Refractive-index profiling of azimuthally asymmetric optical fibers by microinterferometric optical phase tomography.
Accurate nondestructive refractive-index profiling is needed in the modeling, design, and manufacturing of optical fibers and fiber devices. Most profile measurement techniques cannot correctly characterize fibers with small or irregular refractive-index variations over their cross sections. Microinterferometric optical phase tomography (MIOPT) is a technique that allows measurement of fiber refractive-index profiles exhibiting such variations. We present the first demonstration, to our knowledge, of MIOPT. The profile of a polarization-maintaining fiber is measured by MIOPT and shown to be in agreement with (destructive) fiber end-face measurements. MIOPT is also applied to the limiting case of a symmetric single-mode fiber.


Light echoes from ancient supernovae in the Large Magellanic Cloud.
The light from historical supernovae could in principle still be visible as scattered-light echoes centuries after the explosion. The detection of light echoes could allow us to pinpoint the supernova event both in position and age and, most importantly, permit the acquisition of spectra to determine the 'type' of the supernova centuries after the direct light from the explosion first reached Earth. Although echoes have been discovered around some nearby extragalactic supernovae, targeted searches have not found any echoes in the regions of historical Galactic supernovae. Here we report three faint variable-surface-brightness complexes with high apparent proper motions pointing back to three of the six smallest (and probably youngest) previously catalogued supernova remnants in the Large Magellanic Cloud, which are believed to have been thermonuclear (type Ia) supernovae. Using the distance and apparent proper motions of these echo arcs, we estimate ages of 610 and 410 years for two of them.


High protective efficacy of rice bran against human rotavirus diarrhea via enhancing probiotic growth, gut barrier function, and innate immunity.
Previously, we showed that rice bran (RB) was able to reduce human rotavirus (HRV) diarrhea in gnotobiotic pigs. Here, we investigated its effect on the growth of diarrhea-reducing probiotic Lactobacillus rhamnosus GG (LGG) and Escherichia coli Nissle (EcN), and the resulting effects on HRV diarrhea, gut epithelial health, permeability and innate immune responses during virulent HRV challenge. On 3, 5, and 7 days of age pigs were inoculated with 2 × 10(4) colony-forming-units LGG+EcN to initiate colonization. Daily RB supplementation (replacing 10% calorie intake) was started at 5 days of age and continued until euthanasia. A subset of pigs in each group was challenged orally with 10(5) focus-forming-units of virulent HRV at 33 days of age. RB completely prevented HRV diarrhea in LGG+EcN colonized pigs. RB significantly promoted the growth of both probiotic strains in the gut (~5 logs) and increased the body-weight-gain at 4-5 weeks of age compared to non-RB group. After HRV challenge, RB-fed pigs had significantly lower ileal mitotic index and villus width, and significantly increased intestinal IFN-γ and total IgA levels compared to non-RB group. Therefore, RB plus LGG+EcN colonization may represent a highly effective therapeutic approach against HRV and potentially a variety of other diarrhea-inducing enteric pathogens.


Dimerization of the Klenow fragment of Escherichia coli DNA polymerase I is linked to its mode of DNA binding.
Upon associating with a proofreading polymerase, the nascent 3' end of a DNA primer/template has two possible fates. Depending upon its suitability as a substrate for template-directed extension or postsynthetic repair, it will bind either to the 5'-3' polymerase active site, yielding a polymerizing complex, or to the 3'-5' exonuclease site, yielding an editing complex. In this investigation, we use a combination of biochemical and biophysical techniques to probe the stoichiometry, thermodynamic, and kinetic stability of the polymerizing and editing complexes. We use the Klenow fragment of Escherichia coli DNA polymerase I (KF) as a model proofreading polymerase and oligodeoxyribonucleotide primer/templates as model DNA substrates. Polymerizing complexes are produced by mixing KF with correctly base paired (matched) primer/templates, whereas editing complexes are produced by mixing KF with multiply mismatched primer/templates. Electrophoretic mobility shift titrations carried out with matched and multiply mismatched primer/templates give rise to markedly different electrophoretic patterns. In the case of the matched primer/template, the KF.DNA complex is represented by a slow moving band. However, in the case of the multiply mismatched primer/template, the complex is predominantly represented by a fast moving band. Analytical ultracentrifugation measurements indicate that the fast and slow moving bands correspond to 1:1 and 2:1 KF.DNA complexes, respectively. Fluorescence anisotropy titrations reveal that KF binds with a higher degree of cooperativity to the matched primer/template. Taken together, these results indicate that KF is able to dimerize on a DNA primer/template and that dimerization is favored when the first molecule is bound in the polymerizing mode, but disfavored when it is bound in the editing mode. We suggest that self-association of the polymerase may play an important and as yet unexplored role in coordinating high-fidelity DNA replication.


Single unpaired nucleotides facilitate HIV-1 reverse transcriptase displacement synthesis through duplex RNA.
During reverse transcription of viral RNA, HIV-1 reverse transcriptase (RT) encounters RNA stem-loop structures that require displacement synthesis activity in which RT disrupts the RNA helix to access the template strand. A primer extension assay was developed to assess HIV-1 RT RNA displacement synthesis activity in vitro. Initial results revealed that HIV-1 RT performs only limited amounts of RNA displacement through long stretches of RNA duplex, with the majority of synthesis stalling at sequence-dependent pause positions. DNA displacement synthesis through the same sequence, however, proceeded rapidly to the end of the template. The RNA folding algorithm mfold indicated that the presence of an unpaired nucleotide, or "bulge," along the RNA duplex would promote helix melting ahead of the DNA primer terminus to create a small gap of nondisplacement synthesis. Primer extension assays using substrates possessing single-nucleotide bulges in the nontemplate strand near pause sites resulted in diminished pausing at positions within the predicted melted region. Surprisingly, the bulges also reduced pausing distal to the bulge at positions that are expected to remain base-paired. Further analysis revealed that stalling during RNA displacement synthesis results from the displaced RNA re-annealing to the template strand thus forcing the primer terminus to become unpaired and, therefore, not extendable. Introduction of a bulge facilitates displacement synthesis through distal regions by increasing RT processivity in the vicinity of a bulge and reducing the impact of branch migration on primer extension.


Participatory development and implementation of a community research workshop: experiences from a community-based participatory research partnership.
Although community-based participatory research (CBPR) principles stress the importance of "equitable partnerships" and an "empowering and power-sharing process that attends to social inequalities," descriptions of actual projects often focus on the challenges confronted in academic-community partnerships. These challenges occur in the context of economic and power inequities and the frequently limited diversity of researchers. Less often does this discourse attend to the link between the principles of CBPR and their empowering potential for community members who internalize and use these principles to hold outside partners accountable to these ideals. This article documents the participatory development and implementation of a community research workshop, the community and organizational contexts, the content of the workshop, and lessons learned. Workshop objectives included increasing community knowledge of the research process, positively impacting community members' perceptions and attitudes about research, and improving researchers' understanding of community knowledge, perceptions, and experiences with research. This project was conducted as a part of the larger United States Department of Agriculture, Agriculture Research Service (USDA ARS) Delta Nutrition Intervention Research Initiative (Delta NIRI). The workshop was developed by a joint academic-community team in partnership with a community-based workshop advisory committee (WAC) and implemented in three rural communities of the lower Mississippi Delta. Development included a dry run with the WAC, a pilot workshop, and a focus group to refine the final content and format. Applying participatory principles to the development of the community research workshop resulted in the creation of a mutually acceptable workshop and co-learning experience that empowered community members in their involvement in other community research projects.


Cloning of a functional promoter of the human sodium/iodide-symporter gene.
We have cloned and sequenced genomic DNA from a human library extending 1300 bp upstream the 5'-untranslated sequence of the cDNA coding for the sodium/iodide symporter. In transient transfection assays this sequence exhibited promoter activity, which could be confined to nucleotides -443 to -395 relative to the ATG start codon. This minimal promoter, including a putative GC- and TATA- box, was preferentially activated in the rat thyroid cell line FRTL-5, but was also active in non-thyroidal cells, such as COS-7 and Chinese-hamster ovary, albeit to a markedly lower extent.


Inhibition of in vitro peripheral myelin formation by monoclonal anti-galactocerebroside.
This work investigates the role of galactocerebroside (GalC) in peripheral myelin formation. A monoclonal antibody against GalC was introduced into a myelinating culture system consisting of rat sensory neurons and Schwann cells, without other cell types. At levels that saturated Schwann cell surface GalC, anti-GalC IgG prevented by more than 99% the appearance of myelin sheaths. Ensheathment and basal lamina deposition were unaffected and many Schwann cells were in the 1:1 relationship that typically develops between Schwann cells and axons prior to myelination. Thus, the anti-GalC antibody did not interfere with the formation of the mesaxon but prevented its elongation. When experimentally restrained from myelination, Schwann cells did not accumulate the myelin proteins PO and basic protein; only low levels were expressed. The proposed mechanism of inhibition is the removal of GalC from Schwann cell surfaces by internalization of the GalC-anti-GalC antigen-antibody complex. This apparently prevented the interaction of adjacent cell surfaces during the elongation of Schwann cell membranes that constitute the myelin lamellae.


Distributed ARTMAP: a neural network for fast distributed supervised learning.
Distributed coding at the hidden layer of a multi-layer perceptron (MLP) endows the network with memory compression and noise tolerance capabilities. However, an MLP typically requires slow off-line learning to avoid catastrophic forgetting in an open input environment. An adaptive resonance theory (ART) model is designed to guarantee stable memories even with fast on-line learning. However, ART stability typically requires winner-take-all coding, which may cause category proliferation in a noisy input environment. Distributed ARTMAP (dARTMAP) seeks to combine the computational advantages of MLP and ART systems in a real-time neural network for supervised learning. An implementation algorithm here describes one class of dARTMAP networks. This system incorporates elements of the unsupervised dART model, as well as new features, including a content-addressable memory (CAM) rule for improved contrast control at the coding field. A dARTMAP system reduces to fuzzy ARTMAP when coding is winner-take-all. Simulations show that dARTMAP retains fuzzy ARTMAP accuracy while significantly improving memory compression.


