Vitamin D deficiency and clinical outcomes related to septic shock in children with critical illness: a systematic review.
Low vitamin D blood levels are related to many clinical outcomes in children with critically illness. However, the relationship of it and septic shock has not been systematically analyzed. The objective of this review was to evaluate the effect of vitamin D on septic shock and predict if vitamin D administration can improve prognosis of it. Online databases were searched up to June 1st, 2017 for studies on the relation of vitamin D deficiency (VDD) and clinical outcomes on septic shock in children with critical illness. The primary end point was the effect of VDD on occurrence of septic shock. The secondary endpoints were the association of VDD and clinical outcomes related to septic shock. We summarized the strength of association between VDD and each factor on septic shock. Individual factors were defined as strong, moderate, weak, or inconclusive according to the numbers of the article supporting the relation between them. Eight studies published between 2012 and 2017, for a total of 1367 patients, were included in the final analysis. We extracted eight patient-level factors and among them one showed strong association of VDD and septic shock. Four factors demonstrated moderate or weak strength of evidence for it: nonresolution of shock, catecholamine refractory shock, fluid boluses, vasopressor use. But evidence for the association between VDD and severity of illness, stay of pediatric intensive care unit (PICU), are weak. Most of the articles showed no significant association between VDD and mortality. Among critically ill children, VDD might be associated with the occurrence and resolution of septic shock. A larger multicenter trial could conclusively confirm these findings. Further research is also needed to identify vitamin D administration for better outcomes in pediatric patients.


Cytokines and serum cause alpha 2 beta 1 integrin-mediated contraction of collagen gels by cultured retinal pigment epithelial cells.
Integrins, heterodimeric cell surface glycoproteins, are involved in cell-substratum and cell-cell interactions. The role of these molecules in cytokine-mediated contraction of extracellular matrix by retinal pigment epithelial cells has been investigated in a model system that may mimic epiretinal membrane contraction during retinal detachment in proliferative vitreoretinopathy. Retinal pigment epithelial cells were cultured on three-dimensional collagen gels that they cause to contract. The involvement of new protein synthesis and C-kinase-mediated signal transduction were studied using specific inhibitors. Cell surface integrins synthesized by pigment epithelial cells were identified using immunofluorescence, and the same antibodies were used in gel contraction assays to identify the integrin species responsible for force transduction. Contraction of collagen type I gels was small without cytokines but was greatly enhanced in the presence of serum or IL1 plus TGF beta. It was dependent on new protein synthesis. Contraction induced by the combination of cytokines was dependent on active protein kinases, whereas that induced by serum was not because only the former was inhibited by staurosporine, a C-kinase inhibitor. Pigment epithelial cells were found to produce beta 1, alpha 2, and alpha 5 integrins, but only alpha 2 and beta 1 appeared to participate in the contraction process because only antibodies against these integrins inhibited contraction. Retinal pigment epithelial cells contract an extracellular matrix in vitro in a manner similar to epiretinal membrane contraction in vivo. This contraction is mediated via cell surface glycoproteins of the integrin family that bind directly to extracellular matrix molecules.


A comprehensive assessment of PM emissions from paved roads: real-world Emission Factors and intense street cleaning trials.
Compliance with air quality standards requires control of source emissions: fine exhaust particles are already subject to regulation but vehicle fleets increase whilst the non-exhaust emissions are totally uncontrolled. Emission inventories are scarce despite their suitability for researchers and regulating agencies for managing air quality and PM reduction measures. Only few countries in Europe proposed street cleaning as a possible control measure, but its effectiveness is still far to be determined. This study offers first estimates of Real-world Emission Factors for PM(10) and brake-wear elements and the effect on PM(10) concentrations induced by intense street cleaning trials. A straightforward campaign was carried out in the city of Barcelona with hourly elemental composition of fine and coarse PM to detect any short-term effect of street cleaning on specific tracers of non-exhaust emissions. Samples were analyzed by Particle Induced X-Ray Emission. Real-world Emission Factor for PM(10) averaged for the local fleet resulted to be 97 mg veh(-1) km(-1). When compared to other European studies, our EF resulted higher than what found in UK, Germany, Switzerland and Austria but lower than Scandinavian countries. For brake-related elements, total EFs were estimated, accounting for the sum of direct and resuspension emissions, in 7400, 486, 106 and 86 microg veh(-1) km(-1), respectively for Fe, Cu, Sn and Sb. In PM(2.5)Fe and Cu emission factors were respectively 4884 and 306 microg veh(-1) km(-1). Intense street cleaning trials evidenced a PM(10) reduction at kerbside of 3 microg m(-3) (mean daily levels of 54 microg m(-3)), with respect to reference stations. It is important to remark that such benefit could only be detected in small time-integration periods (12:00-18:00) since in daily values this benefit was not noticed. Hourly PM elemental monitoring allowed the identification of mineral and brake-related metallic particles as those responsible of the PM(10) reduction.


