracellular glutamate, respectively. Strikingly, disruption of the phosphorylation sites of GarA was sufficient to recapitulate defects caused by pknG deletion. The results suggest that GarA is a cellular target of PknG and the metabolomics data demonstrate that the function of this signaling system is in metabolic regulation. This function in amino acid homeostasis is conserved amongst the Actinobacteria and provides an example of the close relationship between metabolism and virulence.


Discordant hepatic fatty acid oxidation and triglyceride hydrolysis leads to liver disease.
To extract energy from stored lipids, fatty acids must first be liberated from triglyceride before their β-oxidation in mitochondria in a coordinated and stepwise manner. To determine the independent and interdependent roles of hepatic triglyceride hydrolysis and fatty acid oxidation, mice were generated with a liver-specific defect in triglyceride hydrolysis (AtglL-/-), fatty acid oxidation (Cpt2L-/-), or both (double knockout). The loss of either gene resulted in the compensatory increase in the other, demonstrating their coordination. The loss of individual components of fatty acid catabolism (carnitine palmitoyl transferase 2 [Cpt2], adipose triglyceride lipase [Atgl], and Pparα) resulted in largely independent effects on hepatocyte morphology, intermediary metabolism, and gene expression in response to fasting. However, high-fat feeding revealed the interdependent role of Atgl and Cpt2, as the loss of only one of the genes resulted in steatosis (fatty liver) but the loss of both components resulted in significant steatohepatitis (inflammation and fibrosis). Lipolysis and β-oxidation are intimately linked within a continuous pathway, and disruption of their coordination leads to unique cellular and molecular phenotypes that ultimately result in liver disease.


Caenorhabditis elegans N-glycan core beta-galactoside confers sensitivity towards nematotoxic fungal galectin CGL2.
The physiological role of fungal galectins has remained elusive. Here, we show that feeding of a mushroom galectin, Coprinopsis cinerea CGL2, to Caenorhabditis elegans inhibited development and reproduction and ultimately resulted in killing of this nematode. The lack of toxicity of a carbohydrate-binding defective CGL2 variant and the resistance of a C. elegans mutant defective in GDP-fucose biosynthesis suggested that CGL2-mediated nematotoxicity depends on the interaction between the galectin and a fucose-containing glycoconjugate. A screen for CGL2-resistant worm mutants identified this glycoconjugate as a Galbeta1,4Fucalpha1,6 modification of C. elegans N-glycan cores. Analysis of N-glycan structures in wild type and CGL2-resistant nematodes confirmed this finding and allowed the identification of a novel putative glycosyltransferase required for the biosynthesis of this glycoepitope. The X-ray crystal structure of a complex between CGL2 and the Galbeta1,4Fucalpha1,6GlcNAc trisaccharide at 1.5 A resolution revealed the biophysical basis for this interaction. Our results suggest that fungal galectins play a role in the defense of fungi against predators by binding to specific glycoconjugates of these organisms.


Prevalence and risk factors for Chlamydia trachomatis, Neisseria gonorrhoeae and Trichomonas vaginalis infection in pregnant women in Papua New Guinea.
To determine the prevalence of, and risk factors associated with, Chlamydia trachomatis, Neisseria gonorrhoeae and Trichomonas vaginalis infection in pregnant women in Madang, Papua New Guinea (PNG). A cross-sectional survey was conducted among 400 pregnant women presenting to antenatal clinics. Sociodemographic and behavioural data were collected and real-time PCR diagnostic methods were used to detect the presence of chlamydia, gonorrhoea and trichomonas in self-collected vaginal swabs. The relationships between symptoms, sociodemographic and behavioural factors and infection were assessed. The prevalence of C. trachomatis was 11.1%, N. gonorrhoeae was 9.7% and T. vaginalis was 21.3%. One-third of women (33.7%) had at least one infection. The most common symptom was abdominal pain (48.0%), but only abnormal vaginal discharge was consistently associated with infection (p<0.001). Women diagnosed with vaginal discharge syndrome were more likely to have at least one treatable infection (50.0% (47/94) vs 26.8% (68/254), p<0.001), yet 59.1% of women with infection would have been missed by the current clinically-based syndromic diagnosis. Risk factors included having a partner at perceived risk of infection, maternal extramarital intercourse, early sexual debut, lack of formal education, urban residence and smoking. 78.8% of women reported never using condoms. The prevalences of T. vaginalis, C. trachomatis and N. gonorrhoeae were high among pregnant women in coastal PNG. The poor performance of clinically based syndromic diagnosis suggests that alternative strategies are urgently required to improve detection and reduce the burden of sexually transmitted infections and their associated adverse pregnancy outcomes in this population.


Mycoplasma genitalium is associated with cervicitis and HIV infection in an urban Australian STI clinic population.
To investigate the prevalence of the genital mollicutes, Mycoplasma genitalium (MG), Mycoplasma hominis (MH), Ureaplasma urealyticum (UU) and Ureaplasma parvum (UP), and their associations with cervicitis in a sexually transmitted infection (STI) clinic population. Clinical correlates of MG infection were also assessed. 527 women were enrolled in a cross-sectional study at two STI clinics in Sydney between June 2006 and January 2010. Genital mollicutes were detected by multiplex PCR testing of cervical swabs, and associations with cervicitis were analysed. Cervicitis was defined as >30 polymorphonuclear cells per high-power field in at least three non-adjacent fields of cervical mucus on Gram stain. MG was found in 4.0% of women, MH in 17.1%, UU in 14.1%, and UP in 51.8%. MG was the only mollicute associated with cervicitis (unadjusted prevalence ratio (PR) 1.85, 95% CI 1.52 to 2.26, p<0.0001), and this association remained after adjustment for Chlamydia trachomatis (CT) infection (adjusted PR 1.24 (95% CI 1.04 to 1.48), p=0.02). MG was significantly associated with women being HIV positive (p=0.03), but not with age, vaginal discharge, commercial sex work, being of culturally and linguistically diverse background, or concurrent CT infection. Two of the 21 women with MG had ectopic pregnancies. The authors recommend wider application of PCR testing for MG in STI services, particularly in high-risk women and those with cervicitis or HIV infection.


Factors associated with quality of life among family caregivers of terminally ill cancer patients.
Limited research has examined the quality of life (QOL) and its correlates among family caregivers (FCs) during the final stage of terminal cancer. The purpose of this study was to investigate the determinants of overall QOL and its subdomains among Korean FCs at the very end of life. For this cross-sectional study, we enrolled 299 FCs of terminal cancer patients from seven palliative care units. To assess FCs' QOL and its predictors, we used the Caregiver Quality Of Life Index-Cancer, which contains four domains. Possible determinants of caregiver QOL were categorized into patient, caregiver, and environmental factors. A multiple regression model was used to identify factors associated with FCs' QOL. Variance in each Caregiver Quality Of Life Index-Cancer domain was explained by different factors. FCs of younger patient felt more burden but were more likely to adapt positively. Emotional distress of FCs was strongly associated with total QOL, burdensomeness, and disruptiveness. Positive adaptation was related to more visits for care, FCs' religiousness, more social support, and satisfactory perceived quality of care. Financial concerns were more likely in married FCs, FCs with less social support, or low incomes. Emotional distress of FCs was the most important factor determining the overall and negative aspects of FCs' QOL, whereas various environmental factors were associated with positive coping. Appropriate support programs directed at these factors are needed to maintain and improve FCs' QOL.