Antihypertensive effect of pioglitazone is not invariably associated with increased insulin sensitivity.
Hypertension is often associated with insulin resistance, and several chemically diverse agents that increase insulin sensitivity attenuate the development of experimental hypertension. We undertook the present study to determine whether attenuation of hypertension by pioglitazone, a thiazolidinedione derivative that increases insulin sensitivity without increasing insulin secretion, is specifically related to its effect on insulin-mediated glucose uptake. Pioglitazone administered daily by oral gavage (20 mg/kg per day) for 3 weeks attenuated the development of hypertension in both the Dahl salt-sensitive (DS) rat (an insulin-resistant model of hypertension) and the one-kidney, one clip rat (a model of hypertension not associated with insulin resistance). Based on euglycemic insulin clamp studies in conscious animals, the glucose clearance rate was increased (P < .05) in pioglitazone-treated DS rats (36 +/- 3 mg/kg per minute) compared with control DS rats (27 +/- 1 mg/kg per minute). However, pioglitazone did not affect the glucose clearance rate in one-kidney, one clip hypertensive rats. Metformin, an unrelated agent that also improves glucose tolerance, had no significant effect on blood pressure or glucose clearance rate in either DS or one-kidney, one clip rats. Thus, the hypotensive effect of pioglitazone is not invariably associated with its capacity to improve insulin-induced glucose utilization.


Citrobacter rodentium Relies on Commensals for Colonization of the Colonic Mucosa.
We investigated the role of commensals at the peak of infection with the colonic mouse pathogen Citrobacter rodentium. Bioluminescent and kanamycin (Kan)-resistant C. rodentium persisted avirulently in the cecal lumen of mice continuously treated with Kan. A single Kan treatment was sufficient to displace C. rodentium from the colonic mucosa, a phenomenon not observed following treatment with vancomycin (Van) or metronidazole (Met). Kan, Van, and Met induce distinct dysbiosis, suggesting C. rodentium relies on specific commensals for colonic colonization. Expression of the master virulence regulator ler is induced in germ-free mice, yet C. rodentium is only seen in the cecal lumen. Moreover, in conventional mice, a single Kan treatment was sufficient to displace C. rodentium constitutively expressing Ler from the colonic mucosa. These results show that expression of virulence genes is not sufficient for colonization of the colonic mucosa and that commensals are essential for a physiological infection course.


Comparative integrated omics: identification of key functionalities in microbial community-wide metabolic networks.
Mixed microbial communities underpin important biotechnological processes such as biological wastewater treatment (BWWT). A detailed knowledge of community structure and function relationships is essential for ultimately driving these systems towards desired outcomes, e.g., the enrichment in organisms capable of accumulating valuable resources during BWWT. A comparative integrated omic analysis including metagenomics, metatranscriptomics and metaproteomics was carried out to elucidate functional differences between seasonally distinct oleaginous mixed microbial communities (OMMCs) sampled from an anoxic BWWT tank. A computational framework for the reconstruction of community-wide metabolic networks from multi-omic data was developed. These provide an overview of the functional capabilities by incorporating gene copy, transcript and protein abundances. To identify functional genes, which have a disproportionately important role in community function, we define a high relative gene expression and a high betweenness centrality relative to node degree as gene-centric and network topological features, respectively. Genes exhibiting high expression relative to gene copy abundance include genes involved in glycerolipid metabolism, particularly triacylglycerol lipase, encoded by known lipid accumulating populations, e.g., CandidatusMicrothrix parvicella. Genes with a high relative gene expression and topologically important positions in the network include genes involved in nitrogen metabolism and fatty acid biosynthesis, encoded by Nitrosomonas spp. and Rhodococcus spp. Such genes may be regarded as 'keystone genes' as they are likely to be encoded by keystone species. The linking of key functionalities to community members through integrated omics opens up exciting possibilities for devising prediction and control strategies for microbial communities in the future.


Genome Analysis of Carbaryl-Degrading Strain Pseudomonas putida XWY-1.
Carbaryl was a widely used pesticide in the agriculture industry. The toxicity against non-target organisms and the environmental pollution it caused became the focus of public concern. However, the microbial mechanism of carbaryl degradation was not fully investigated. In the study, we reported the complete genome of the carbaryl-degrading Pseudomonas putida strain XWY-1, which consists of a chromosome (5.9 Mbp) and a plasmid (0.4 Mbp). The carbaryl degradation genes are located on the plasmid. The study on the genome will facilitate to further elucidate the carbaryl degradation and advance the potential biotechnological applications of P. putida strain XWY-1.


Real-Time Methylation-Specific Polymerase Chain Reaction for MGMT Promoter Methylation Clinical Testing in Glioblastoma: An Alternative Detection Method for a Heterogeneous Process.
To develop and evaluate a real-time methylation-specific polymerase chain reaction (RT-MSP) MGMT assay, with a particular focus on small biopsies and indeterminate testing results. We assessed formalin-fixed paraffin-embedded glioblastoma or gliosarcoma specimens (n = 641). A test-validation group (n = 51) with previously obtained reference laboratory (RL) results was used to determine performance characteristics of the RT-MSP assay. An indeterminate (equivocal) category was established for cases that could not be clearly classified as positive or negative. Overall agreement of RT-MSP and RL results was 91% (41/45 nonindeterminate cases). Discordant cases were tested by pyrosequencing, and results were most concordant with RT-MSP. Among cases with limited amounts of tissue (n = 7), six yielded valid results by RT-MSP (all negative); the single invalid result consisted of a stereotactic biopsy specimen obtained 14 years prior. A subset of indeterminate cases obtained during clinical testing (n = 18/575 [3%]) was also evaluated by pyrosequencing and showed a heterogeneous pattern of methylation across the eight interrogated CpG sites. The RT-MSP assay that we developed in-house is a robust clinical detection method for the heterogeneous process of MGMT promoter methylation in glioblastoma.


Evolution of the neural crest viewed from a gene regulatory perspective.
Neural crest cells are a vertebrate innovation and form a wide variety of embryonic cell types as diverse as peripheral neurons and facial skeleton. They undergo complex migration and differentiation processes from their site of origin in the developing central nervous system to their final destinations in the periphery. In this review, we summarize recent data on the current formulation of a gene regulatory network underlying neural crest formation and its roots at the base of the vertebrate lineage. Analyzing neural crest formation from a gene regulatory viewpoint provides insights into both the developmental mechanisms and evolutionary origins of this vertebrate-specific cell type.


Improving Management Strategies of Plant Diseases Using Sequential Sensitivity Analyses.
Improvement of management strategies of epidemics is often hampered by constraints on experiments at large spatiotemporal scales. A promising approach consists of modeling the biological epidemic process and human interventions, which both impact disease spread. However, few methods enable the simultaneous optimization of the numerous parameters of sophisticated control strategies. To do so, we propose a heuristic approach (i.e., a practical improvement method approximating an optimal solution) based on sequential sensitivity analyses. In addition, we use an economic improvement criterion based on the net present value, accounting for both the cost of the different control measures and the benefit generated by disease suppression. This work is motivated by sharka (caused by Plum pox virus), a vector-borne disease of prunus trees (especially apricot, peach, and plum), the management of which in orchards is mainly based on surveillance and tree removal. We identified the key parameters of a spatiotemporal model simulating sharka spread and control and approximated optimal values for these parameters. The results indicate that the current French management of sharka efficiently controls the disease, but it can be economically improved using alternative strategies that are identified and discussed. The general approach should help policy makers to design sustainable and cost-effective strategies for disease management.


Oral misoprostol for preventing postpartum haemorrhage in home births in rural Bangladesh: how effective is it?
Evidence exists about prevention of postpartum haemorrhage (PPH) by oral administration of misoprostol in low-income countries, but effectiveness of prevention by lay community health workers (CHW) is not sufficient. This study aimed to investigate whether a single dose (400 µg) of oral misoprostol could prevent PPH in a community home-birth setting and to assess its acceptability and feasibility among rural Bangladeshi women. This quasi-experimental trial was conducted among 2,017 rural women who had home deliveries between November 2009 and February 2010 in two rural districts of northern Bangladesh. In the intervention district 1,009 women received 400 µg of misoprostol immediately after giving birth by the lay CHWs, and in the control district 1,008 women were followed after giving birth with no specific intervention against PPH. Primary PPH (within 24 hours) was measured by women's self-reported subjective measures of the normality of blood loss using the 'cultural consensus model.' Baseline data provided socio-economic, reproductive, obstetric, and bleeding disorder information. The incidence of primary PPH was found to be lower in the intervention group (1.6%) than the control group (6.2%) (p<0.001). Misoprostol provided 81% protection (RR: 0.19; 95% CI: 0.08-0.48) against developing primary PPH. The proportion of retained and manually removed placentae was found to be higher in the control group compared to the intervention group. Women in the control group were more likely to need an emergency referral to a higher level facility and blood transfusion than the intervention group. Unexpectedly few women experienced transient side effects of misoprostol. Eighty-seven percent of the women were willing to use the drug in future pregnancy and would recommend to other pregnant women. Community-based distribution of oral misoprostol (400 µg) by CHW appeared to be effective, safe, acceptable, and feasible in reducing the incidence of PPH in rural areas of Bangladesh. This strategy should be scaled up across the country where access to skilled attendance is limited.


HIV-1 vaccines and adaptive trial designs.
Developing a vaccine against the human immunodeficiency virus (HIV) poses an exceptional challenge. There are no documented cases of immune-mediated clearance of HIV from an infected individual, and no known correlates of immune protection. Although nonhuman primate models of lentivirus infection have provided valuable data about HIV pathogenesis, such models do not predict HIV vaccine efficacy in humans. The combined lack of a predictive animal model and undefined biomarkers of immune protection against HIV necessitate that vaccines to this pathogen be tested directly in clinical trials. Adaptive clinical trial designs can accelerate vaccine development by rapidly screening out poor vaccines while extending the evaluation of efficacious ones, improving the characterization of promising vaccine candidates and the identification of correlates of immune protection.