Malignant thymoma associated with myasthenia gravis, Graves' disease, and SIADH.
Patients with thymoma are likely to present with associated autoimmunologic disorders. The occurrence of syndrome of inappropriate antidiuretic hormone (SIADH) attributable to thymoma is extremely rare. We herein present an extremely rare case of a 59-year-old man patient who was discovered to have malignant thymoma associated with myasthenia gravis, Graves' disease, and SIADH. He was admitted for evaluation and treatment of hyponatremia (Na 125 mEq/l). SIADH was diagnosed, and thymoma was identified as its cause. The patient was also found to have both Graves' disease and myasthenia gravis. The hyponatremia was normalized with water restriction and 3% saline therapy before thymectomy. The thymic tumor was a Masaoka stage III thymoma that resulted in direct invasion to the wall of the innominate vein, but there was no finding of invasion to other mediastinal organs. Complete thymectomy with innominate vein graft was performed. Microscopic histopathology findings corresponded to those of a mixed-type thymoma and type B2. However, immunohistochemical stain for antidiuretic hormone was negative in the tumor cells. Adjuvant radiation therapy was employed postoperatively, and the patient's postoperative recovery was uneventful. He subsequently reached a euthyroid state. And the reversal to normal sodium and osmolality levels was continued after the tumor removal without any further management for hyponatremia. The observation of this interesting case and a literature review provided us with the opportunity to explore the pathogenesis and clinical aspects of thymoma-related autoimmune and/or endocrine disorders which must be suspected in patients with thymoma.


Cross-species genomics matches driver mutations and cell compartments to model ependymoma.
Understanding the biology that underlies histologically similar but molecularly distinct subgroups of cancer has proven difficult because their defining genetic alterations are often numerous, and the cellular origins of most cancers remain unknown. We sought to decipher this heterogeneity by integrating matched genetic alterations and candidate cells of origin to generate accurate disease models. First, we identified subgroups of human ependymoma, a form of neural tumour that arises throughout the central nervous system (CNS). Subgroup-specific alterations included amplifications and homozygous deletions of genes not yet implicated in ependymoma. To select cellular compartments most likely to give rise to subgroups of ependymoma, we matched the transcriptomes of human tumours to those of mouse neural stem cells (NSCs), isolated from different regions of the CNS at different developmental stages, with an intact or deleted Ink4a/Arf locus (that encodes Cdkn2a and b). The transcriptome of human supratentorial ependymomas with amplified EPHB2 and deleted INK4A/ARF matched only that of embryonic cerebral Ink4a/Arf(-/-) NSCs. Notably, activation of Ephb2 signalling in these, but not other, NSCs generated the first mouse model of ependymoma, which is highly penetrant and accurately models the histology and transcriptome of one subgroup of human supratentorial tumour. Further, comparative analysis of matched mouse and human tumours revealed selective deregulation in the expression and copy number of genes that control synaptogenesis, pinpointing disruption of this pathway as a critical event in the production of this ependymoma subgroup. Our data demonstrate the power of cross-species genomics to meticulously match subgroup-specific driver mutations with cellular compartments to model and interrogate cancer subgroups.


Rab27A and its effector MyRIP link secretory granules to F-actin and control their motion towards release sites.
The GTPase Rab27A interacts with myosin-VIIa and myosin-Va via MyRIP or melanophilin and mediates melanosome binding to actin. Here we show that Rab27A and MyRIP are associated with secretory granules (SGs) in adrenal chromaffin cells and PC12 cells. Overexpression of Rab27A, GTPase-deficient Rab27A-Q78L, or MyRIP reduced secretory responses of PC12 cells. Amperometric recordings of single adrenal chromaffin cells revealed that Rab27A-Q78L and MyRIP reduced the sustained component of release. Moreover, these effects on secretion were partly suppressed by the actin-depolymerizing drug latrunculin but strengthened by jasplakinolide, which stabilizes the actin cortex. Finally, MyRIP and Rab27A-Q78L restricted the motion of SGs in the subplasmalemmal region of PC12 cells, as measured by evanescent-wave fluorescence microscopy. In contrast, the Rab27A-binding domain of MyRIP and a MyRIP construct that interacts with myosin-Va but not with actin increased the mobility of SGs. We propose that Rab27A and MyRIP link SGs to F-actin and control their motion toward release sites through the actin cortex.


Surfactant and metal ion effects on the mechanical properties of alginate hydrogels.
This paper addresses the controlled variation of the mechanical properties of alginate gel beads by changing the alginate concentration or by adding different surfactants or cross-linking cations. Alginate beads containing nonionic Brij 35 or anionic sodium dodecyl sulfate (SDS) surfactants were prepared with two different types of cations (Ca2+, Ba2+) as crosslinkers. Compression measurements were performed to investigate the effect of the surfactant and cation types and their concentrations on the Young's modulus of alginate beads. The Young's modulus was determined by using Hertz theory. For all types of alginate gel beads the Young's modulus showed an increasing value for increasing alginate contents. Addition of the anionic surfactant SDS increases the Young's modulus of the alginate beads while the addition of non-ionic surfactant Brij 35 leads to a decrease in Young's modulus. This opposite behavior is related to the contrary effect of both surfactants on the charge of the alginate beads. When Ba2+ ions were used as crosslinker cation, the Young's modulus of the beads with the surfactant SDS was found to be approximately two times higher than the modulus of beads with the surfactant Brij 35. An ion specific effect was found for the crosslinking ability of divalent cations.