Qualitative methods in implementation research: An introduction.
Qualitative methods are a valuable tool in implementation research because they help to answer complex questions such as how and why efforts to implement best practices may succeed or fail, and how patients and providers experience and make decisions in care. This article orients the novice implementation scientist to fundamentals of qualitative methods and their application in implementation research, describing: 1) implementation-related questions that can be addressed by qualitative methods; 2) qualitative methods commonly used in implementation research; 3) basic sampling and data collection procedures; and 4) recommended practices for data analysis and ensuring rigor. To illustrate qualitative methods decision-making, a case example is provided of a study examining implementation of a primary care-based collaborative care management model for women Veterans with anxiety, depression, and PTSD.


Development and implementation of a mobile device-based pediatric electronic decision support tool as part of a national practice standardization project.
Implementing evidence-based practices requires a multi-faceted approach. Electronic clinical decision support (ECDS) tools may encourage evidence-based practice adoption. However, data regarding the role of mobile ECDS tools in pediatrics is scant. Our objective is to describe the development, distribution, and usage patterns of a smartphone-based ECDS tool within a national practice standardization project. We developed a smartphone-based ECDS tool for use in the American Academy of Pediatrics, Value in Inpatient Pediatrics Network project entitled "Reducing Excessive Variation in the Infant Sepsis Evaluation (REVISE)." The mobile application (app), PedsGuide, was developed using evidence-based recommendations created by an interdisciplinary panel. App workflow and content were aligned with clinical benchmarks; app interface was adjusted after usability heuristic review. Usage patterns were measured using Google Analytics. Overall, 3805 users across the United States downloaded PedsGuide from December 1, 2016, to July 31, 2017, leading to 14 256 use sessions (average 3.75 sessions per user). Users engaged in 60 442 screen views, including 37 424 (61.8%) screen views that displayed content related to the REVISE clinical practice benchmarks, including hospital admission appropriateness (26.8%), length of hospitalization (14.6%), and diagnostic testing recommendations (17.0%). Median user touch depth was 5 [IQR 5]. We observed rapid dissemination and in-depth engagement with PedsGuide, demonstrating feasibility for using smartphone-based ECDS tools within national practice improvement projects. ECDS tools may prove valuable in future national practice standardization initiatives. Work should next focus on developing robust analytics to determine ECDS tools' impact on medical decision making, clinical practice, and health outcomes.


Essential fatty acid diet supplementation. Effects on peripheral nerve and skeletal muscle function and capillarization in streptozocin-induced diabetic rats.
Effects of essential fatty acids on nerve conduction, hypoxic resistance, skeletal muscle contractile properties, and capillary density were examined in streptozocin-induced diabetic rats. Nondiabetic and diabetic controls and three diabetic groups treated with 10% supplements of corn oil, evening primrose oil (Efamol), or a mixture of 80% evening primrose oil and 20% fish oil (Efamol Marine) for 2 mo were used. Efamol and Efamol Marine increased plasma gamma-linolenic acid levels, but arachidonic acid was elevated only with Efamol. Diabetes resulted in 15-29% reductions in sciatic motor and sensory saphenous nerve conduction velocity. Efamol prevented conduction deficits more effectively than Efamol Marine, and corn oil had no effect. In vitro measurement of sciatic nerve hypoxic resistance revealed a 49% increase in the time taken for action potential amplitude to decline by 50% with diabetes. Corn oil had no significant effect. With Efamol, hypoxic resistance was within the nondiabetic range. Efamol Marine produced intermediate results. Functional improvements may relate to enhanced vasa nervorum perfusion, because endoneurial capillary density increased by 22% with Efamol, angiogenesis perhaps resulting from eicosanoid production from arachidonic acid. Soleus muscle contractions were prolonged by diabetes. This was partially corrected by treatment, Efamol being most effective. Extensor digitorum longus muscle had reduced tetanic tension with diabetes, and this was prevented by all treatments. Soleus showed a modest increase in capillarization with Efamol, which may have contributed to reduced susceptibility to fatigue. The data suggest involvement of abnormal fatty acid metabolism in the etiology of diabetic neuropathy and myopathy.


Reducing INDEL calling errors in whole genome and exome sequencing data.
INDELs, especially those disrupting protein-coding regions of the genome, have been strongly associated with human diseases. However, there are still many errors with INDEL variant calling, driven by library preparation, sequencing biases, and algorithm artifacts. We characterized whole genome sequencing (WGS), whole exome sequencing (WES), and PCR-free sequencing data from the same samples to investigate the sources of INDEL errors. We also developed a classification scheme based on the coverage and composition to rank high and low quality INDEL calls. We performed a large-scale validation experiment on 600 loci, and find high-quality INDELs to have a substantially lower error rate than low-quality INDELs (7% vs. 51%). Simulation and experimental data show that assembly based callers are significantly more sensitive and robust for detecting large INDELs (>5 bp) than alignment based callers, consistent with published data. The concordance of INDEL detection between WGS and WES is low (53%), and WGS data uniquely identifies 10.8-fold more high-quality INDELs. The validation rate for WGS-specific INDELs is also much higher than that for WES-specific INDELs (84% vs. 57%), and WES misses many large INDELs. In addition, the concordance for INDEL detection between standard WGS and PCR-free sequencing is 71%, and standard WGS data uniquely identifies 6.3-fold more low-quality INDELs. Furthermore, accurate detection with Scalpel of heterozygous INDELs requires 1.2-fold higher coverage than that for homozygous INDELs. Lastly, homopolymer A/T INDELs are a major source of low-quality INDEL calls, and they are highly enriched in the WES data. Overall, we show that accuracy of INDEL detection with WGS is much greater than WES even in the targeted region. We calculated that 60X WGS depth of coverage from the HiSeq platform is needed to recover 95% of INDELs detected by Scalpel. While this is higher than current sequencing practice, the deeper coverage may save total project costs because of the greater accuracy and sensitivity. Finally, we investigate sources of INDEL errors (for example, capture deficiency, PCR amplification, homopolymers) with various data that will serve as a guideline to effectively reduce INDEL errors in genome sequencing.


The psychosis high-risk state: a comprehensive state-of-the-art review.
During the past 2 decades, a major transition in the clinical characterization of psychotic disorders has occurred. The construct of a clinical high-risk (HR) state for psychosis has evolved to capture the prepsychotic phase, describing people presenting with potentially prodromal symptoms. The importance of this HR state has been increasingly recognized to such an extent that a new syndrome is being considered as a diagnostic category in the DSM-5. To reframe the HR state in a comprehensive state-of-the-art review on the progress that has been made while also recognizing the challenges that remain. Available HR research of the past 20 years from PubMed, books, meetings, abstracts, and international conferences. Critical review of HR studies addressing historical development, inclusion criteria, epidemiologic research, transition criteria, outcomes, clinical and functional characteristics, neurocognition, neuroimaging, predictors of psychosis development, treatment trials, socioeconomic aspects, nosography, and future challenges in the field. Relevant articles retrieved in the literature search were discussed by a large group of leading worldwide experts in the field. The core results are presented after consensus and are summarized in illustrative tables and figures. The relatively new field of HR research in psychosis is exciting. It has the potential to shed light on the development of major psychotic disorders and to alter their course. It also provides a rationale for service provision to those in need of help who could not previously access it and the possibility of changing trajectories for those with vulnerability to psychotic illnesses.