A randomised, controlled, crossover trial of oral midazolam and nitrous oxide for paediatric dental sedation.
A randomised, controlled, crossover trial was designed to assess the safety and effectiveness of oral midazolam sedation for orthodontic extractions. Forty-six ASA physical status I children aged 10-16 years were recruited. Each child required two treatment sessions. Sedation with either oral midazolam 0.5 mg.kg-1 or nitrous oxide in oxygen was used at the first visit, the alternative being used at the second visit. Blood pressure, heart rate, arterial oxygen saturation, and sedation and behavioural scores were recorded every 5 min. Anxiety levels and postoperative satisfaction were also recorded. Blood pressure, heart rate and arterial oxygen saturation in both groups were similar and within acceptable clinical limits. The median [range] lowest arterial oxygen saturation levels for subjects in the midazolam and nitrous oxide groups were 95 [90-100]% and 98 [93-100]%, respectively. The median [range] time to the maximum level of sedation in the midazolam group was 20 [5-65] min compared with 5 [5-10] min in the nitrous oxide group (p < 0.001). The median [range] duration of treatment was similar in both groups (midazolam group: 10 [5-30] min, nitrous oxide group: 10 [5-25] min). Seventy-four per cent of subjects were prepared to have oral midazolam sedation again, 54% preferring it. Oral midazolam appears to be a safe and acceptable form of sedation for 10-16-year-old paediatric dental patients.


White blood cell and platelet counts can be used to differentiate between infection and the normal response after splenectomy for trauma: prospective validation.
Transient elevations of the serum white blood cell count (WBC) and platelet count (PC) are normal physiologic responses after splenectomy. The clinician is often challenged to identify an infection in a postsplenectomy patient with an elevated WBC. A previous retrospective study found that a WBC greater than 15 x 10/microL and a PC/WBC ratio < 20 on postoperative day 5, in addition to an Injury Severity Score > 16, were highly associated with infection and should not be considered as part of the physiologic response to splenectomy. The current study intends to prospectively validate the WBC and PC/WBC ratio on postoperative day 5 as markers of infection after splenectomy for trauma. Consecutive trauma patients admitted to an urban, Level I trauma center who underwent splenectomy from June 2002 to December 2004 were collected prospectively. In addition to admission demographics, variables collected included daily WBC, PC, and PC/WBC ratio during the first 10 postoperative days. Outcome was the presence of infection. Patients with infection (infected group) were compared with those without infection (noninfected group). Injury Severity Score > 16, postoperative day 5 WBC > 15 x 10/microL, and PC/WBC ratio < 20 were investigated as risk factors for postsplenectomy infection. There were 96 trauma patients who underwent splenectomy during the study period, and 44 (46%) developed a postoperative infection. Infectious complications included pneumonia (n = 30 [31%]), followed by septicemia (n = 20 [21%]), urinary tract infection (n = 12 [13), abdominal abscess (n = 9 [9%]), and wound infection (n = 4 [4%]). Postoperative day 5 was the first day that infected patients had a higher WBC (16 +/- 6 x 10/microL vs. 14 +/- 4 x 10/microL, p = 0.03) and a lower PC/WBC ratio (15 +/- 9 vs. 24 +/- 12, p = 0.002) than noninfected patients. The presence of two or more risk factors for infection was associated with a 79% rate of infection, and no patient developed an infection if all three risk factors were absent. On postoperative day 5 after splenectomy for trauma, a WBC greater than 15 x 10/microL and a PC/WBC ratio less than 20 are reliable markers of infection.


Must every child with long QT syndrome take a beta blocker?
Long QT syndrome is the most commonly recognised cause of sudden cardiac death in children. With a prevalence of 1 in 2000, family screening is identifying large numbers of hitherto asymptomatic gene carriers in the community, about a third of whom have a normal QT interval. The mainstay of treatment is long term uninterrupted beta blocker therapy, a treatment with many potential side effects. This article reviews the evidence and suggests a cohort who may, after assessment in a specialised cardiac-genetic clinic, be spared this treatment because of very low baseline risk. These are asymptomatic boys and prepubertal girls with a heart rate corrected QT interval persistently less than 470 ms who do not indulge in high risk activities (especially swimming) and do not have a missense mutation in the c-loop region of the KCNQ1 (long QT 1) gene.


Reducing Emotional Distress for Childhood Hypoglycemia in Parents (REDCHiP): Protocol for a Randomized Clinical Trial to Test a Video-Based Telehealth Intervention.
Despite the introduction of new insulin analogs, insulin pumps, and continuous glucose monitoring (CGM), young children with type 1 diabetes mellitus (T1D) remain vulnerable to episodes of hypoglycemia because of their unpredictable eating and activity patterns and high degree of insulin sensitivity. Caregivers and young children living with T1D learn to fear hypoglycemia because it is uncomfortable, unpredictable, and dangerous. Up to 60% of caregivers of young children with T1D report moderate to severe levels of fear of hypoglycemia, and caregiver fear of hypoglycemia relates to lower quality of life for families and suboptimal child glycemic control. Yet, until recently, there have been no studies reporting on a targeted intervention to treat caregiver fear of hypoglycemia in families of young children. The aim of this project is to conduct a randomized clinical trial of an innovative, video-based telehealth intervention to treat fear of hypoglycemia in caregivers of young children with T1D versus a relevant, age-appropriate attention control intervention. We created the Reducing Emotional Distress for Childhood Hypoglycemia in Parents (REDCHiP) intervention by merging age-appropriate T1D education and behavioral parenting strategies with cognitive behavioral therapy strategies that are effective for reducing fear and promoting adaptive coping. REDCHiP uses 10 video-based telehealth sessions that are a combination of group and individual sessions. We will recruit up to 180 families of young children with T1D to participate in this clinical trial from two pediatric diabetes clinics located in the midwestern and southern United States. Once families have been enrolled, we will randomize caregivers based on child age (age 2-3 years or 4-5 years), child sex, and family CGM use to participate in the REDCHiP or attention control intervention. Families will complete 3 assessment visits that coincide with study entry, end of treatment, and 3-month posttreatment. At each assessment visit, we will collect questionnaire data from caregivers, accelerometry data from caregivers and children, CGM data from children, and a blood sample to measure glycated hemoglobin levels from children. Recruitment began in July 2019, and enrollment is ongoing. The first wave of intervention delivery began in December 2019. We anticipate completing enrollment in 2023. Final reporting of results will occur within 12 months of the primary completion date. If the REDCHiP intervention is efficacious, next steps will be to examine multiple implementation strategies to determine how best to disseminate the intervention to pediatric diabetes clinics around the world. ClinicalTrials.gov NCT03914547; https://clinicaltrials.gov/ct2/show/NCT03914547. PRR1-10.2196/17877.


Testing of SHIRPA, a mouse phenotypic assessment protocol, on Dmd(mdx) and Dmd(mdx3cv) dystrophin-deficient mice.
The SHIRPA protocol was proposed as a rapid, comprehensive screening method for qualitatively abnormal phenotypes in the mouse (Rogers et al., Mamm Genome 8, 711, 1997). This screening technique is currently being used to identify mutants induced by N-ethylnitrosourea (ENU) mutagenesis (Brown and Nolan, Hum Mol Genet 7, 1627, 1998). SHIRPA can be used to identify mutants with neuromuscular abnormalities, but the sensitivity of the protocol is unknown. We tested two dystrophin-deficient mutants Dmd(mdx) and Dmd(mdx3cv), both of which are indistinguishable from wild-type by a simple visual assessment, at different ages, using the primary screen of the SHIRPA protocol. The most dramatic observation was that both Dmd(mdx) and Dmd(mdx3cv) mice showed extreme fatigue after testing, while mice from the same C57BL strains appeared unaffected. Each strain of dystrophin-deficient mice showed a different profile in locomotor activity and deficiencies in the wire maneuver, righting reflex, and negative geotaxis tests. Furthermore, the wire maneuver test indicated an earlier onset of muscular impairment in Dmd(mdx) than Dmd(mdx3cv) mice. These data suggest that the SHIRPA primary screen is effective not only in identifying subtle neuromuscular mutants, but also in distinguishing qualitative differences between mutants with neuromuscular abnormalities.


Intraspecific polymorphism, interspecific divergence, and the origins of function-altering mutations in deer mouse hemoglobin.
Major challenges for illuminating the genetic basis of phenotypic evolution are to identify causative mutations, to quantify their functional effects, to trace their origins as new or preexisting variants, and to assess the manner in which segregating variation is transduced into species differences. Here, we report an experimental analysis of genetic variation in hemoglobin (Hb) function within and among species of Peromyscus mice that are native to different elevations. A multilocus survey of sequence variation in the duplicated HBA and HBB genes in Peromyscus maniculatus revealed that function-altering amino acid variants are widely shared among geographically disparate populations from different elevations, and numerous amino acid polymorphisms are also shared with closely related species. Variation in Hb-O2 affinity within and among populations of P. maniculatus is attributable to numerous amino acid mutations that have individually small effects. One especially surprising feature of the Hb polymorphism in P. maniculatus is that an appreciable fraction of functional standing variation in the two transcriptionally active HBA paralogs is attributable to recurrent gene conversion from a tandemly linked HBA pseudogene. Moreover, transpecific polymorphism in the duplicated HBA genes is not solely attributable to incomplete lineage sorting or introgressive hybridization; instead, it is mainly attributable to recurrent interparalog gene conversion that has occurred independently in different species. Partly as a result of concerted evolution between tandemly duplicated globin genes, the same amino acid changes that contribute to variation in Hb function within P. maniculatus also contribute to divergence in Hb function among different species of Peromyscus. In the case of function-altering Hb mutations in Peromyscus, there is no qualitative or quantitative distinction between segregating variants within species and fixed differences between species.