An mRNA Gene Expression-Based Signature to Identify FGFR1-Amplified Estrogen Receptor-Positive Breast Tumors.
Fibroblast growth factor receptor 1 (FGFR1) amplification drives poor prognosis and is an emerging therapeutic target. We sought to construct a multigene mRNA expression signature to efficiently identify FGFR1-amplified estrogen receptor-positive (ER+) breast tumors. Five independent breast tumor series were analyzed. Genes discriminative for FGFR1 amplification were screened transcriptome-wide by receiver operating characteristic analyses. The METABRIC series was leveraged to construct/evaluate four approaches to signature composition. A locked-down signature was validated with 651 ER+ formalin-fixed, paraffin-embedded tissues (the University of British Columbia-tamoxifen cohort). A NanoString nCounter assay was designed to profile selected genes. For a gold standard, FGFR1 amplification was determined by fluorescent in situ hybridization (FISH). Prognostic effects of FGFR1 amplification were assessed by survival analyses. Eight 8p11-12 genes (ASH2L, BAG4, BRF2, DDHD2, LSM1, PROSC, RAB11FIP1, and WHSC1L1) together with the a priori selected FGFR1 gene, highly discriminated FGFR1 amplification (area under the receiver operating characteristic curve ≥0.82, all genes and all cohorts). The nine-gene signature Call-FGFR1-amp accurately identified FGFR1 FISH-amplified ER+ tumors in the University of British Columbia-tamoxifen cohort (specificity, 0.94; sensitivity, 0.96) and exhibited prognostic effects (disease-specific survival hazard ratio, 1.57; 95% CI, 1.14-2.16; P = 0.005). Call-FGFR1-amp includes several understudied 8p11-12 amplicon-driven oncogenes and accurately identifies FGFR1-amplified ER+ breast tumors. Our study demonstrates an efficient approach to diagnosing rare amplified therapeutic targets with FISH as a confirmatory assay.


Synthesis of an α-phosphono-α,α-difluoroacetamide analogue of the diphosphoinositol pentakisphosphate 5-InsP7.
Diphosphoinositol phosphates (PP-InsPs) are an evolutionarily ancient group of signalling molecules that are essential to cellular and organismal homeostasis. As the detailed mechanisms of PP-InsP signalling begin to emerge, synthetic analogues of PP-InsPs containing stabilised mimics of the labile diphosphate group can provide valuable investigational tools. We synthesised 5-PCF2Am-InsP5 (1), a novel fluorinated phosphonate analogue of 5-PP-InsP5, and obtained an X-ray crystal structure of 1 in complex with diphosphoinositol pentakisphosphate kinase 2 (PPIP5K2). 5-PCF2Am-InsP5 binds to the kinase domain of PPIP5K2 in a similar orientation to that of the natural substrate 5-PP-InsP5 and the PCF2Am structure can mimic many aspects of the diphosphate group in 5-PP-InsP5. We propose that 1, the structural and electronic properties of which are in some ways complementary to those of existing phosphonoacetate and methylenebisphosphonate analogues of 5-PP-InsP5, may be a useful addition to the expanding array of chemical tools for the investigation of signalling by PP-InsPs. The PCF2Am group may also deserve attention for wider application as a diphosphate mimic.


Acoustic landmarks contain more information about the phone string than other frames for automatic speech recognition with deep neural network acoustic model.
Most mainstream automatic speech recognition (ASR) systems consider all feature frames equally important. However, acoustic landmark theory is based on a contradictory idea that some frames are more important than others. Acoustic landmark theory exploits quantal nonlinearities in the articulatory-acoustic and acoustic-perceptual relations to define landmark times at which the speech spectrum abruptly changes or reaches an extremum; frames overlapping landmarks have been demonstrated to be sufficient for speech perception. In this work, experiments are conducted on the TIMIT corpus, with both Gaussian mixture model (GMM) and deep neural network (DNN)-based ASR systems, and it is found that frames containing landmarks are more informative for ASR than others. It is discovered that altering the level of emphasis on landmarks by re-weighting acoustic likelihood tends to reduce the phone error rate (PER). Furthermore, by leveraging the landmark as a heuristic, one of the hybrid DNN frame dropping strategies maintained a PER within 0.44% of optimal when scoring less than half (45.8% to be precise) of the frames. This hybrid strategy outperforms other non-heuristic-based methods and demonstrate the potential of landmarks for reducing computation.