Passive immunotherapy for N-truncated tau ameliorates the cognitive deficits in two mouse Alzheimer's disease models.
Clinical and neuropathological studies have shown that tau pathology better correlates with the severity of dementia than amyloid plaque burden, making tau an attractive target for the cure of Alzheimer's disease. We have explored whether passive immunization with the 12A12 monoclonal antibody (26-36aa of tau protein) could improve the Alzheimer's disease phenotype of two well-established mouse models, Tg2576 and 3xTg mice. 12A12 is a cleavage-specific monoclonal antibody which selectively binds the pathologically relevant neurotoxic NH226-230 fragment (i.e. NH2htau) of tau protein without cross-reacting with its full-length physiological form(s). We found out that intravenous administration of 12A12 monoclonal antibody into symptomatic (6 months old) animals: (i) reaches the hippocampus in its biologically active (antigen-binding competent) form and successfully neutralizes its target; (ii) reduces both pathological tau and amyloid precursor protein/amyloidβ metabolisms involved in early disease-associated synaptic deterioration; (iii) improves episodic-like type of learning/memory skills in hippocampal-based novel object recognition and object place recognition behavioural tasks; (iv) restores the specific up-regulation of the activity-regulated cytoskeleton-associated protein involved in consolidation of experience-dependent synaptic plasticity; (v) relieves the loss of dendritic spine connectivity in pyramidal hippocampal CA1 neurons; (vi) rescues the Alzheimer's disease-related electrophysiological deficits in hippocampal long-term potentiation at the CA3-CA1 synapses; and (vii) mitigates the neuroinflammatory response (reactive gliosis). These findings indicate that the 20-22 kDa NH2-terminal tau fragment is crucial target for Alzheimer's disease therapy and prospect immunotherapy with 12A12 monoclonal antibody as safe (normal tau-preserving), beneficial approach in contrasting the early Amyloidβ-dependent and independent neuropathological and cognitive alterations in affected subjects.


Water, hydration, and health.
This review examines the current knowledge of water intake as it pertains to human health, including overall patterns of intake and some factors linked with intake, the complex mechanisms behind water homeostasis, and the effects of variation in water intake on health and energy intake, weight, and human performance and functioning. Water represents a critical nutrient, the absence of which will be lethal within days. Water's importance for the prevention of nutrition-related noncommunicable diseases has received more attention recently because of the shift toward consumption of large proportions of fluids as caloric beverages. Despite this focus, there are major gaps in knowledge related to the measurement of total fluid intake and hydration status at the population level; there are also few longer-term systematic interventions and no published randomized, controlled longer-term trials. This review provides suggestions for ways to examine water requirements and encourages more dialogue on this important topic.


Plasma pharmacokinetics and synovial fluid concentrations after oral administration of single and multiple doses of celecoxib in greyhounds.
To determine the plasma pharmacokinetics and synovial fluid concentrations after oral administration of single and multiple doses of celecoxib in Greyhounds. 7 adult Greyhounds. Dogs received celecoxib (median dose, 11.8 mg/kg [range, 11.5 to 13.6 mg/kg], PO, q 24 h) for 10 days. Blood samples were collected prior to administration of celecoxib and serially for 24 hours after the 1st and 10th doses were administered. A synovial joint catheter was placed into a stifle joint in each dog for collection of synovial fluid samples. Concentrations of celecoxib in plasma and synovial fluid were quantified by use of a validated liquid chromatography/mass spectrometry method. Identification of hydroxy- and carboxyl-celecoxib in plasma and synovial fluid was also performed. Pharmacokinetic parameters were determined by use of noncompartmental analysis. Administration of multiple doses of celecoxib resulted in a significant decrease (40%) in median area under the curve (AUC) values and a corresponding decrease in median maximum concentrations (Cmax; 2,620 to 2,032 ng/mL) between the 1st and 10th doses. Synovial fluid concentrations were less than the corresponding plasma concentrations at all times except 24 hours after administration of the 10th dose of celecoxib. Celecoxib distributes into the synovial fluid of Greyhounds. Although the exact mechanism for the decreases in AUC and Cmax is not known, results suggested that the plasma pharmacokinetics of celecoxib are different after administration of multiple doses in Greyhounds. These findings warrant further investigation on the absorption, distribution, metabolism, and elimination of celecoxib in Greyhounds and other breeds of dogs.


The educational preparation of nursing staff undertaking pre-assessment of surgical patients--a discussion of the issues.
This article discusses the education and training needs of nursing staff undertaking the pre-assessment of surgical patients in the context of role development within health care. The authors undertook this piece of work as part of a project to inform the development of a competency framework for use by registered nurses working in the field of pre-assessment screening and preparation of surgical patients. A selective review of the literature on the education and training needs of pre-assessment nurses, and nurses undertaking expanded roles has been undertaken and some of the emerging issues are debated. The nature of current preparation for these roles and the apparent lack of any consistent approach to education and training for staff adjusting their scope of professional practice is debated. A brief review of the nature of competence and some of the different models including occupational competence models are presented. Finally, the implications of these for the development of a strategy for the acquisition and demonstration of knowledge and skills in pre-assessment nursing staff are presented.


Nanocomposite Gel as Injectable Therapeutic Scaffold: Microstructural Aspects and Bioactive Properties.
The development of tissue scaffolds able to provide proper and accelerated regeneration of tissue is a main task of tissue engineering. We developed a nanocomposite gel that may be used as an injectable therapeutic scaffold. The nanocomposite gel is based on biocompatible gelling agents with embedded nanoparticles (iron oxide, silver, and hydroxyapatite) providing therapeutic properties. We have investigated the microstructure of the nanocomposite gel exposed to different substrates (porous materials and biological tissue). Here we show that the nanocomposite gel has the ability to self-reassemble mimicking the substrate morphology: exposition on porous mineral substrate caused reassembling of nanocomposite gel into 10× smaller scale structure; exposition to a section of humerus cortical bone decreased the microstructure scale more than twice (to ≤3 μm). The reassembling happens through a transitional layer which exists near the phase separation boundary. Our results impact the knowledge of gels explaining their abundance in biological organisms from the microstructural point of view. The results of our biological experiments showed that the nanocomposite gel may find diverse applications in the biomedical field.


Avoiding Trouble Ahead: Lessons Learned and Suggestions for Economic Evaluations of COVID-19 Vaccines.
With vaccines for coronavirus disease 2019 (COVID-19) being introduced in countries across the world, policy makers are facing many practical considerations about how best to implement a vaccination programme. The supply of vaccines is insufficient for the global population, so decisions must be made as to which groups are prioritised for any vaccination and when. Furthermore, the aims of vaccination programmes will differ between countries, with some prioritising economic benefits that could stem from the relaxation of non-pharmaceutical interventions and others seeking simply to reduce the number of COVID-19 cases or deaths. This paper aims to share the experiences and lessons learned from conducting economic evaluations in Singapore and Thailand on hypothetical COVID-19 vaccines to provide a basis for other countries to develop their own contextualised economic evaluations, with particular focus on the key uncertainties, technical challenges, and characteristics that modellers should consider in partnership with key stakeholders. Which vaccines, vaccination strategies, and policy responses are most economically beneficial remains uncertain. It is therefore important for all governments to conduct their own analyses to inform local policy responses to COVID-19, including the implementation of COVID-19 vaccines in both the short and the long run. It is essential that such studies are designed, and ideally conducted, before vaccines are introduced so that policy decisions and implementation procedures are not delayed.