Novel assessment of bone using time-resolved transcutaneous Raman spectroscopy.
With fragility fractures increasing as the population ages, there is a need for improved means to estimate risk of fracture. We recorded Raman spectra of both the mineral and organic phases of bone transcutaneously, a technology with potential to enhance bone quality and fracture risk assessment. The current "gold standard" assessment of bone quality is BMD determined by DXA. However, this accounts for only 60-70% of bone strength. X-rays are absorbed by the mineral phase of bone, whereas the organic phase remains essentially invisible; however, bone strength is critically dependent on both phases. We report, for the first time, a Raman spectroscopic technique that analyses both phases of bone beneath unbroken skin by eliminating spectral components of overlying tissues. We used an 800-nm laser (1-kHz, 1-ps pulses) with a synchronized 4-ps Kerr gate with variable picosecond delay that effectively shuttered out photons from overlying tissues. We measured bone Raman spectra at a point 2 mm above the carpus from two mouse genotypes with extreme differences in bone matrix quality: wildtype and oim/oim (matched for age, sex, and weight). Typical depth was 1.1 mm. We repeated the measurements with overlying tissues removed down to bone. Oim/oim mice produce only homotrimeric collagen, which results in poorly mineralized bone tissue. The main spectral features were present from both bone phases. The spectral bands were in similar ratios when measured through the skin or directly from bone (in both genotypes). The band of the mineral phase (phosphate nu1) was smaller in oim/oim mice when measured directly from bone and through skin. The band associated with a particular vibrational mode of organic phase collagen (CH2 wag) showed a frequency shift between the genotypes. This novel technique allowed us, for the first time, to make objective transcutaneous spectral measurements of both the mineral and the organic phases of bones and distinguish between normal and unhealthy bone tissue. After further optimization, this technology may help improve fracture risk assessments and open opportunities for screening in anticipation of the predicted increase in fragility fractures.


Differential regulation of the expression of Period2 protein in the limbic forebrain and dorsomedial hypothalamus by daily limited access to highly palatable food in food-deprived and free-fed rats.
Circadian clock genes are rhythmically expressed in many areas of the brain and body and are thought to underlie most endogenous circadian behaviors and physiological processes. Daily rhythms of clock gene expression throughout the brain and body are normally coordinated by the suprachiasmatic nucleus (SCN), but they are also strongly influenced by daily temporal restrictions of food availability. Here, we studied the effects of a daily restricted presentation of highly palatable complete meal replacement, chocolate Ensure Plus (Ensure) in food-deprived (restricted feeding, RF) and free-fed (restricted treat, RT) rats, on the expression of the clock protein, Period2 (PER2) in regions of the brain involved in motivational and emotional regulation; these include the oval nucleus of the bed nucleus of the stria terminalis (BNSTov), the central nucleus of the amygdala (CEA), the basolateral amygdala (BLA), the dentate gyrus (DG) and the dorsomedial hypothalamus (DMH). RF and RT rats consumed similar amounts of Ensure, but changes in the pattern of PER2 expression were seen only in the RF condition, suggesting that changes in PER2 expression in these regions are triggered by the daily alleviation of a negative metabolic state associated with RF and are independent of the positive incentive properties of the consumed substance, per se. In contrast, the expression of the immediate early gene, Fos, was increased in these regions by both RF and RT schedules, showing that signals concerning the incentive value of the consumed food reach these regions. No changes in either PER2 or Fos expression were observed in the SCN of RF or RT rats. These findings demonstrate that mechanisms leading to changes in the expression of PER2 and those affecting the induction of Fos under RF and RT are, at least in part, dissociable.


Cytomorphological Patterns of Nerve Aspirates in Pure Neuritic Leprosy-A Single Centre Cross-Sectional Observational Study.
Pure neuritic leprosy (PNL) poses a diagnostic challenge because of absence of skin patches, inconclusive skin biopsies and nerve conduction studies. Nerve biopsy though the diagnostic gold standard, is invasive, requires expertise, and may not be feasible in all cases. Fine needle aspiration cytology (FNAC) of accessible thickened nerves can be utilized as a minimally invasive diagnostic modality in PNL. This study was carried out to describe cytomorphological patterns of nerve aspirates in patients of PNL for diagnosis and classification of leprosy and study its advantage, if any, over skin biopsy. Twenty-seven treatment naive clinically diagnosed patients of PNL were included in this cross-sectional study carried out from January 2017 to December 2018 at a tertiary care centre in Western India. FNAC was done from a clinically involved nerve and aspirates were evaluated for cytomorphological characteristics and the presence of Acid-Fast Lepra bacilli. Nerve aspirates were diagnostic in 10 (37%) patients while 17 (63%) aspirates showed non-specific or no inflammation. Of the diagnostic aspirates, six (22.2%) were classified as tuberculoid leprosy, three (11.1%) as lepromatous and one (3.7%) as borderline leprosy. Mycobacterium leprae were demonstrated among three (11.1%) of these aspirates. In comparison, only three (11.1%) skin biopsies were diagnostic of leprosy with features of indeterminate spectrum. Remaining 24 skin biopsies showed normal histology in 20 (74.1%) cases to perivascular lymphocytic infiltrate in four (14.8%) cases. Our study demonstrates that FNAC of clinically thickened nerves has a better diagnostic yield than skin biopsy in PNL and shows all spectrums of leprosy. It also offers the advantage of sampling major nerve trunks without the fear of residual neurological deficit. However, most of the smears were paucicellular and a negative aspirate does not rule out leprosy.


Multidimensional Predictors of Susceptibility and Resilience to Social Defeat Stress.
Previous studies identified several separate risk factors for stress-induced disorders. However, an integrative model of susceptibility versus resilience to stress including measures from brain-body domains is likely to yield a range of multiple phenotypic information to promote successful adaptation to stress. We used computational and molecular approaches to test whether 1) integrative brain-body behavioral, immunological, and structural domains characterized and predicted susceptibility or resilience to social defeat stress (SDS) in mice and 2) administration of acetyl-L-carnitine promoted resilience at the SDS paradigm. Our findings identified multidimensional brain-body predictors of susceptibility versus resilience to SDS. The copresence of anxiety, decreased hippocampal volume, and elevated systemic interleukin-6 characterized a susceptible phenotype that developed behavioral and neurobiological deficits after exposure to SDS. The susceptible phenotype showed social withdrawal and impaired transcriptomic-wide changes in the ventral dentate gyrus after SDS. At the individual level, a computational approach predicted whether a given animal developed SDS-induced social withdrawal, or remained resilient, based on the integrative in vivo measures of anxiety and immune system function. Finally, we provide initial evidence that administration of acetyl-L-carnitine promoted behavioral resilience at the SDS paradigm. The current findings of multidimensional brain-body predictors of susceptibility versus resilience to stress provide a starting point for in vivo models of mechanisms predisposing apparently healthy individuals to develop the neurobiological and behavioral deficits resulting from stress exposure. This framework can lead to novel therapeutic strategies to promote resilience in susceptible phenotypes.


Neurologic disorders in HIV-positive orphans: 10 years of follow up.
Neuropsychic manifestations of AIDS are still noticeable especially in developing countries. The aim of this short communication is to describe psychological, behavioral and neurologic disorders caused by either HIV-related disorders, or drug related toxicities in HIV-infected children from Cambodia (Phnom Penh, Sihanoukville) treated during 10 years with highly active antiretroviral therapy (HAART). One hundred and thirty seven (137) HIV-positive children (age 2-19 years) treated with HAART since 2003 (6-10 years follow up) have been analyzed concerning opportunistic infections, other co-infections, renal parameters, hematologic parameters, chest X-ray, antiretroviral treatment, anti-tuberculotics and antibiotics treatment. We recorded prospectively all data since the start of HAART from 2003-2005 up to December 2012. Occurrence of drug related neuritis due to stavudine (HAART) was less than 1% and was associated with anti-tuberculous agents accompanying HAART in HIV- and tuberculosis co-infected patients. Co-infections with neurotropic viruses were more frequent: 1 case of CMV retinitis, 18 cases of herpes zoster neuritis and 37 cases of generalized HZV infections (varicella), after onset HAART in children were recorded. All children responded well to anti-viral therapy with ganciclovir (CMV), vanciclovir or acyclovir (HZV) in combination with first line HAART. Neurologic disorders in children with HAART are less frequent than in adults. Anti-retrovirals and anti-tuberculosis drugs seem to be safe and less toxic in children then in adults. Co-infections with neurotropic viruses were more frequent, however, were successfully treated with anti-virals.


All-optical tunable filters based on optomechanical effects in two-dimensional photonic crystal cavities.
All-optical tunable filters are basic elements for various micro-optical circuits. Obtaining all-optical tunability remains a challenge for micro-optical circuits. Optical forces with significant effects in nanophotonic systems provide new ways for wavelength tuning. In this Letter, the optomechanical effects in two-dimensional photonic crystal cavities are investigated. Simulations based on the finite element method demonstrate that forces arise in single and coupled cavities with movable rods inside. The optical force controls the positions of the movable rods and, thus, the resonance wavelength of the cavity, based on which tunable filter is designed. The operating wavelength of the cavity or the filter for the signal can be tuned by a control light with a different frequency. The results have potential applications for various integrated circuits.


Early-branching gut fungi possess a large, comprehensive array of biomass-degrading enzymes.
The fungal kingdom is the source of almost all industrial enzymes in use for lignocellulose bioprocessing. We developed a systems-level approach that integrates transcriptomic sequencing, proteomics, phenotype, and biochemical studies of relatively unexplored basal fungi. Anaerobic gut fungi isolated from herbivores produce a large array of biomass-degrading enzymes that synergistically degrade crude, untreated plant biomass and are competitive with optimized commercial preparations from Aspergillus and Trichoderma. Compared to these model platforms, gut fungal enzymes are unbiased in substrate preference due to a wealth of xylan-degrading enzymes. These enzymes are universally catabolite-repressed and are further regulated by a rich landscape of noncoding regulatory RNAs. Additionally, we identified several promising sequence-divergent enzyme candidates for lignocellulosic bioprocessing.


Metallurgy of soft spheres with hard core: From BCC to Frank-Kasper phases.
Understanding how soft particles can fill the space is still an open question. Structures far from classical FCC or BCC phases are now commonly experimentally observed in many different systems. Models based on pair interaction between soft particles are at present much studied in 2D. Pair interactions with two different lengths have been shown to lead to quasicrystalline architectures. It is also the case for a hard core with a square repulsive shoulder potential. In 3D, global approaches have been proposed for instance by minimizing the interface area between the deformed objects in the case of foams or micellar systems or using a self-consistent mean-field theory in copolymer melts. In this paper we propose to compare a strong van der Waals attraction between spherical hard cores and an elastic energy associated to the deformation of the soft corona. This deformation is measured as the shift between the deformed shell compared to a corona with a perfect spherical symmetry. The two main parameters in this model are: the hard-core volume fraction and the weight of the elastic energy compared to the van der Waals one. The elastic energy clearly favours the BCC structure but large van der Waals forces favor Frank and Kasper phases. This result opens a route towards controlling the building of nanoparticle superlattices with complex structures and thus original physical properties.