Stages of embryonic development in the amphipod crustacean, Parhyale hawaiensis.
Studying the relationship between development and evolution and its role in the generation of biological diversity has been reinvigorated by new techniques in genetics and molecular biology. However, exploiting these techniques to examine the evolution of development requires that a great deal of detail be known regarding the embryonic development of multiple species studied in a phylogenetic context. Crustaceans are an enormously successful group of arthropods and extant species demonstrate a wide diversity of morphologies and life histories. One of the most speciose orders within the Crustacea is the Amphipoda. The embryonic development of a new crustacean model system, the amphipod Parhyale hawaiensis, is described in a series of discrete stages easily identified by examination of living animals and the use of commonly available molecular markers on fixed specimens. Complete embryogenesis occurs in 250 h at 26 degrees C and has been divided into 30 stages. This staging data will facilitate comparative analyses of embryonic development among crustaceans in particular, as well as between different arthropod groups. In addition, several aspects of Parhyale embryonic development make this species particularly suitable for a broad range of experimental manipulations.


Transient in situ measurement of kombucha biofilm growth and mechanical properties.
Kombucha is a traditional beverage obtained by the fermentation of sugared tea by a symbiotic culture of bacteria and yeast which has recently re-emerged as a popular lifestyle product with potential health benefits. The characteristic feature of kombucha is the formation of a cellulosic biofilm due to the excretion of bacterial cellulose with high purity and crystallinity. Despite the growing industrial and technological interest in kombucha, current characterization techniques rely on the periodic sampling of tea broth or biofilm and ex situ analysis of its biochemical or microbial composition. Here, we use interfacial shear rheology (ISR) for the transient in situ determination of kombucha biofilm growth directly at the interface. ISR revealed that kombucha biofilm formation is a two step process with clearly distinguishable growth phases. The first phase can be attributed to the initial adsorption of bacteria at the air-water interface and shows great variability, probably due to varying bacteria content and composition. The second phase is initiated by bacterial cellulose excretion and shows astonishing reproducibility regarding onset and final mechanical properties. Hence, ISR qualifies as a new in situ characterization technique for kombucha biofilm growth and bacterial cellulose production.


[Post-TUR-P stress urinary incontinence successfully treated by periurethral injection of autologous fat to the prostate: a case report].
A 77-year-old man had been suffering from stress urinary incontinence for 2 years since he had received transurethral resection of prostate (TUR-P) for benign prostatic hypertrophy. A 60-min pad test yielded 3 g of urine. Prostatic urethra was widely open and the external sphincteric injury was suggested because of the short membraneous urethra on the urethrogram. Urethral pressure profile indicated his maximal urethral closing pressure (MUCP) of 24 cmH2O and functional urethral length of 1.6 cm and cystometry demonstrated an underactive bladder, indicating that his incontinence was caused by sphincteric injury. Autologous fat injection therapy was performed in the lithotomy position under spinal anesthesia. Fifteen ml of subcutaneous fat was obtained from his lower abdomen by liposuction through a 15G needle, and 10 ml was injected submucosally from the perineum at 6 o'clock area of the prostatic apex under the guidance of transrectal echography using a 15G needle. The patient became completely dry after the procedure. MUCP and FUL increased to 35 cmH2O and 1.9 cm, respectively, although longer follow up is necessary. The advantage of autologous fat injection to the prostate for post-TUR-P SUI patients is briefly discussed.


Predicting metal-metal interactions. I. The influence of strain on nanoparticle and metal adlayer stabilities.
Strain-engineering of bimetallic nanomaterials is an important design strategy for developing new catalysts. Herein, we introduce an approach for including strain effects into a recently introduced, density functional theory (DFT)-based alloy stability model. The model predicts adsorption site stabilities in nanoparticles and connects these site stabilities with catalytic reactivity and selectivity. Strain-based dependencies will increase the model's accuracy for nanoparticles affected by finite-size effects. In addition to the stability of small nanoparticles, strain also influences the heat of adsorption of epitaxially grown metal-on-metal adlayers. In this respect, we successfully benchmark the strain-including alloy stability model with previous experimentally determined trends in the heats of adsorption of Au and Cu adlayers on Pt (111). For these systems, our model predicts stronger bimetallic interactions in the first monolayer than monometallic interactions in the second monolayer. We explicitly quantify the interplay between destabilizing strain effects and the energy gained by forming new metal-metal bonds. While tensile strain in the first Cu monolayer significantly destabilizes the adsorption strength, compressive strain in the first Au monolayer has a minimal impact on the heat of adsorption. Hence, this study introduces and, by comparison with previous experiments, validates an efficient DFT-based approach for strain-engineering the stability, and, in turn, the catalytic performance, of active sites in bimetallic alloys with atomic level resolution.