Plasmodium knowlesi invasion following spread by infected mosquitoes, macaques and humans.
Plasmodium knowlesi is increasingly recognized as a major cause of malaria in Southeast Asia. Anopheles leucosphyrous group mosquitoes transmit the parasite and natural hosts include long-tailed and pig-tailed macaques. Despite early laboratory experiments demonstrating successful passage of infection between humans, the true role that humans play in P. knowlesi epidemiology remains unclear. The threat posed by its introduction into immunologically naïve populations is unknown despite being a public health priority for this region. A two-host species mathematical model was constructed to analyse this threat. Global sensitivity analysis using Monte Carlo methods highlighted the biological processes of greatest influence to transmission. These included parameters known to be influential in classic mosquito-borne disease models (e.g. vector longevity); however, interesting ecological components that are specific to this system were also highlighted: while local vectors likely have intrinsic preferences for certain host species, how plastic these preferences are, and how this is shaped by local conditions, are key determinants of parasite transmission potential. Invasion analysis demonstrates that this behavioural plasticity can qualitatively impact the probability of an epidemic sparked by imported infection. Identifying key vector sub/species and studying their biting behaviours constitute important next steps before models can better assist in strategizing disease control.


Homogeneous/Inhomogeneous-Structured Dielectrics and their Energy-Storage Performances.
The demand for dielectric capacitors with higher energy-storage capability is increasing for power electronic devices due to the rapid development of electronic industry. Existing dielectrics for high-energy-storage capacitors and potential new capacitor technologies are reviewed toward realizing these goals. Various dielectric materials with desirable permittivity and dielectric breakdown strength potentially meeting the device requirements are discussed. However, some significant limitations for current dielectrics can be ascribed to their low permittivity, low breakdown strength, and high hysteresis loss, which will decrease their energy density and efficiency. Thus, the implementation of dielectric materials for high-energy-density applications requires the comprehensive understanding of both the materials design and processing. The optimization of high-energy-storage dielectrics will have far-reaching impacts on the sustainable energy and will be an important research topic in the near future.


Comparison of the catalytic properties of the botulinum neurotoxin subtypes A1 and A5.
Clostridium botulinum neurotoxins (BoNTs) cause the life-threatening disease botulism through the inhibition of neurotransmitter release by cleaving essential SNARE proteins. There are seven serologically distinctive types of BoNTs and many subtypes within a serotype have been identified. BoNT/A5 is a recently discovered subtype of type A botulinum neurotoxin which possesses a very high degree of sequence similarity and identity to the well-studied A1 subtype. In the present study, we examined the endopeptidase activity of these two BoNT/A subtypes and our results revealed significant differences in substrate binding and cleavage efficiency between subtype A5 and A1. Distinctive hydrolysis efficiency was observed between the two toxins during cleavage of the native substrate SNAP-25 versus a shortened peptide mimic. N-terminal truncation studies demonstrated that a key region of the SNAP-25, including the amino acid residues at 151 through 154 located in the remote binding region of the substrate, contributed to the differential catalytic properties between A1 and A5. Elevated binding affinity of the peptide substrate resulted from including these important residues and enhanced BoNT/A5's hydrolysis efficiency. In addition, mutations of these amino acid residues affect the proteolytic performance of the two toxins in different ways. This study provides a better understanding of the biological activity of these toxins, their performance characteristics in the Endopep-MS assay to detect BoNT in clinical samples and foods, and is useful for the development of peptide substrates.


The microwave syndrome or electro-hypersensitivity: historical background.
Microwave generating equipment first became common during World War 2 with the development of radar. Soviet bloc countries reported that individuals exposed to microwaves frequently developed headaches, fatigue, loss of appetite, sleepiness, difficulty in concentration, poor memory, emotional instability, and labile cardiovascular function, and established stringent exposure standards. For a variety of reasons these reports were discounted in Western countries, where the prevailing belief was that there could be no adverse health effects of electromagnetic fields (EMFs) that were not mediated by tissue heating. The reported Soviet effects were at lower intensities than those that cause heating. However, there were several accidental exposures of radar operators in Western countries that resulted in persistent symptoms similar to those described above. The Soviets irradiated the US Embassy in Moscow with microwaves during the period 1953-1975, and while no convincing evidence of elevated cancer rates was reported, there were reports of "microwave illness". Officials passed these complaints off as being due to anxiety, not effects of the microwave exposure. There is increasing evidence that the "microwave syndrome" or "electro-hypersensitivity" (EHS) is a real disease that is caused by exposure to EMFs, especially those in the microwave range. The reported incidence of the syndrome is increasing along with increasing exposure to EMFs from electricity, WiFi, mobile phones and towers, smart meters and many other wireless devices. Why some individuals are more sensitive is unclear. While most individuals who report having EHS do not have a specific history of an acute exposure, excessive exposure to EMFs, even for a brief period of time, can induce the syndrome.


Students' use of caffeine, alcohol, dietary supplements, and illegal substances for improving academic performance in a New Zealand university.
This study aimed to describe patterns of use and attitudes towards a broad variety of substances for improving academic performance at a New Zealand university. 685 students (from 1800 invited) completed an online questionnaire (38% response rate). They were asked about their lifetime and current substance use for improving academic performance, as well as their reasons for use, attitudes and perceptions of: caffeine, alcohol, dietary supplements, prescription stimulants, other prescription substances, and illicit substances. 80% (95% CI: 76.3, 82.5) reported ever using any substance to help improve academic performance, mainly to stay awake and improve concentration. Caffeine (70%, 95% CI: 66.3, 73.3) and dietary supplements (32%, 95% CI: 28.3, 35.5) were most commonly used. 4% (95% CI: 2.7, 5.9) reported use of prescription stimulants, mostly methylphenidate, and another 4% (95% CI: 2.7, 5.9) reported using illicit substances for improving academic performance. Users of prescription stimulants were more likely than non-users to believe that they were safe, morally acceptable, and that they should be available legally for enhancing academic performance. We close with discussions on broadening the focus of substances for improving academic performance in public health debates. Further qualitative research from small countries is also needed to move towards a place-based approach for clarifying ethical implications, inform policy in universities, and understand how injustices are created through the use of and ability to purchase different substances.


Older adults with and without stroke reduce cadence to meet the demands of talking.
Cognitive tasks performed while walking can be challenging for older adults, especially for those with stroke. Conversational speech requires attention and working memory. The purpose of this study was to examine how older adults with and without stroke meet the demands of walking while talking. Community-dwelling older adults, 12 without stroke and 24 with, were videotaped walking an irregular elliptical pathway. Audio recordings were made as subjects discussed topics such as describing a memorable vacation. Each participant performed in single and dual task conditions: speaking, walking, and speaking while walking. Primary measures of interest included cadence and speech rate. Components of language including measures of fluency, grammatical complexity, and semantic content were analyzed to examine additional changes in speech. Paired t-tests were used to compare single and dual task performance for each group. Group differences for dual task effects were examined with independent sample t tests. Cadence decreased with the addition of talking for those without stroke, P < .007, and those with stroke, P < .001. Speech rates did not change with walking for either group; those without stroke did not alter the language components. Participants with stroke reduced the grammatical complexity and semantic content of speech when walking, P's < .013. Those without stroke spent more time doing both tasks at once than those with stroke, P < .023. Clinicians can expect older adults to reduce walking speed to meet the demands of walking and talking. Older adults with stroke may use additional strategies to walk and talk simultaneously.