Microbial risk factors of cardiovascular and cerebrovascular diseases: potential therapeutical options.
Infection and inflammation may have a crucial role in the pathogenesis of atherosclerosis. This hypothesis is supported by an increasing number of reports on the interaction between chronic infection, inflammation, and atherogenesis. Assessment of serological and inflammatory markers of infection may be useful adjuncts in identifying those patients who are at a higher risk of developing vascular events, and in whom more aggressive treatments might be warranted.


Chia seeds (Salvia hispanica): health promoting properties and therapeutic applications – a review
Chia has been known for over 5,500 years. Chia seeds were one of the most important components of the diet of Mayas and Aztecs. The chemical composition and technological properties of chia give the plant a high nutritional potential. Chia is a good source of polyunsaturated fatty acids: omega-3 and omega-6, soluble dietary fiber. It also contains appreciable amount of proteins and phytochemicals. Nutritional value of chia is the reason why it is used in prophylaxis of several non-infectious diseases such as obesity, hypertension, cardiovascular diseases (CVDs), cancer and diabetes. Nutritional and therapeutic aspects of chia are currently being researched by many scientific centres. The aim of this article is to present the nutritional and therapeutic values of chia.


Novel therapy for the treatment of human carcinoid.
Development of effective treatment for patients with carcinoid tumors has been hampered by lack of an experimental model. The authors have established the only long-term cell line of a functioning human pancreatic carcinoid tumor (BON) that produces tumors in nude mice. In this study the authors examined the effect of three agents, alpha-interferon (IFN), a somatostatin analog, SMS 201-995 (SMS), and an inhibitor of polyamine biosynthesis, alpha-difluoromethylornithine (DFMO), on the growth of BON tumors. BON was implanted bilaterally as 3-mm2 pieces (subcutaneously [sc]) into male BALB/c nude mice. In the first study, 23 mice were randomized to four groups: control, IFN (1 x 10(6) units, sc, four times a day), IFN + SMS (300 micrograms/kg, intraperitoneally, three times a day), and IFN + 3% DFMO in drinking water. Treatments were initiated on day of tumor implantation. In the second study, mice were randomized to six groups: control, IFN, SMS, DFMO, IFN + SMS, IFN + DFMO, and IFN + SMS + DFMO. Treatments were started on day 15 after tumor implantation. Tumor area and body weights were measured weekly. In both studies mice were killed on day 28 after BON implantation and tumors removed, weighed, and analyzed for DNA and RNA content. In the first study, IFN either alone or in combination with SMS or DFMO suppressed BON tumor growth. When treatment was initiated after established tumor growth (study 2), however, the only effective treatments for suppression of growth of BON were IFN + DFMO and IFN + DFMO + SMS.(ABSTRACT TRUNCATED AT 250 WORDS)


Sunitinib treatment for patients with clear-cell metastatic renal cell carcinoma: clinical outcomes and plasma angiogenesis markers.
Sunitinib is a protein tyrosine kinase-inhibitor targeting VEGFR, c-kit and PDGFR. It has been approved for the treatment of metastatic renal-cell carcinoma and gastrointestinal stromal tumors. Although it has been shown to prolong disease-free and overall survival in renal-cell carcinoma patients, only 70% of the treated population receive a clinical benefit (CB) from the treatment. Markers that could predict clinical benefit to sunitinib would be an important aid in monitoring and following their treatment. We assessed the outcome and plasma proangiogenic factors in patients with metastatic renal cell carcinoma (mRCC) treated with sunitinib in our institution. We have treated 42 patients with metastatic clear-cell renal carcinoma with sunitinib. Plasma concentrations of VEGF-A, sVEGFR2 and PDGF were determined by ELISA. At the time of analysis 39 patients were evaluable for response and 30 patients had obtained a clinical benefit (CB). Median progression-free survival was 268 days (8.93 months) and median overall survival was 487 days (16.23 months). Interestingly, disease stabilization or objective response resulted in comparable overall survival. Most treatment-related adverse events were of mild-to-moderate intensity with one treatment-related death. Plasma sVEGFR2 and PDGF levels had no predictive value. Fold-increase in plasma VEGF was significantly lower in patients that obtained a CB as compared to patients that progressed after two cycles of treatment. Plasma VEGF did not increase in patients with initial CB at the time of progression. Sunitinib showed substantial activity in mRCC. Disease stabilization or objective response resulted in comparable overall survival and both outcomes should be considered positive. Fold-increase in plasma VEGF predicts for CB and could be a candidate marker. Progression after initial CB is not associated with elevated plasma VEGF, implying a different mechanism of resistance.


The Impact of Pro-Inflammatory Cytokines on Alternative Splicing Patterns in Human Islets.
Alternative splicing (AS) within the β cell has been proposed as one potential pathway that may exacerbate autoimmunity and unveil novel immunogenic epitopes in type 1 diabetes (T1D). We employed a computational strategy to prioritize pathogenic splicing events in human islets treated with IL-1β + IFN-γ as an ex vivo model of T1D and coupled this analysis with a k-mer based approach to predict RNA binding proteins involved in AS. In total, 969 AS events were identified in cytokine-treated islets, with the majority (44.8%) involving a skipped exon. ExonImpact identified 129 events predicted to impact protein structure. AS occurred with high frequency in MHC Class II-related mRNAs, and targeted qPCR validated reduced inclusion of Exon5 in the MHC Class II gene HLA-DMB. Single molecule RNA FISH confirmed increased HLA-DMB splicing in pancreatic sections from human donors with established T1D and autoantibody positivity. Serine and Arginine Rich Splicing Factor 2 was implicated in 37.2% of potentially pathogenic events, including Exon5 exclusion in HLA-DMB. Together, these data suggest that dynamic control of AS plays a role in the β cell response to inflammatory signals during T1D evolution.


Milrinone and homeostasis to treat cerebral vasospasm associated with subarachnoid hemorrhage: the Montreal Neurological Hospital protocol.
For the treatment of cerebral vasospasm, current therapies have focused on increasing blood flow through blood pressure augmentation, hypervolemia, the use of intra-arterial vasodilators, and angioplasty of proximal cerebral vessels. Through a large case series, we present our experience of treating cerebral vasospasm with a protocol based on maintenance of homeostasis (correction of electrolyte and glucose disturbances, prevention and treatment of hyperthermia, replacement of fluid losses), and the use of intravenous milrinone to improve microcirculation (the Montreal Neurological Hospital protocol). Our objective is to describe the use milrinone in our practice and the neurological outcomes associated with this approach. Large case series based on the review of all patients diagnosed with delayed ischemic neurologic deficits after aneurysmal subarachnoid hemorrhage between April 1999 and April 2006. 88 patients were followed for a mean time of 44.6 months. An intravenous milrinone infusion was used for a mean of 9.8 days without any significant side effects. No medical complications associated with this protocol were observed. There were five deaths; of the surviving patients, 48.9 % were able to go back to their previous baseline and 75 % had a good functional outcome (modified Rankin scale ≤ 2). A protocol using intravenous milrinone, and the maintenance of homeostasis is simple to use and requires less intensive monitoring and resources than the standard triple H therapy. Despite the obvious limitations of this study's design, we believe that it would be now appropriate to proceed with formal prospective studies of this protocol.


Penile sensitivity in men with premature ejaculation and erectile dysfunction.
Previous research indicates that penile sensitivity is typically lower in men with erectile dysfunction than in age-matched controls. On the assumption that sensitivity might be greater in men with short ejaculation latency (premature ejaculation), the present research investigated penile threshold (sensitivity) to vibrotactile stimulation in men with premature ejaculation, erectile dysfunction, or a combination of the two. Premature ejaculators showed thresholds commensurate with controls, while men with erectile dysfunction, or combined erectile dysfunction and premature ejaculation, showed significantly elevated thresholds. Although premature ejaculators did not show penile hypersensitivity, there was a significant correlation in this group between ejaculation latency and threshold. Overall, these findings argue against a primary role for penile sensitivity in ejaculation latency, and suggest that other somatic factors or cognitive factors may play the more critical role in premature ejaculation.


Education for foreign-trained dentists in the United States: currently available findings and need for further research.
Foreign-trained dentists interested in seeking employment in the United States face numerous challenges, starting with the fact that their degrees are often not valid for U.S. practice because of international differences in the style of education and clinical practice. A small number of North American dental schools have offered modified predoctoral programs for graduates of foreign dental schools since the 1970s, and currently, numerous U.S. dental schools offer such educational programs. The purpose of this literature review was to investigate what has been reported about barriers encountered by foreign-trained dentists in seeking professional opportunities in the United States, focusing especially on factors affecting the admissions process into predoctoral and residency programs, the learning process, and employment of foreign-trained dentists in the United States. This study concludes that published findings do not support the generalization that all foreign-trained dentists seeking employment in the United States have had the same barriers, and the authors conclude that there is a need for further research on this topic. Supplemental information can improve the transition of foreign-trained dentists into a culturally diverse environment. In addition, with greater availability of data, the need for the establishment of assistance programs for this population can be assessed.


Breast reduction as an alternative treatment option for early breast cancer in women with macromastia.
Macromastia has been considered a relative contraindication to breast conservation therapy because of difficulties with postoperative radiation therapy and cosmesis. This study evaluates the feasibility of the inferior pedicle reduction mammaplasty as a component of breast conservation therapy for patients with early breast cancer. A retrospective review identified 6 patients with macromastia receiving oncologic treatment of breast cancer and simultaneous breast reduction. Mean age was 43.5 +/- 8.7 (mean +/- SD) years, and all breast cancers were stage I or II, averaging 2.3 +/- 1.5 cm in size. All patients underwent a Wise-pattern inferior pedicle breast reduction after cancer extirpation and received postoperative radiation as part of their treatment. They were evaluated for postoperative complications, esthetic outcome of the breasts, and local recurrence. Patients in this series were followed for an average of 30.3 months, with no significant postoperative complications and recurrences. Breast reduction incisions healed primarily and adjuvant radiation was completed without a delay. All patients were pleased with the esthetic result and had improvement of their symptoms related to macromastia. Thus, we believe that breast reduction is a reasonable and safe option for early breast cancer patients with macromastia who desire breast conservation therapy. Our combined oncologic and reconstructive approach may improve the outcome of this group of patients with early breast cancers.