Capture-recapture to estimate completeness of tuberculosis surveillance in two communities in South Africa.
Reliable surveillance is essential for any tuberculosis (TB) control programme; however, under-registration of TB cases due to under-notification of patients on treatment or failure to initiate treatment has been well-documented internationally. To determine the contribution of capture-recapture methods in estimating the completeness of bacteriologically confirmed pulmonary TB registration in two high-incident communities in South Africa. Record linkage between the TB treatment register and two laboratory sputum TB result registers and three-source log-linear capture-recapture analysis. The number of bacteriologically confirmed pulmonary TB cases in the TB treatment register was 243, with an additional 63 cases identified in the two laboratory databases, resulting in 306 TB cases. The observed completeness of the TB treatment register was 79%. The log-linear model estimated 326 (95%CI 314-355) TB cases, resulting in an estimated completeness of registration of 75% (95%CI 68-77). Capture-recapture can be useful in evaluating the completeness of TB control surveillance and registration, including in resource-limited settings; however, methodology and results should be carefully assessed. Interventions are needed to increase the completeness of registration and to reduce the number of initial defaulters.


Regulation of Pax-3 expression in the dermomyotome and its role in muscle development.
The segmented mesoderm in vertebrates gives rise to a variety of cell types in the embryo including the axial skeleton and muscle. A number of transcription factors containing a paired domain (Pax proteins) are expressed in the segmented mesoderm during embryogenesis. These include Pax-3 and a closely related gene, Pax-7, both of which are expressed in the segmental plate and in the dermomyotome. In this paper, we show that signals from the notochord pattern the expression of Pax-3, Pax-7 and Pax-9 in somites and the subsequent differentiation of cell types that arise from the somitic mesoderm. We directly assess the role of the Pax-3 gene in the differentiation of cell types derived from the dermomyotome by analyzing the development of muscle in splotch mouse embryos which lack a functional Pax-3 gene. A population of Pax-3-expressing cells derived from the dermomyotome that normally migrate into the limb are absent in homozygous splotch embryos and, as a result, limb muscles are lost. No abnormalities were detected in the trunk musculature of splotch embryos indicating that Pax-3 is necessary for the development of the limb but not trunk muscle.


Ca(2+)- and GTP-dependent exocytosis in mouse pancreatic beta-cells involves both common and distinct steps.
1. The effects of GTP and Ca2+ on secretion from single pancreatic beta-cells were studied using capacitance measurements as an indicator of exocytosis. 2. GTP or GTP gamma S produced a concentration-dependent increase in cell capacitance in the absence of intracellular calcium. There was no effect of cyclic AMP or BAPTA an GTP-induced secretion. 3. In the absence of GTP, the relationship between intracellular calcium concentration and the maximum rate of secretion was fitted by the Hill equation with a slope factor of 2.5 and half-maximal activation at 1.6 microM intracellular Ca2+. Similar values were obtained in the presence of GTP gamma S, suggesting GTP does not alter the sensitivity of the secretory machinery to Ca2+. 4. GDP beta S alone had no effect on cell capacitance but caused a dose-dependent inhibition of exocytosis induced by infusion of either GTP gamma S or Ca2+, suggesting both stimuli involve G-protein activation. GDP beta S was without effect on exocytosis evoked by depolarization-mediated Ca2+ entry. 5. The time course of exocytosis following rapid elevation of GTP gamma S by photolysis of a caged precursor was dependent on the intracellular Ca2+ and cyclic AMP concentrations. 6. Our results are interpreted in terms of a model in which the secretory pathways stimulated by Ca2+ and GTP contain both common and separate parts.


Acute ANIT toxicity in male IL-10 knockout and wild-type mice.
The innate immune response is known to modify hepatocellular injury induced by toxicants. To assess the role of IL-10, a component of the innate immune response, in toxicant-induced injury of biliary epithelium, wild-type (WT) and IL-10 knockout mice (KO) were given a single toxic dose (50 mg/kg) of alpha-napthylisothiocyanate (ANIT) and assessed at twenty-four-hour intervals for four days following treatment. Clinical signs of toxicity were greater in WT mice. Unexpectedly, over the course of the study, there was a consistent tendency for ANIT-treated IL-10 KO mice to have less hepatocellular injury than WT mice. However, changes in the biliary epithelium differed in that there was more histologic evidence of inflammation and necrosis on days 2 and 3, respectively, in ANIT-treated IL-10 KO mice compared with WT mice. Proliferation of biliary epithelium and hepatocytes was greater and/or occurred earlier in the ANIT-treated IL-10 KO mice compared with the ANIT-treated WT mice, suggesting a greater reparative response was needed for recovery after toxicant injury in the IL-10 KO mice. Overall, our data suggest that IL-10 KO mice have less hepatocellular injury than WT mice following a toxic dose of ANIT and that biliary epithelial injury is accentuated in the KO mice.