Early rehabilitation targeting cognition, behavior, and motor function after lumbar fusion: a randomized controlled trial.
Open label randomized controlled trial with 3-, 6-, 12-month, and 2- to 3-year follow-up. To investigate the effectiveness of a psychomotor therapy focusing on cognition, behavior, and motor relearning compared with exercise therapy applied during the first 3 months after lumbar fusion. Postoperative management after lumbar fusion commonly focuses on analgesic pain control and activities of daily living. After 3 months, exercise therapy is often implemented. No randomized controlled trial has investigated early rehabilitation techniques conducted during the first 3 months after surgery. The study recruited 107 patients, aged 18 to 65 years, selected for lumbar fusion because of 12 months of symptomatic spinal stenosis, spondylosis, degenerative/isthmic spondylolisthesis, or degenerative disc disease. The exercise therapy group received a home program focusing on pain contingent training of back, abdominal, and leg muscle functional strength and endurance, stretching, and cardiovascular fitness. The psychomotor therapy group received a home program and 3 outpatient sessions focusing on modifying maladaptive pain cognitions, behaviors, and motor control.Rated questionnaires investigating functional disability, pain, health-related quality of life, functional self-efficacy, outcome expectancy, fear of movement/(re)injury, and coping were assessed at 3, 6, 12 months, and 2 to 3 years after surgery. Follow-up rates were 93% at 12 months and 81% at 2 to 3 years after surgery. Psychomotor therapy improved functional disability, self-efficacy, outcome expectancy, and fear of movement/(re)injury significantly more than exercise therapy at respective follow-up occasions. Similar results occurred for pain coping but group differences were nonsignificant at 2 to 3 years follow-up. Potentially clinical relevant higher reoperation rates occurred after psychomotor therapy but rates were within normal ranges. The study shows that postoperative rehabilitation can be safely implemented during the first 3 months after lumbar fusion and should include measures to modify psychological as well as motor functions.


How Does iReadMore Therapy Change the Reading Network of Patients with Central Alexia?
Central alexia (CA) is an acquired reading disorder co-occurring with a generalized language deficit (aphasia). The roles of perilesional and ipsilesional tissue in recovery from poststroke aphasia are unclear. We investigated the impact of reading training (using iReadMore, a therapy app) on the connections within and between the right and left hemisphere of the reading network of patients with CA. In patients with pure alexia, iReadMore increased feedback from left inferior frontal gyrus (IFG) region to the left occipital (OCC) region. We aimed to identify whether iReadMore therapy was effective through a similar mechanism in patients with CA. Participants with chronic poststroke CA (n = 23) completed 35 h of iReadMore training over 4 weeks. Reading accuracy for trained and untrained words was assessed before and after therapy. The neural response to reading trained and untrained words in the left and right OCC, ventral occipitotemporal, and IFG regions was examined using event-related magnetoencephalography. The training-related modulation in effective connectivity between regions was modeled at the group level with dynamic causal modeling. iReadMore training improved participants' reading accuracy by an average of 8.4% (range, -2.77 to 31.66) while accuracy for untrained words was stable. Training increased regional sensitivity in bilateral frontal and occipital regions, and strengthened feedforward connections within the left hemisphere. Our data suggest that iReadMore training in these patients modulates lower-order visual representations, as opposed to higher-order, more abstract representations, to improve word-reading accuracy.SIGNIFICANCE STATEMENT This is the first study to conduct a network-level analysis of therapy effects in participants with poststroke central alexia. When patients trained with iReadMore (a multimodal, behavioral, mass practice, computer-based therapy), reading accuracy improved by an average 8.4% on trained items. A network analysis of the magnetoencephalography data associated with this improvement revealed an increase in regional sensitivity in bilateral frontal and occipital regions and strengthening of feedforward connections within the left hemisphere. This indicates that in patients with CA iReadMore engages lower-order, intact resources within the left hemisphere (posterior to their lesion locations) to improve word reading. This provides a foundation for future research to investigate reading network modulation in different CA subtypes, or for sentence-level therapy.


The use of alloderm for the correction of nasal contour deformities.
What rhinoplasty surgeon has not been frustrated by unmet expectations from unreliable graft materials? The quest for an ideal graft continues. Septal cartilage is not always adequate in amount or substance. Ear cartilage may cause unsightly irregularities over time. Cranial bone or rib harvest sites add to the complexity of the procedure and can be intimidating for many operators. This article describes the authors' successful experience with AlloDerm onlay grafts for the correction of nasal contour deformities in 58 primary and secondary rhinoplasty cases by means of the open and endonasal approaches. Forty-two patients received an open-approach procedure; the remaining 16 received grafting through an endonasal or closed approach. Thirty-seven of the patients were secondary rhinoplasty patients, and some underwent multiple nasal corrections. The indications, intraoperative surgical technique of graft placement, and representative results will be discussed. Long-term follow-up showed good results, though partial graft resorption occurred in some patients. Overall, this experience with AlloDerm for nasal augmentation was encouraging.


ISB recommendation on definitions of joint coordinate system of various joints for the reporting of human joint motion--part I: ankle, hip, and spine. International Society of Biomechanics.
The Standardization and Terminology Committee (STC) of the International Society of Biomechanics (ISB) proposes a general reporting standard for joint kinematics based on the Joint Coordinate System (JCS), first proposed by Grood and Suntay for the knee joint in 1983 (J. Biomech. Eng. 105 (1983) 136). There is currently a lack of standard for reporting joint motion in the field of biomechanics for human movement, and the JCS as proposed by Grood and Suntay has the advantage of reporting joint motions in clinically relevant terms. In this communication, the STC proposes definitions of JCS for the ankle, hip, and spine. Definitions for other joints (such as shoulder, elbow, hand and wrist, temporomandibular joint (TMJ), and whole body) will be reported in later parts of the series. The STC is publishing these recommendations so as to encourage their use, to stimulate feedback and discussion, and to facilitate further revisions. For each joint, a standard for the local axis system in each articulating bone is generated. These axes then standardize the JCS. Adopting these standards will lead to better communication among researchers and clinicians.


Multiple effects of a short-term dexamethasone treatment in human skeletal muscle and adipose tissue.
Glucocorticoids are frequently prescribed drugs with important side-effects such as glucose intolerance and tissue remodeling. The goal was to explore the molecular basis of the response of skeletal muscle and adipose tissue during a short-term dexamethasone treatment to better understand the induction of side-effects of glucocorticoids on these metabolic tissues. Fifteen healthy male subjects were assigned to a 4-day treatment with dexamethasone at 4 mg/day. The primary outcome measures were changes in gene expression profiling of subcutaneous skeletal muscle and adipose tissue. Urinary cortisol, plasma, and metabolic biochemistry were also assessed. In both tissues the prominent observation was a response to stress and increased inflammatory responses. An upregulation of the serum amyloid A was detected in skeletal muscle, adipose tissue, and plasma, whereas circulating levels of C reactive protein, another acute phase protein, decreased along with a worsened insulin sensitivity index. As tissue-specific features, tissue remodeling was shown in skeletal muscle while the adipose tissue exhibited a decreased energy metabolism. Several limitations might be raised due to the small number of subjects investigated: a possible cross talk with the mineralocorticoid receptor, and a single time point may not identify regulations occurring during longitudinal treatment. In line with the known physiological effect of glucocorticoids the early modulation of stress response genes was observed. An unexpected feature was the upregulation of the inflammatory and immune pathways. The identification of novel impact on two glucocorticoid target tissues provides a molecular basis for the design of more specific glucocorticoids devoid of adverse effects.