Comparison of Acute Ischemic Stroke Care and Outcomes Between Comprehensive Stroke Centers and Primary Stroke Centers in the United States.
To improve stroke care, the Brain Attack Coalition recommended establishing primary stroke center (PSC) and comprehensive stroke center (CSC) certification. This study aimed to compare ischemic stroke care and in-hospital outcomes between CSCs and PSCs. We analyzed patients with acute ischemic stroke who were hospitalized at stroke centers participating in Get With The Guidelines-Stroke from 2013 to 2015. Multivariable logistic regression models were generated to examine the association between stroke center certification (CSC versus PSC) and performances and outcomes. This study included 722 941 patients who were admitted to 134 CSCs and 1047 PSCs. Both CSCs and PSCs had good conformity to 7 performance measures and the summary defect-free care measure. Among emergency department admissions, CSCs had higher intravenous tPA (tissue-type plasminogen activator) and endovascular thrombectomy rates than PSCs (14.3% versus 10.3%, 4.1% versus 1.0%, respectively). Door to intravenous tPA time was shorter at CSCs (median, 52 versus 61 minutes; adjusted risk ratio, 0.92; 95% confidence interval, 0.89-0.95). More patients at CSCs had door to intravenous tPA time ≤60 minutes (79.7% versus 65.1%; adjusted odds ratio, 1.48; 95% confidence interval, 1.25-1.75). For transferred patients, CSCs and PSCs had comparable overall performance in defect-free care, except higher endovascular thrombectomy therapy rates. The overall in-hospital mortality was higher at CSCs in both emergency department admissions (4.6% versus 3.8%; adjusted odds ratio, 1.14; 95% confidence interval, 1.01-1.29) and transferred patients (7.7% versus 6.8%; adjusted odds ratio, 1.17; 95% confidence interval, 1.05-1.32). In-hospital outcomes were comparable between CSCs and PSCs in patients who received intravenous tPA or endovascular thrombectomy. CSCs and PSCs achieved similar overall care quality for patients with acute ischemic stroke. CSCs exceeded PSCs in timely acute reperfusion therapy for emergency department admissions, whereas PSCs had lower risk-adjusted in-hospital mortality. This information may be important for acute stroke triage and targeted quality improvement.


A new precision medicine initiative at the dawn of exascale computing.
Which signaling pathway and protein to select to mitigate the patient's expected drug resistance? The number of possibilities facing the physician is massive, and the drug combination should fit the patient status. Here, we briefly review current approaches and data and map an innovative patient-specific strategy to forecast drug resistance targets that centers on parallel (or redundant) proliferation pathways in specialized cells. It considers the availability of each protein in each pathway in the specific cell, its activating mutations, and the chromatin accessibility of its encoding gene. The construction of the resulting Proliferation Pathway Network Atlas will harness the emerging exascale computing and advanced artificial intelligence (AI) methods for therapeutic development. Merging the resulting set of targets, pathways, and proteins, with current strategies will augment the choice for the attending physicians to thwart resistance.


Psychosocial Vulnerability Among Patients Contacting a Norwegian Sexual Assault Center.
In this study, the objective was to assess the occurrence of specific vulnerability factors among adult and adolescent females attending a Norwegian sexual assault center (SAC). We also explored assault characteristics and investigated whether these characteristics differed between the group of patients with vulnerability factors compared with the group without such factors. We conducted a retrospective descriptive study of 573 women ≥ 12 years of age attending the SAC at St. Olavs Hospital, Trondheim, Norway, between July 1, 2003 and December 31, 2010. A patient was considered vulnerable if at least one of the following features was present: intellectual or physical disability; history of present/former mental health problems; history of present/former alcohol/substance abuse; or former sexual assault. At least one vulnerability factor was present in 59% of the cases. More than one vulnerability factor was present in 29%. Reporting at least one vulnerability factor was associated with a higher patient age, unemployment, a higher frequency of reported light/moderate physical violence, and the documentation of minor body injury. In contrast, those without vulnerability more often were students assaulted during night time, by a casual or stranger assailant and reporting a higher intake of alcohol prior to the assault. There are obvious patterns of differences in the nature of sexual assaults reported among victims with specific vulnerability factors compared with victims without these factors. Future research should address these differences and possible solutions for better protection of especially vulnerable individuals against sexual offenses, such as those with mental health and substance abuse difficulties.


Global Routine Vaccination Coverage, 2018.
Endorsed by the World Health Assembly in 2012, the Global Vaccine Action Plan 2011-2020 (GVAP) (1) calls on all countries to reach ≥90% national coverage with all vaccines in the country's national immunization schedule by 2020. Building on previous analyses (2) and using the World Health Organization (WHO) and United Nations Children's Fund (UNICEF) global vaccination coverage estimates as of 2018, this report presents global, regional, and national vaccination coverage estimates and trends, including vaccination dropout rates. According to these estimates, global coverage with the first dose of diphtheria and tetanus toxoids and pertussis-containing vaccine (DTP1) remained relatively unchanged from 2010 (89%) to 2018 (90%). Global coverage with the third DTP dose (DTP3) followed a similar global trend to that of DTP1, remaining relatively consistent from 2010 (84%) to 2018 (86%) (3). Globally, 19.4 million children (14%) were not fully vaccinated in 2018, and among them, 13.5 million (70%) did not receive any DTP doses. Overall, dropout rates from DTP1 to DTP3 decreased globally from 6% in 2010 to 4% in 2018. Global coverage with the first dose of measles-containing vaccine (MCV1) remained between 84% and 86% during 2010-2018. Among countries that offer a second MCV dose (MCV2) during the second year of life, coverage increased from 19% in 2007 to 54% in 2018; among countries offering MCV2 to older age groups (children aged 3-14 years), coverage also increased, from 36% in 2007 to 69% in 2018 (3). Globally, the estimated difference in coverage with MCV1 and MCV2 in 2018 was 17%. However, among new and underused vaccines, global coverage increased from 2007 to 2018 for completed series of rotavirus vaccine, pneumococcal conjugate vaccine (PCV), rubella vaccine, Haemophilus influenzae type b vaccine (Hib), and hepatitis B vaccine (HepB). To reach global vaccination coverage goals for vaccines recommended during childhood, adolescence, and adulthood, tailored strategies that address local determinants for incomplete vaccination are needed, including targeting hard-to-reach and hard-to-vaccinate populations.


Utility estimates for patients with Type 2 diabetes mellitus after experiencing a myocardial infarction or stroke: a systematic review.
A systematic review identified studies eliciting utility decrements from myocardial infarction (MI) and stroke in patients with Type 2 diabetes mellitus (T2DM) and examined their use in economic models of new diabetes treatments. In 16 utility studies in patients with T2DM, utility decrements in the first year ranged from 0.017 to 0.226 for MI and from 0.034 to 0.590 for stroke. Sixteen of 19 economic evaluations of new treatments for T2DM included utility decrements for an MI and/or stroke from one of the 16 utility studies. Decrements for MI ranged from 0.012 to 0.180 in the first year. Decrements for stroke ranged from 0.044 to 0.690 in the first year. Utility studies in patients with T2DM provide little information about changes in utility decrements by time since the event and by disease severity. Cost-effectiveness studies do not always indicate how these values were used in the analysis.


Dearth by a Thousand Cuts? Accounting for Gender Differences in Top-Ranked Publication Rates in Social Psychology.
Publication in the Journal of Personality and Social Psychology, a flagship indicator of scientific prestige, shows dramatic gender disparities. A bibliometric analysis included yoked-control authors matched for Ph.D. prestige and cohort. Though women publish less, at slower annual rates, they are more cited in handbooks and textbooks per JPSP-article-published. No gender differences emerged on variables reflecting differential qualifications. Many factors explain gender discrepancy in productivity. Among top publishers, per-year rate and first authorship especially differ by gender; rate uniquely predicts top-male productivity, whereas career-length uniquely predicts top-female productivity. Among men, across top-publishers and controls, productivity correlates uniquely with editorial negotiating and being married. For women, no personal variables predict productivity. A separate inquiry shows tiny gender differences in acceptance rates per JPSP article submitted; discrimination would be a small-but-plausible contributor, absent independent indicators of manuscript quality. Recent productivity rates mirror earlier gender disparities, suggesting gender gaps will continue.


Therapy-Induced Senescence: Opportunities to Improve Anticancer Therapy.
Cellular senescence is an essential tumor suppressive mechanism that prevents the propagation of oncogenically activated, genetically unstable, and/or damaged cells. Induction of tumor cell senescence is also one of the underlying mechanisms by which cancer therapies exert antitumor activity. However, an increasing body of evidence from preclinical studies demonstrates that radiation and chemotherapy cause accumulation of senescent cells (SnCs) both in tumor and normal tissue. SnCs in tumors can, paradoxically, promote tumor relapse, metastasis, and resistance to therapy, in part, through expression of the senescence-associated secretory phenotype. In addition, SnCs in normal tissue can contribute to certain radiation- and chemotherapy-induced side effects. Because of its multiple roles, cellular senescence could serve as an important target in the fight against cancer. This commentary provides a summary of the discussion at the National Cancer Institute Workshop on Radiation, Senescence, and Cancer (August 10-11, 2020, National Cancer Institute, Bethesda, MD) regarding the current status of senescence research, heterogeneity of therapy-induced senescence, current status of senotherapeutics and molecular biomarkers, a concept of "one-two punch" cancer therapy (consisting of therapeutics to induce tumor cell senescence followed by selective clearance of SnCs), and its integration with personalized adaptive tumor therapy. It also identifies key knowledge gaps and outlines future directions in this emerging field to improve treatment outcomes for cancer patients.