Halobacillus campisalis sp. nov., containing meso-diaminopimelic acid in the cell-wall peptidoglycan, and emended description of the genus Halobacillus.
A Gram-positive or variable, motile and coccoid or oval-shaped bacterial strain, ASL-17(T), was isolated from a marine solar saltern of the Yellow Sea in Korea and its exact taxonomic position was investigated by a polyphasic approach. Strain ASL-17(T) grew optimally at pH 7.0-8.0 and 37 degrees C. Phylogenetic analysis based on 16S rRNA gene sequences showed that strain ASL-17(T) is most closely affiliated phylogenetically to the genus Halobacillus. Strain ASL-17(T) exhibited 16S rRNA gene sequence similarity values of 97.7-98.6 % to the type strains of recognized Halobacillus species. Interestingly, strain ASL-17(T) had cell-wall peptidoglycan based on meso-diaminopimelic acid, unlike other Halobacillus species. It contained MK-7 as the predominant menaquinone. The major fatty acids were anteiso-C(15 : 0), anteiso-C(17 : 0) and iso-C(16 : 0). The DNA G+C content was 42.1 mol%. DNA-DNA relatedness data and differential phenotypic properties demonstrated that strain ASL-17(T) can be differentiated from recognized Halobacillus species. On the basis of phenotypic, chemotaxonomic, phylogenetic and genetic data, strain ASL-17(T) represents a novel species of the genus Halobacillus, for which the name Halobacillus campisalis sp. nov. is proposed. The type strain is ASL-17(T) (=KCTC 13144(T) =CCUG 54360(T)).


The Effect of Epidural Steroid Injection on Postoperative Outcome in Patients From the Lumbar Spinal Stenosis Outcome Study.
Retrospective analysis of data from patients participating in the Lumbar Spinal Stenosis Outcome Study (LSOS). The aim of LSOS was to assess clinical outcomes after surgical or nonoperative treatment in patients with and without prior epidural steroid injections. Epidural steroid injections (ESI), a common treatment modality, reduce symptoms in the short-term, but according to a subgroup analysis from the Spine Patient Outcomes Research Trial (SPORT) they reduce the amount of improvement after subsequent surgical or nonoperative treatment. The data of 281 patients with lumbar spinal stenosis who had completed baseline and 6-month follow-up assessments were analyzed. Patients completed the Spinal Stenosis Measure (SSM). Changes in the SSM scores from baseline to follow-up were compared between patients with and without prior ESI, for the surgical and nonsurgical treatment groups. The mean (SD) age of the patients was 75 (8.7) years. 229 patients underwent surgery and 111 of these had received an ESI in the 12 months before surgery. Of the 52 patients treated nonoperatively, 29 had received a prior ESI. The unadjusted changes (improvement) in the SSM-symptom scores between baseline and 6 months' follow up were: surgery and prior ESI 0.95, surgery and no prior ESI 0.78 (P = 0.15); no surgery and prior ESI 0.28, no surgery and no prior ESI 0.29 (P = 0.85). When adjusted for confounding factors, the reduction in SSM-symptom score was greater for surgery than for nonoperative treatment by 0.41 points (P < 0.001); the effect of having had an ESI prior to study entry was -0.08 (P = 0.40). The analysis of outcomes in the LSOS cohort provided no evidence that ESIs have a negative effect on the short-term outcome of surgery or nonoperative treatment in patients with lumbar spinal stenosis. 3.


Changing currents: a strategy for understanding and predicting the changing ocean circulation.
Within the context of UK marine science, we project a strategy for ocean circulation research over the next 20 years. We recommend a focus on three types of research: (i) sustained observations of the varying and evolving ocean circulation, (ii) careful analysis and interpretation of the observed climate changes for comparison with climate model projections, and (iii) the design and execution of focused field experiments to understand ocean processes that are not resolved in coupled climate models so as to be able to embed these processes realistically in the models. Within UK-sustained observations, we emphasize smart, cost-effective design of the observational network to extract maximum information from limited field resources. We encourage the incorporation of new sensors and new energy sources within the operational environment of UK-sustained observational programmes to bridge the gap that normally separates laboratory prototype from operational instrument. For interpreting the climate-change records obtained through a variety of national and international sustained observational programmes, creative and dedicated UK scientists should lead efforts to extract the meaningful signals and patterns of climate change and to interpret them so as to project future changes. For the process studies, individual scientists will need to work together in team environments to combine observational and process modelling results into effective improvements in the coupled climate models that will lead to more accurate climate predictions.


Cerebrospinal fluid biomarkers and rate of cognitive decline in very mild dementia of the Alzheimer type.
Cerebrospinal fluid (CSF) levels of Abeta peptide 1-42 (Abeta 42), tau, and phosphorylated tau (ptau) are potential biomarkers of Alzheimer disease. To determine whether Abeta 42, tau, and ptau predict the rate of cognitive change in individuals with very mild dementia of the Alzheimer type (DAT). Retrospective analysis of CSF biomarkers and clinical data. An academic Alzheimer disease research center. Research volunteers in a longitudinal study of aging and cognition. Participants (n = 49) had a clinical diagnosis of very mild DAT with a Clinical Dementia Rating (CDR) of 0.5 at the time of lumbar puncture. All the participants had at least 1 follow-up assessment (mean [SD] follow-up, 3.5 [1.8] years). Baseline CSF levels of Abeta 42, Abeta 40, tau, and ptau at threonine 181 (ptau181) and the rate of dementia progression as measured using the CDR sum of boxes (CDR-SB) score and psychometric performance. The rate of dementia progression was significantly more rapid in individuals with lower baseline CSF Abeta 42 levels, higher tau or ptau181 levels, or high tau: Abeta 42 ratios. For example, the annual change in the CDR-SB score was 1.1 for the lowest 2 tertiles of Abeta 42 values and 0.3 for the highest tertile of Abeta 42 values. In individuals with very mild DAT, lower CSF Abeta 42 levels, high tau or ptau181 levels, or high tau:Abeta 42 ratios quantitatively predict more rapid progression of cognitive deficits and dementia. Biomarkers of CSF may be useful prognostically and to identify individuals who are more likely to progress for participation in therapeutic clinical trials.