The chimeric genome of Sphaerochaeta: nonspiral spirochetes that break with the prevalent dogma in spirochete biology.
Spirochaetes is one of a few bacterial phyla that are characterized by a unifying diagnostic feature, namely, the helical morphology and motility conferred by axial periplasmic flagella. Their unique morphology and mode of propulsion also represent major pathogenicity factors of clinical spirochetes. Here we describe the genome sequences of two coccoid isolates of the recently described genus Sphaerochaeta which are members of the phylum Spirochaetes based on 16S rRNA gene and whole-genome phylogenies. Interestingly, the Sphaerochaeta genomes completely lack the motility and associated signal transduction genes present in all sequenced spirochete genomes. Additional analyses revealed that the lack of flagella is associated with a unique, nonrigid cell wall structure hallmarked by a lack of transpeptidase and transglycosylase genes, which is also unprecedented in spirochetes. The Sphaerochaeta genomes are highly enriched in fermentation and carbohydrate metabolism genes relative to other spirochetes, indicating a fermentative lifestyle. Remarkably, most of the enriched genes appear to have been acquired from nonspirochetes, particularly clostridia, in several massive horizontal gene transfer events (>40% of the total number of genes in each genome). Such a high level of direct interphylum genetic exchange is extremely rare among mesophilic organisms and has important implications for the assembly of the prokaryotic tree of life. Spiral shape and motility historically have been the unifying hallmarks of the phylum Spirochaetes. These features also represent important virulence factors of highly invasive pathogenic spirochetes such as the causative agents of syphilis and Lyme disease. Through the integration of genome sequencing, microscopy, and physiological studies, we conclusively show that the spiral morphology and motility of spirochetes are not universal morphological properties. In particular, we found that the genomes of the members of the recently described genus Sphaerochaeta lack the genes encoding the characteristic flagellar apparatus and, in contrast to most other spirochetes, have acquired many metabolic and fermentation genes from clostridia. These findings have major implications for the isolation and study of spirochetes, the diagnosis of spirochete-caused diseases, and the reconstruction of the evolutionary history of this important bacterial phylum. The Sphaerochaeta sp. genomes offer new avenues to link ecophysiology with the functionality and evolution of the spirochete flagellar apparatus.


GenHtr: a tool for comparative assessment of genetic heterogeneity in microbial genomes generated by massive short-read sequencing.
Microevolution is the study of short-term changes of alleles within a population and their effects on the phenotype of organisms. The result of the below-species-level evolution is heterogeneity, where populations consist of subpopulations with a large number of structural variations. Heterogeneity analysis is thus essential to our understanding of how selective and neutral forces shape bacterial populations over a short period of time. The Solexa Genome Analyzer, a next-generation sequencing platform, allows millions of short sequencing reads to be obtained with great accuracy, allowing for the ability to study the dynamics of the bacterial population at the whole genome level. The tool referred to as GenHtr was developed for genome-wide heterogeneity analysis. For particular bacterial strains, GenHtr relies on a set of Solexa short reads on given bacteria pathogens and their isogenic reference genome to identify heterogeneity sites, the chromosomal positions with multiple variants of genes in the bacterial population, and variations that occur in large gene families. GenHtr accomplishes this by building and comparatively analyzing genome-wide heterogeneity genotypes for both the newly sequenced genomes (using massive short-read sequencing) and their isogenic reference (using simulated data). As proof of the concept, this approach was applied to SRX007711, the Solexa sequencing data for a newly sequenced Staphylococcus aureus subsp. USA300 cell line, and demonstrated that it could predict such multiple variants. They include multiple variants of genes critical in pathogenesis, e.g. genes encoding a LysR family transcriptional regulator, 23 S ribosomal RNA, and DNA mismatch repair protein MutS. The heterogeneity results in non-synonymous and nonsense mutations, leading to truncated proteins for both LysR and MutS. GenHtr was developed for genome-wide heterogeneity analysis. Although it is much more time-consuming when compared to Maq, a popular tool for SNP analysis, GenHtr is able to predict potential multiple variants that pre-exist in the bacterial population as well as SNPs that occur in the highly duplicated gene families. It is expected that, with the proper experimental design, this analysis can improve our understanding of the molecular mechanism underlying the dynamics and the evolution of drug-resistant bacterial pathogens.


Risk of depression in family caregivers: unintended consequence of COVID-19.
Coronavirus disease 2019 (COVID-19) is likely to exacerbate the symptoms of poor mental health in family caregivers. To investigate whether rates of depressive symptomatology increased in caregivers during COVID-19 and whether the unintended consequences of health protective measures, i.e., social isolation, exacerbated this risk. Another aim was to see if caregivers accessed any online/phone psychological support during COVID. Data (1349 caregivers; 6178 non-caregivers) was extracted from Understanding Society, a UK population-level data-set. The General Health Questionnaire cut-off scores identified those who are likely to have depression. After adjustment for confounding caregivers had a higher risk of having depressive symptoms compared with non-caregivers, odds ratio (OR) = 1.22 (95% CI 1.05-1.40, P = 0.008) evidenced by higher levels of depression pre-COVID-19 (16.7% caregivers v. 12.1% non-caregivers) and during the COVID-19 pandemic (21.6% caregivers v. 17.9% non-caregivers), respectively. Further, higher levels of loneliness increased the risk of depression symptoms almost four-fold in caregivers, OR = 3.85 (95% 95% CI 3.08-4.85, P < 0.001), whereas accessing therapy attenuated the risk of depression (43%). A total of 60% of caregivers with depression symptoms reported not accessing any therapeutic support (for example online or face to face) during the COVID-19 pandemic. COVID-19 has had a negative impact on family caregivers' mental health with loneliness a significant contributor to depressive symptomatology. However, despite these detriments in mental health, the majority of caregivers do not access any online or phone psychiatric support. Finally, psychiatric services and healthcare professionals should aim to focus on reducing feelings of loneliness to support at-risk caregivers.


Radial nerve palsy owing to localized hypertrophic neuropathy (intraneural perineurioma) in early childhood.
Localized hypertrophic neuropathy, also termed intraneural perineurioma, is a rare disorder of unknown etiology that produces a slowly progressive painless focal lesion of a peripheral nerve. It is characterized histologically by concentric whorls ("onion bulbs") of epithelial membrane antigen-reactive, S-100 protein-negative perineurial cells surrounding nerve fibers. We report a radial nerve palsy in a child aged 2 years in whom the diagnosis of localized hypertrophic neuropathy was made by biopsy. Resection of the affected nerve segment and sural nerve grafting produced no useful recovery after 3 years, probably because of the long duration of denervation. When this mononeuropathy presents in early childhood, uncertainty over the time of onset can lead to difficulty in distinguishing this potentially treatable lesion from congenital and other causes of nerve palsy.