[Oral administration of intravenous preparation of Vitamin K for excessive anticoagulation due to warfarin].
Anticoagulation therapy with warfarin, a common clinical practice, needs to be monitored using protombine time expressed as the International Normalized Ratio (INR); when safety range is exceeded, Vitamin K (Vit-K) could be administered with preference orally. In Venezuela the specific oral preparation for Vit-K is not available. This is a double blinded, randomized, placebo controlled, clinical trial; 20 patients, age 18-60 year with initial INR ≥ 6, ≤ 10, were randomized to oral Vit-K 1.25mg (prepared from intravenous presentation) or placebo plus withholding warfarin. INR < 3.5 at 24 hours of treatment (the primary end point) was achieved by 70% among Vit-K, and 20% among placebo patients; given an absolute risk reduction (ARR), of 50% (CI95%: 14.4-85.6) p = 0.028, NNT 2 (CI95%: 1.3 - 6.9). No adverse events were recorded including INR < 2 at 24 hours of treatment administration. Our results are consistent with studies where specific oral presentation of Vit-K was used. The results indicate that oral administration of Vit-K, prepared from an intravenous Vit-K preparation, is safe and more effective to revert excessive anticoagulation than simply withholding warfarin, in places where specific preparation of oral Vit-K is not available or too expensive.


Transferring policies for treating sexually transmitted infections: what's wrong with global guidelines?
The paper uses a case study of the development of syndromic management for treating sexually transmitted infections (STIs) and subsequent policies recommending worldwide use of syndromic management guidelines. These treatment policies emerged in the late 1970s from researchers and public health physicians working in sub-Saharan Africa where they had to treat large numbers of STIs in difficult circumstances. Syndromic management was initially developed in specific local epidemiological and resource situations. By the late 1980s, the World Health Organization had adopted syndromic management as policy, and began to promote it globally in the form of algorithms and training guidelines. Dissemination was assisted by the context of the rapid spread of HIV/AIDS and the apparent effectiveness of syndromic management for treating STIs and slowing the transmission of HIV/AIDS. In the mid 1990s, international donors interested in HIV control and women's reproductive health took it up, and encouraged national programmes to adopt the new guidelines. Implementation, however, was a great deal more complex than anticipated, and was exacerbated by differences between three rather separate policy networks involved in the dissemination and execution of the global guidelines. The analysis focuses on two parts of the process of policy transfer: the organic development of scientific and medical consensus around a new policy for the treatment of STIs; and the formulation and subsequent dissemination of international policy guidelines. Using a political science approach, we analyze the transition from clinical tools to global guidelines, and the associated debates that accompanied their use. Finally, we comment on the way current global guidelines need to be adapted, given the growth in knowledge.


The reliability of postural balance measures in single and dual tasking in elderly fallers and non-fallers.
The purpose of this study was to determine the reliability of a forceplate postural balance protocol in a group of elderly fallers and non-fallers. The measurements were tested in single and dual-task conditions, with and without vision. 37 elderly (mean age 73 +/- 6 years) community-dwellers were included in this study. All were tested in a single (two-legged stance) and in a dual-task (two-legged stance while counting backwards aloud in steps of 7's) condition, with and without vision. A forceplate was used for registering postural variables: the maximal and the root-mean-square amplitude in medio-lateral (Max-ML, RMS-ML) and antero-posterior (Max-AP, RMS-AP) direction, mean velocity (MV), and the area of the 95% confidence ellipse (AoE). Reliability of the test protocol was expressed with intraclass correlation coefficients (ICC), with 95% limits of agreement (LoA), and with the smallest detectable difference (SDD). The ICCs for inter-rater reliability and test-retest reliability of the balance variables were r = 0.70-0.89. For the variables Max-AP and RMS-AP the ICCs were r = 0.52-0.74. The SDD values were for variable Max-ML and Max-AP between 0.37 cm and 0.83 cm, for MV between 0.48 cm/s and 1.2 cm/s and for AoE between 1.48 cm2 and 3.75 cm2. The LoA analysis by Bland-Altman plots showed no systematic differences between test-retest measurements. The study showed good reliability results for group assessment and no systematic errors of the measurement protocol in measuring postural balance in the elderly in a single-task and dual-task condition.


Intermediate filament interactions can be altered by HSP27 and alphaB-crystallin.
HSP27 and alphaB-crystallin are both members of the small heat shock protein family. alphaB-crystalllin has been proposed to modulate intermediate filaments and recently a mutation in alphaB-crystallin has been identified as the genetic basis of desmin related myopathy. This disease is characterised in its pathology by aggregates of intermediate filaments associated with alphaB-crystallin. Here we report that HSP27 like alphaB-crystallin is associated with glial fibrillary acidic protein and vimentin intermediate filament networks in unstressed U373MG astrocytoma cells. HSP27 is also associated with keratin filaments in MCF7 cells, indicating that this association is not restricted to a particular intermediate filament type. The association of sHSPs with both the soluble and filamentous intermediate filament fractions of U373 cells was demonstrated biochemically. Heat shock or drug treatments induced a co-collapse of intermediate filaments and associated small heat shock proteins. These data show that the presence of HSP27 or alphaB-crystallin could not prevent filament collapse and suggest that the purpose of this association is more than just filament binding. Indeed, in U373MG cells the intermediate filament association with small heat shock proteins is similar to that observed for another protein chaperone, HSC70. In order to discern the effect of different chaperone classes on intermediate filament network formation and maintenance, several in vitro assays were assessed. Of these, falling ball viscometry revealed a specific activity of small heat shock proteins compared to HSC70 that was apparently inactive in this assay. Intermediate filaments form a gel in the absence of small heat shock proteins. In contrast, inclusion of alphaB-crystallin or HSP27 prevented gel formation but not filament assembly. The transient transfection of GFAP into MCF7 cells was used to show that the induction of a completely separate network of intermediate filaments resulted in the specific association of the endogenous HSP27 with these new GFAP filaments. These data lead us to propose that one of the major functions of the association of small heat shock proteins with intermediate filaments is to help manage the interactions that occur between filaments in their cellular networks. This is achieved by protecting filaments against those non-covalent interactions that result when they come into very close proximity as seen from the viscosity experiments and which have the potential to induce intermediate filament aggregation as seen in some disease pathologies.


Kinetoplast DNA of normal and mutant Trypanosoma brucei.
Kinetoplast DNA (kDNA) sequence organization, transcription, and alterations in dyskinetoplastic (Dk) mutants were examined in Trypanosoma brucei, using physically isolated and recombinant kDNA sequences. Maxicircles renatured as a single sequence class and had no homology with minicircles. Total minicircle complexity was greater than 300 kb. Minicircle sequence organization is complex. Different minicircles have sequences in common and comprise varying fractions of the kDNA network. Transcripts of the same maxicircle restriction fragments, representing most of the maxicircle, were detected in both bloodstream and cultured procyclic form RNA. Presumptive mitochondrial ribosomal RNA coding sequences were localized to a specific maxicircle segment. No minicircle transcription was detected. All Dk mutants examined had substantial reduction of kDNA sequences. No kDNA sequences could be detected in one mutant examined in detail. Another Dk mutant was found to contain sequences homologous to kDNA. These DNA sequences had the same electrophoretic mobility as maxicircle and minicircle restriction fragments.


The study protocol of a cluster-randomised controlled trial of family-mediated personalised activities for nursing home residents with dementia.
Following admission to a nursing home, the feelings of depression and burden that family carers may experience do not necessarily diminish. Additionally, they may experience feelings of guilt and grief for the loss of a previously close relationship. At the same time, individuals with dementia may develop symptoms of depression and agitation (BPSD) that may be related to changes in family relationships, social interaction and stimulation. Until now, interventions to alleviate carer stress and BPSD have treated carers and relatives separately rather than focusing on maintaining or enhancing their relationships. One-to-one structured activities have been shown to reduce BPSD and also improve the caring experience, but barriers such as a lack of resources impede the implementation of activities in aged care facilities. The current study will investigate the effect of individualised activities based on the Montessori methodology administered by family carers in residential care. We will conduct a cluster-randomised trial to train family carers in conducting personalised one-to-one activities based on the Montessori methodology with their relatives. Montessori activities derive from the principles espoused by Maria Montessori and subsequent educational theorists to promote engagement in learning, namely task breakdown, guided repetition, progression in difficulty from simple to complex, and the careful matching of demands to levels of competence. Persons with dementia living in aged care facilities and frequently visiting family carers will be included in the study. Consented, willing participants will be randomly assigned by facility to a treatment condition using the Montessori approach or a control waiting list condition. We hypothesise that family carers conducting Montessori-based activities will experience improvements in quality of visits and overall relationship with the resident as well as higher self-rated mastery, fewer depressive symptoms, and a better quality of life than carers in the waiting list condition. We hypothesise that training family carers to deliver personalised activities to their relatives in a residential setting will make visits more satisfying and may consequently improve the quality of life for carers and their relatives. These beneficial effects might also reduce nursing staff burden and thus impact positively on residential facilities. Australian New Zealand Clinical Trials Registry - ACTRN12611000998943.


Rapid glycation with D-ribose induces globular amyloid-like aggregations of BSA with high cytotoxicity to SH-SY5Y cells.
D-ribose in cells and human serum participates in glycation of proteins resulting in advanced glycation end products (AGEs) that affect cell metabolism and induce cell death. However, the mechanism by which D-ribose-glycated proteins induce cell death is still unclear. Here, we incubated D-ribose with bovine serum albumin (BSA) and observed changes in the intensity of fluorescence at 410 nm and 425 nm to monitor the formation of D-ribose-glycated BSA. Comparing glycation of BSA with xylose (a control for furanose), glucose and fructose (controls for pyranose), the rate of glycation with D-ribose was the most rapid. Protein intrinsic fluorescence (335 nm), Nitroblue tetrazolium (NBT) assays and Western blotting with anti-AGEs showed that glycation of BSA incubated with D-ribose occurred faster than for the other reducing sugars. Protein intrinsic fluorescence showed marked conformational changes when BSA was incubated with D-ribose. Importantly, observations with atomic force microscopy showed that D-ribose-glycated BSA appeared in globular polymers. Furthermore, a fluorescent assay with Thioflavin T (ThT) showed a remarkable increase in fluorescence at 485 nm in the presence of D-ribose-glycated BSA. However, ThT fluorescence did not show the same marked increase in the presence of xylose or glucose. This suggests that glycation with D-ribose induced BSA to aggregate into globular amyloid-like deposits. As observed by Hoechst 33258 staining, 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) and cell counting kit-8 (CCK-8) assay, lactate dehydrogenase (LDH) activity assay, flow cytometry using Annexin V and Propidium Iodide staining and reactive oxygen species (ROS) measurements, the amyloid-like aggregation of glycated BSA induced apoptosis in the neurotypic cell line SH-SY5Y. Glycation with D-ribose induces BSA to misfold rapidly and form globular amyloid-like aggregations which play an important role in cytotoxicity to neural cells.