[Efficacy of crystalloid cardioplegia against immature myocardium].
Previous reports have not suggested a critical answer for the question, if the efficacy of crystalloid cardioplegic (St' Thomas Hospital) solution against immature myocardium was the same as that against mature myocardium, or not. The author in this study, therefore, investigated 72 isolated puppy (2-4 weeks old) hearts dividing them at random into three groups according to the different doses to be administered, namely, Group A: single-dose of 10 ml/kg of cardioplegia; Group B: multiple-dose of cardioplegia with the initial dose of 10 ml/kg followed by 5 ml/kg every 20 minutes; and Group C: no use of cardioplegia. They were subjected to 120 minutes of ischemic arrest at 15 degrees C and subsequent 30 minutes of reperfusion. Ultrastructural changes of the myocardium were studied systematically and, in particular, semiquantification was carried out on mitochondria. Gravimetric and high energy phosphate (HEP) content of myocardium, and recovery of left ventricular end-systolic pressure volume ratio (Emax), spontaneous defibrillation ratio were also studied. Electron microscopic study showed that ischemic myocardial change with global ischemia was severer and more frequent in Group C as compared to Groups A and B, which coincided with less HEP content in Group C. Intracellular rarefaction following global ischemia was less frequent in Group A than in Group B or C, which corresponded to the result of gravimetric myocardial water content study. Spontaneous defibrillation in Group C was evidently prolonged, although there was no significant difference in the left ventricular function among the groups. The author should recommend single-dose administration of cardioplegia with topical cooling against immature myocardium, because this cardioplegia was effective in either single- or multiple-dose, and intracellular myocardial edema was lesser in the case of single-dose than in multiple-dose.


Surgical and clinical efficacy of sacroiliac joint fusion: a systematic review of the literature.
The sacroiliac joint (SIJ) and surgical intervention for treating SIJ pain or dysfunction has been a topic of much debate in recent years. There has been a resurgence in the implication of this joint as the pain generator for many patients experiencing low-back pain, and new surgical methods are gaining popularity within both the orthopedic and neurosurgical fields. There is no universally accepted gold standard for diagnosing or surgically treating SIJ pain. The authors systematically reviewed studies on SIJ fusion in the neurosurgical and orthopedic literature to investigate whether sufficient evidence exists to support its use. A literature search was performed using MEDLINE, Google Scholar, and OvidSP-Wolters Kluwer Health for all articles regarding SIJ fusion published from 2000 to 2014. Original, peer-reviewed, prospective or retrospective scientific papers with at least 2 patients were included in the study. Exclusion criteria included follow-up shorter than 1-year, nonsurgical treatment, inadequate clinical data as determined by 2 independent reviewers, non-English manuscripts, and nonhuman subjects. A total of 16 peer-reviewed journal articles met the inclusion criteria: 5 consecutive case series, 8 retrospective studies, and 3 prospective cohort studies. A total of 430 patients were included, of whom 131 underwent open surgery and 299 underwent minimally invasive surgery (MIS) for SIJ fusion. The mean duration of follow-up was 60 months for open surgery and 21 months for MIS. SIJ degeneration/arthrosis was the most common pathology among patients undergoing surgical intervention (present in 257 patients [59.8%]), followed by SIJ dysfunction (79 [18.4%]), postpartum instability (31 [7.2%]), posttraumatic (28 [6.5%]), idiopathic (25 [5.8%]), pathological fractures (6 [1.4%]), and HLA-B27+/rheumatoid arthritis (4 [0.9%]). Radiographically confirmed fusion rates were 20%-90% for open surgery and 13%-100% for MIS. Rates of excellent satisfaction, determined by pain reduction, function, and quality of life, ranged from 18% to 100% with a mean of 54% in open surgical cases. For MIS patients, excellent outcome, judged by patients' stated satisfaction with the surgery, ranged from 56% to 100% (mean 84%). The reoperation rate after open surgery ranged from 0% to 65% (mean 15%). Reoperation rate after MIS ranged from 0% to 17% (mean 6%). Major complication rates ranged from 5% to 20%, with 1 study that addressed safety reporting a 56% adverse event rate. Surgical intervention for SIJ pain is beneficial in a subset of patients. However, with the difficulty in accurate diagnosis and evidence for the efficacy of SIJ fusion itself lacking, serious consideration of the cause of pain and alternative treatments should be given before performing the operation.