Comparison of Sono-guided Capsular Distension with Fluoroscopically Capsular Distension in Adhesive Capsulitis of Shoulder.
To investigate the short-term effects and advantages of sono-guided capsular distension, compared with fluoroscopically guided capsular distension in adhesive capsulitis of shoulder. In this prospective, randomized, and controlled trial, 23 patients (group A) were given an intra-articular injection of a mixture of 0.5% lidocaine (9 ml), contrast dye (10 ml), and triamcinolone (20 mg); they received the injection once every 2 weeks, for a total of 6 weeks, under sono-guidance. Twenty-five patients (group B) were treated similarly, under fluoroscopic guidance. Instructions for the self-exercise program were given to all subjects, without physiotherapy and medication. Effects were then assessed using a visual numeric scale (VNS), and the shoulder pain and disability index (SPADI), as well as a range of shoulder motion examinations which took place at the beginning of the study and 2 and 6 weeks after the last injection. Incremental cost-effective ratio (ICER), effectiveness, preference, and procedure duration were evaluated 6 weeks post-injection. The VNS, SPADI, and shoulder motion range improved 2 weeks after the last injection and continued to improve until 6 weeks, in both groups. However, no statistical differences in changes of VNS, SPADI, ROM, and effectiveness were found between these groups. Patients preferred sono-guided capsular distension to fluoroscopically guided capsular distension due to differences in radiation hazards and positional convenience. Procedure time was shorter for sono-guided capsular distension than for fluoroscopically guided capsular distension. Sono-guided capsular distension has comparable effects with fluoroscopically guided capsular distension for treatment of adhesive capsulitis of the shoulder. Sono-guided capsular distension can be substituted for fluoroscopic capsular distension and can be advantageous from the viewpoint of radiation hazard mitigation, time, cost-effectiveness and convenience.


Synergistic gold and enamine catalysis: intermolecular α-alkylation of aldehydes with allenamides.
Aldehydes can be α-alkylated with allenamides by the combined action of an organocatalyst and a gold complex. The reaction requires the simultaneous generation of an enamine and a gold-activated allenamide. Importantly, by using a chiral amine as organocatalyst it is possible to obtain aldehyde products featuring all-carbon quaternary stereocenter at their α-position, with moderate to good levels of enantioselectivity.


Ultraviolet scattering propagation modeling: analysis of path loss versus range.
Modeling of the complex atmospheric propagation of deep-ultraviolet (UV) radiation is important for applications such as non-line-of-sight (NLOS) UV communications. Building upon prior work in which it was observed that short-range, singly scattered NLOS path loss varies linearly with range, we formalize this relationship, generalizing it to consider any order of scattering and more-general system characteristics. In particular, we derive the approximate relationship PL[proportionality]r(2-n) between path loss PL and range r for nth-order scattered radiation, and investigate the region of validity of this approximation. Insight arising from the analysis can be invaluable in the development and study of UV systems, as demonstrated by numerical results that illustrate implications of the analysis.


Vitamin B6 and cardiovascular disease.
While overt vitamin B6 deficiency is not a frequent finding nowadays in medical practice, evidence suggests that insufficiency of this vitamin is rather widespread in a quite large portion of the population such as the elderly or in not unusual conditions such as that of alcohol addiction. Moreover, a mild deficiency in B6 vitamin is a state that may be associated with an increased risk of cardiovascular disease. Epidemiologic evidence from case control and prospective studies have suggested that low dietary intake or reduced blood concentrations of vitamin B6 is associated with an increased risk of cardiovascular disease, although most recent trials demonstrated the ineffectiveness of vitamin B6 supplementation on the prevention of cardiovascular events recurrence. Due to limited and somewhat inconsistent data together with the ample variety of critical functions in which vitamin B6 is involved in the human body, it is very challenging to attempt at establishing a cause and effect relationship between vitamin B6 and risk of cardiovascular disease as it is to delineate the exact mechanism(s) by which vitamin B6 may modulate such risk. In the present chapter we review the currently available knowledge deriving from both epidemiological and mechanistic studies designed to define potential candidate mechanisms for the association of vitamin B6 impairment and risk of cardiovascular disease development.


Fast-convergent algorithm for speckle-based phase retrieval and a design for dynamic wavefront sensing.
Wavefront reconstruction is carried out using sequentially recorded speckle patterns and an iterative phase retrieval method based on wave propagation. A novel fast-convergent algorithm that maintains the propagation distance in the iteration step equal to the distance between measurement planes is demonstrated. Employing the new algorithm, influences of the number of measurement planes, number of iterations, and uncertainties in the detector's transverse and axial positions on the rate of phase convergence are analyzed experimentally. A conceptual design for a dynamic wavefront sensor using arrays of beam splitters and detectors for parallel speckle recording is described.


Microfluidic self-assembly of folate-targeted monomolecular siRNA-lipid nanoparticles.
Non-viral delivery of nucleic acids for therapies based on RNA interference requires a rational design and optimal self-assembly strategies. Nucleic acid particles need to be small, stable and functional in terms of selective cell uptake and controlled release of encapsulated nucleic acids. Here we report on small (∼38 nm) monomolecular nucleic acid/lipid particles (mNALPs) that contain single molecules of short double-stranded oligonucleotides covered by a tight, highly curved lipid bilayer. The particles consist of DOPE, DOTAP, DOPC and DSPE-PEG(2000) and are assembled with 21 bp double-stranded DNA or small interfering RNA by solvent exchange on a hydrodynamic-focusing microfluidic chip. In comparison to vortex mixing by hand this method increases the encapsulation efficiency by 20%, and yields particles with a narrower size distribution, negligible aggregate formation and high stability in blood plasma and serum. Modification of mNALPs with folate-conjugated PEG-lipids results in specific binding and uptake by epithelial carcinoma KB cells overexpressing folate receptors. Binding is significantly reduced by competitive inhibition using free folate and is not observed with non-targeted mNALPs, revealing high specificity. The functionalized mNALPs show gene silencing in the presence of chloroquine, an endosome-destabilizing agent. Together, the robust self-assembly of small-sized mNALPs with their high stability and receptor-specific cell uptake demonstrate that the tight, PEG-grafted lipid-bilayer encapsulation may offer a promising approach towards the delivery of short double-stranded oligonucleotides.


Fatal familial insomnia and familial Creutzfeldt-Jakob disease: disease phenotype determined by a DNA polymorphism.
Fatal familial insomnia (FFI) and a subtype of familial Creutzfeldt-Jakob disease (CJD), two clinically and pathologically distinct diseases, are linked to the same mutation at codon 178 (Asn178) of the prion protein gene. The possibility that a second genetic component modified the phenotypic expression of the Asn178 mutation was investigated. FFI and the familial CJD subtype segregated with different genotypes determined by the Asn178 mutation and the methionine-valine polymorphism at codon 129. The Met129, Asn178 allele segregated with FFI in all 15 affected members of five kindreds whereas the Val129, Asn178 allele segregated with the familial CJD subtype in all 15 affected members of six kindreds. Thus, two distinct disease phenotypes linked to a single pathogenic mutation can be determined by a common polymorphism.


Minimal intervention: advanced lesions.
Minimal intervention techniques are generally considered in relation to initial carious lesions. However, it appears logical to apply the same principles to extensive cavities as well as to the replacement of failed existing restorations. As the cavity becomes larger, there is an increasing need to consider protection of remaining cusps because they become seriously weakened by loss of the central core of the crown and therefore become subject to the development of splits at the base. However, it is possible to develop a protective cavity design without undue sacrifice of remaining tooth structure, at the same time that maintenance of occlusal anatomy and correct contact with the opposing arch are ensured. For larger cavities, special consideration needs to be given to the strength of the restorative material. Glass ionomer is relatively brittle and should not be exposed to undue occlusal load. Resin composites cannot be regarded as universal in their physical properties, and placement is time-consuming. A lamination technique is often useful, combining the advantages of both glass ionomer and resin composite. Amalgam should not be entirely discarded as an option because it has greater strength than both glass ionomer and resin composite and is still useful for the restoration of extensive cavities and for protection and retention of weakened cusps. Minimal intervention principles, designed to limit the loss of natural tooth structure, should be applied to all restorative dentistry. None of the available restorative materials is entirely satisfactory in the long term.