Life-course occupational social class and health in later life: the importance of frequency and timing of measures.
Research investigating associations between social class over the life-course and later health relies primarily on secondary analysis of existing data, limiting the number and timing of available measurements. This paper aims to examine the impact of these constraints on the measurement of life-course occupational social class and subsequent explanatory analyses predicting health in later life. Participants of the UK Boyd Orr Lifegrid Subsample (n = 294), aged an average of 68 years, provided retrospective information on their life-course occupational social class, coded at 6-month intervals. This was used to simulate two types of life-course data: (1) Theoretical: Life stage (four data-points at key life stages); (2) A-theoretical: Panel data (data-points at regular intervals of varying length). The percentage of life time in disadvantage and the predictive value for limiting longstanding illness (LLI) in later life using the full life-course and simulated data was compared. The presence of 'critical periods' of exposure and the role of trajectories of social class were also investigated. Compared with the full data, the life stage approach estimated a higher percentage of life time in disadvantage and emphasised 'transient' periods in disadvantage (e.g. labour market entry). With varying intervals using the a-theoretical approach, there was no clear pattern. Percentage of life time in manual class was a significant predictor of LLI only when using the four-point life stage approach. Occupational social class at labour market entry was a predictor of LLI in later life, suggesting a 'critical period'. Comparison of trajectories of social class further emphasised the importance of the sequence and timing of exposures to disadvantage in determining later health. We conclude that producing a valid summary of life-course occupational social class does not necessarily require a large number of data-points, particularly if guided by relevant theory, and that such measures can reveal important associations with later health.


Street network measures and adults' walking for transport: Application of space syntax.
The street network underpins the walkability of local neighborhoods. We examined whether two street network measures (intersection density and street integration from space syntax) were independently associated with walking for transport (WT); and, to what extent the relationship of street integration with WT may be explained by the presence of destinations. In 2003-2004, adults living in Adelaide, Australia (n=2544) reported their past-week WT frequency and perceived distances to 16 destination types. Marginal models via generalized estimating equations tested mediation effects. Both intersection density and street integration were significantly associated with WT, after adjusting for each other. Perceived destination availability explained 42% of the association of street integration with WT; this may be because of an association between street integration and local destination availability - an important element of neighborhood walkability. The use of space syntax concepts and methods has the potential to provide novel insights into built-environment influences on walking.


Synchronization of chaotic mode hopping.
We propose and demonstrate a scheme for generating synchronized chaotic mode hopping in two wavelength-tunable lasers whose tuning range covers multiple longitudinal modes. Chaotic mode hopping resulting in large hops in wavelength is induced by delayed electrical feedback. We show that, by coupling part of the output of one laser into another, one can synchronize the chaotic mode hopping of two separate lasers and obtain synchronized chaotic on-off modulation patterns in multiple corresponding wavelength bands.


Orbitofrontal cortex encodes memories within value-based schemas and represents contexts that guide memory retrieval.
There are a substantial number of studies showing that the orbitofrontal cortex links events to reward values, whereas the hippocampus links events to the context in which they occur. Here we asked how the orbitofrontal cortex contributes to memory where context determines the reward values associated with events. After rats learned object-reward associations that differed depending on the spatial context in which the objects were presented, neuronal ensembles in orbitofrontal cortex represented distinct value-based schemas, each composed of a systematic organization of the representations of objects in the contexts and positions where they were associated with reward or nonreward. Orbitofrontal ensembles also represent the different spatial contexts that define the mappings of stimuli to actions that lead to reward or nonreward. These findings, combined with observations on complementary memory representation within the hippocampus, suggest mechanisms through which prefrontal cortex and the hippocampus interact in support of context-guided memory.


Device Free Detection in Impulse Radio Ultrawide Bandwidth Systems.
In this paper, an analytical framework is presented for device detection in an impulse radio (IR) ultra-wide bandwidth (UWB) system and its performance analysis is carried out. The Neyman-Pearson (NP) criteria is employed for this device-free detection. Different from the frequency-based approaches, the proposed detection method utilizes time domain concepts. The characteristic function (CF) is utilized to measure the moments of the presence and absence of the device. Furthermore, this method is easily extendable to existing device-free and device-based techniques. This method can also be applied to different pulse-based UWB systems which use different modulation schemes compared to IR-UWB. In addition, the proposed method does not require training to measure or calibrate the system operating parameters. From the simulation results, it is observed that an optimal threshold can be chosen to improve the ROC for UWB system. It is shown that the probability of false alarm, PFA, has an inverse relationship with the detection threshold and frame length. Particularly, to maintain PFA<10-5 for a frame length of 300 ns, it is required that the threshold should be greater than 2.2. It is also shown that for a fix PFA, the probability of detection PD increases with an increase in interference-to-noise ratio (INR). Furthermore, PD approaches 1 for INR >-2 dB even for a very low PFA i.e., PFA=1×10-7. It is also shown that a 2 times increase in the interference energy results in a 3 dB improvement in INR for a fixed PFA=0.1 and PD=0.5. Finally, the derived performance expressions are corroborated through simulation.


Admixture mapping of male nuptial colour and body shape in a recently formed hybrid population of threespine stickleback.
Despite recent progress, we still know relatively little about the genetic architecture that underlies adaptation to divergent environments. Determining whether the genetic architecture of phenotypic adaptation follows any predictable patterns requires data from a wide variety of species. However, in many organisms, genetic studies are hindered by the inability to perform genetic crosses in the laboratory or by long generation times. Admixture mapping is an approach that circumvents these issues by taking advantage of hybridization that occurs between populations or species in the wild. Here, we demonstrate the utility of admixture mapping in a naturally occurring hybrid population of threespine sticklebacks (Gasterosteus aculeatus) from Enos Lake, British Columbia. Until recently, this lake contained two species of sticklebacks adapted to divergent habitats within the lake. This benthic-limnetic species pair diverged in a number of phenotypes, including male nuptial coloration and body shape, which were previously shown to contribute to reproductive isolation between them. However, recent ecological disturbance has contributed to extensive hybridization between the species, and there is now a single, admixed population within Enos Lake. We collected over 500 males from Enos Lake and found that most had intermediate nuptial colour and body shape. By genotyping males with nuptial colour at the two extremes of the phenotypic distribution, we identified seven genomic regions on three chromosomes associated with divergence in male nuptial colour. These genomic regions are also associated with variation in body shape, suggesting that tight linkage and/or pleiotropy facilitated adaptation to divergent environments in benthic-limnetic species pairs.


Long-term follow-up of turned single implants placed in periodontally healthy patients after 16 to 22 years: microbiologic outcome.
Survival rates in implant dentistry today are high, although late failures do occur for many reasons, including peri-implant infections. The primary objective of this study is to investigate microbiota around single turned implants after 16 to 22 years. Secondary objectives are to compare teeth and implants and to correlate microbiologic, radiographic, and clinical parameters. A total of 46 patients with single implants were invited for a clinical examination. Clinical data were collected from implants and contralateral natural teeth. Radiographic bone level was measured around implants. Microbiologic samples were taken from implants, contralateral teeth, and the deepest pocket per quadrant. Samples were analyzed with DNA-DNA hybridization including 40 species. Statistical analysis was performed using Wilcoxon signed-rank tests, McNemar tests, and Spearman correlation coefficients with a 0.05 significance level. Mean follow-up was 18.5 years (range 16 to 22 years). Tannerella forsythia (1.5 × 10(5)) and Veillonella parvula (1.02 × 10(5)) showed the highest concentrations around implants and teeth, respectively. Porphyromonas gingivalis, Prevotella intermedia, and T. forsythia were significantly more present around implants than teeth. Mean counts were significantly higher around implants than teeth for Parvimonas micra, P. gingivalis, P. intermedia, T. forsythia, and Treponema denticola. Total DNA count was correlated to interproximal bleeding index (r = 0.409) and interproximal probing depth (r = 0.307). No correlations were present with plaque index or radiographic bone level. In the present study, bacterial counts around single implants in periodontally healthy patients are rather low. Although pathogenic bacteria are present, some in higher numbers around implants than teeth (five of 40), the majority of implants present with healthy peri-implant tissues without progressive bone loss.


Calcium supplementation during pregnancy for reducing pregnancy induced hypertension.
Pregnancy induced hypertension (PIH) is a common complication in pregnancy and prenatal stage. Because the direct and indirect relationship between low calcium intake and many diseases, such as rachitis, young age myopia and hypertension, calcium supplementation has been a hot topic among nutritionists. Randomized trials of calcium supplementation during pregnancy were conducted in 212 healthy primipara. They were divided into 4 groups and gave 120mg, 240mg, 1g or 2g of calcium daily from 20 to 28 wks of gestation up to delivery respectively. As a result, the incidence of PIH was 8.9%, 7.5%, 8% and 4% respectively in these groups. The control group (106 pregnant women) who did not receive calcium gave an incidence of 18%. Supplementation of 2g of calcium daily showed significant results in lowering the incidence of PIH (P < 0.05) without any adverse effects. In 1992 calcium supplementation was widely used in antenatal-clinic. 200 cases with intake of 2g calcium were compared with corresponding non-calcium supplementation cases, and the incidence of PIH was 7.5% and 16.5% (P < 0.005) respectively. Mediating parathyroid hormone and renin activity are thought to be the effect of calcium on decreasing the incidence of PIH.