"Once I begin to participate, people will run away from me": understanding stigma as a barrier to HIV vaccine research participation in Kenya.
Participation of volunteers in clinical research is essential to the development of effective HIV prevention methods, including an HIV vaccine. This study expands current knowledge of stigma and discrimination related to participation in HIV vaccine research in sub-Saharan Africa by exploring the perception of stigma and discrimination as a barrier to participation in HIV vaccine research in Kenya. Eighteen focus groups with a total of 133 participants and 82 individual interviews were conducted with a range of respondents at two centers in Nairobi, Kenya: a preventive AIDS vaccine trial center; and a preparatory clinical and epidemiological study center. Respondents included peer leaders, community advisory board members, former and current volunteers in clinical research, study staff, community leaders and community members. Data were analyzed using an iterative coding process. Four prominent stigma-related barriers to participation emerged among all respondent groups, across both centers: (1) volunteers are often assumed by family and community members to be HIV positive because of their participation in vaccine research; (2) HIV-related stigma is perceived as pervasive and damaging in the communities where volunteers live, thus they fear consequent stigma if people believe them to be HIV positive; (3) potential volunteers fear being tested for HIV, a prerequisite for participation, because of possible disclosure of HIV status in communities with high perceived HIV-related stigma; and (4) volunteers must carefully manage information about their participation because of misperceptions and assumptions about vaccine research volunteers. HIV-related stigma and discrimination influence people's decisions to join HIV-vaccine related research. Findings underscore a need for integration of stigma-reduction programming into education and outreach activities for volunteers, and the communities in which they live. This is particularly critical for trials recruiting individuals with higher HIV risk, who are often already highly stigmatized.


Implementing an EHR-based Screening and Referral System to Address Social Determinants of Health in Primary Care.
Social determinants affect health, yet there are few systematic clinical strategies in primary care that leverage electronic health record (EHR) automation to facilitate screening for social needs and resource referrals. An EHR-based social determinants of health (SDOH) screening and referral model, adapted from the WE CARE model for pediatrics, was implemented in urban adult primary care. This study aimed to: (1) understand the burden of SDOH among patients at Boston Medical Center; and (2) evaluate the feasibility of implementing a systematic clinical strategy to screen new primary care patients for SDOH, use EHR technology to add these needs to the patient's chart through autogenerated ICD-10 codes, and print patient language-congruent referrals to available resources upon patient request. This observational study assessed the number of patients who were screened to be positive and requested resources for social needs. In addition, we evaluated the feasibility of implementing our SDOH strategy by determining the proportion of: eligible patients screened, providers signing orders for positive patient screenings, and provider orders for resource referral guides among patients requesting resource connections. In total, 1696 of 2420 (70%) eligible patients were screened. Employment (12%), food insecurity (11%), and problems affording medications (11%) were the most prevalent concerns among respondents. In total, 367 of 445 (82%) patients with ≥1 identified needs (excluding education) had the appropriate ICD-10 codes added to their visit diagnoses. In total, 325 of 376 (86%) patients who requested resources received a relevant resource referral guide. Implementing a systematic clinical strategy in primary care using EHR workflows was successful in identifying and providing resource information to patients with SDOH needs.


An all-fiber laser generating cylindrical vector beam.
We proposed and demonstrated an all-fiber laser to generate cylindrical vector beam. A pair of fiber-based collimators was used to select the cylindrical vector beam operating. The radially and azimuthally polarized modes can be switchable just by applying pressure to a section of fiber in our fiber laser system. A 70 cm long Yb-doped fiber was used as gain medium and the lasing wavelength was around 1030 nm.


Sirt3 regulates metabolic flexibility of skeletal muscle through reversible enzymatic deacetylation.
Sirt3 is an NAD(+)-dependent deacetylase that regulates mitochondrial function by targeting metabolic enzymes and proteins. In fasting mice, Sirt3 expression is decreased in skeletal muscle resulting in increased mitochondrial protein acetylation. Deletion of Sirt3 led to impaired glucose oxidation in muscle, which was associated with decreased pyruvate dehydrogenase (PDH) activity, accumulation of pyruvate and lactate metabolites, and an inability of insulin to suppress fatty acid oxidation. Antibody-based acetyl-peptide enrichment and mass spectrometry of mitochondrial lysates from WT and Sirt3 KO skeletal muscle revealed that a major target of Sirt3 deacetylation is the E1α subunit of PDH (PDH E1α). Sirt3 knockout in vivo and Sirt3 knockdown in myoblasts in vitro induced hyperacetylation of the PDH E1α subunit, altering its phosphorylation leading to suppressed PDH enzymatic activity. The inhibition of PDH activity resulting from reduced levels of Sirt3 induces a switch of skeletal muscle substrate utilization from carbohydrate oxidation toward lactate production and fatty acid utilization even in the fed state, contributing to a loss of metabolic flexibility. Thus, Sirt3 plays an important role in skeletal muscle mitochondrial substrate choice and metabolic flexibility in part by regulating PDH function through deacetylation.


Managing shame: an interpersonal perspective.
Experiences of shame are often difficult to manage, not least because of their interpersonal implications. However, limited research attention has been paid to the management and repair of shame, and in particular to the role that social factors may play in this. We aimed to explore these issues by obtaining 50 written first-person accounts of experiences of managing difficult episodes of shame from a cross section of students and employees at a British university. These participant-generated narrative accounts were supplemented by written answers to open-ended questions. Via a contextual constructionist thematic analysis, three overarching themes were identified: The centrality of others' evaluations of the self; Repositioning the self vis-à-vis others, and Being disabled by shame. Discussion focuses on the first two of these themes which together suggest that because the participants saw their shame as produced in interaction with others, effective management and repair of shame depended not just on a changed view of the self but on a repositioning of the self in relation to others. This analysis therefore suggests that repair of shame may often need to be mutually negotiated and as such provides support for theoretical approaches to shame which emphasize the centrality of others' actual or perceived judgements of the self.


Perovskite Color Detectors: Approaching the Efficiency Limit.
Color image sensing by a smartphone or digital camera employs sensor elements with an array of color filters for capturing basic blue, green, and red color information. However, the normalized optical efficiency of such color filter-based sensor elements is limited to only one-third. Optical detectors based on perovskites are described, which can overcome this limitation. An efficient color sensor design has been proposed in this study that uses a vertically stacked arrangement of perovskite diodes. As compared to the conventional color filter-based sensors, the proposed sensor structure can potentially reach normalized optical efficiency approaching 100%. In addition, the proposed sensor design does not exhibit color aliasing or color Moiré effects, which is one of the main limitations for the filter-based sensors. Furthermore, up to our knowledge, for the first time, it could be theoretically shown that both vertically arranged sensor and conventional color filter-based sensor provide almost comparable color errors. The optical properties of the perovskite materials are determined by optical measurements in combination with an energy shift model. The optics of the stacked perovskite sensors is investigated by threedimensional finite-difference timedomain simulations. Finally, colorimetric characterization was carried out to determine the color error of the sensors.