Heteroatom-doped MoSe2 Nanosheets with Enhanced Hydrogen Evolution Kinetics for Alkaline Water Splitting.
Electrochemical water splitting for hydrogen generation is a vital part for the prospect of future energy systems, however, the practical utilization relies on the development of highly active and earth-abundant catalysts to boost the energy conversion efficiency as well as reduce the cost. Molybdenum diselenide (MoSe2 ) is a promising nonprecious metal-based electrocatalyst for hydrogen evolution reaction (HER) in acidic media, but it exhibits inferior alkaline HER kinetics in great part due to the sluggish water adsorption/dissociation process. Herein, the alkaline HER kinetics of MoSe2 is substantially accelerated by heteroatom doping with transition metal ions. Specifically, the Ni-doped MoSe2 nanosheets exhibit the most impressive catalytic activity in terms of lower overpotential and larger exchange current density. The density functional theory (DFT) calculation results reveal that Ni/Co doping plays a key role in facilitating water adsorption as well as optimizing hydrogen adsorption. The present work paves a new way to the development of low-cost and efficient electrocatalysts towards alkaline HER.


The use of laser-light scattering and controlled shear in platelet aggregometry.
Laser-light scattering was used to observe and quantify the dynamics of human blood platelet aggregation in platelet-rich plasma (PRP). Aggregation was performed in a controlled shear environment by placing the PRP in the annular space between a rotating cylindrical rod and a stationary cylindrical tube. The instrument was capable of very sensitive continuous semi-quantitative measurements of chemically-induced microaggregation. As a demonstration of the technique, results are presented for ADP-induced aggregation at doses of 10, 1, and 0.1 microM and collagen-induced aggregation at a dose of 5 micrograms/ml, each at shear rates of 1,000 s-1 and 500 s-1. Extensive aggregation was observed in response to ADP at even the low dose of 0.1 microM, indicating a high sensitivity to microaggregates. The sensitivity of the ultimate size of the ADP-induced aggregates to ADP concentration was shear dependent. The formation of microaggregates by collagen stimulation was shown to be almost immediate, as contrasted with a 10-20 s typical lag when observed turbidometrically. Disaggregation was observed with 1 microM ADP, but this was only partial, as contrasted with the complete recovery of transmittance observed in the turbidometric technique. Electronic particle sizing and counting was employed to semiquantitatively verify the aggregate size distributions found from mathematical conversion of the laser-light scattering data.


Health-related quality of life after induction of labor versus expectant monitoring in gestational hypertension or preeclampsia at term.
Gestational hypertension (GH) and preeclampsia (PE) are major contributors to maternal and neonatal morbidity and mortality. In GH or PE, labor may be either induced or monitored expectantly. We studied maternal health-related quality of life (HR-QoL) after induction of labor versus expectant monitoring in GH or PE at term. We performed the HR-QoL study alongside a multicenter randomized controlled trial comparing induction of labor to expectant monitoring in women with GH or PE after 36 weeks. We used written questionnaires, covering background characteristics, condition-specific issues, and validated measures: the Short-Form (SF-36), European Quality of Life (EuroQoL 6D3L), Hospital Anxiety and Depression Scale (HADS), and Symptom Checklist (SCL-90). Measurements were at the following time points: baseline, 6 weeks postpartum, and 6 months postpartum. A multivariate mixed model with repeated measures was defined to assess the effect of the treatments on the physical component score (PCS) and mental component score (MCS) of the SF-36. Analysis was by intention to treat. We analyzed the data of 491 randomized and 220 nonrandomized women. We did not find treatment effect on long-term HR-QoL (PCS: p = 0.09; MCS: p = 0.82). The PCS improved over time (p < 0.001) and was better in nonrandomized patients (p = 0.02). Despite a clinical benefit of induction of labor, long-term HR-QoL is equal after the induction of labor and expectant management in women with GH or PE beyond 36 weeks of gestation.


Pediatricians' communication about weight with overweight Latino children and their parents.
To examine pediatrician weight-management communication with overweight Latino children and their parents and whether communication differs by pediatrician-patient language congruency. Mixed-methods analysis of video-recorded primary care visits with overweight 6- to 12-year-old children. Three independent reviewers used video/transcript data to identify American Academy of Pediatrics-recommended communication content and establish communication themes/subthemes. Language incongruence (LI) was defined as pediatrician limited Spanish proficiency combined with parent limited English proficiency (LEP). Bivariate analyses examined associations of LI with communication content/themes. The mean child age (N = 26) was 9.5 years old; 81% were obese. Sixty-two percent of parents had LEP. Twenty-seven percent of pediatricians were Spanish-proficient. An interpreter was used in 25% of LI visits. Major themes for how pediatricians communicate overweight included BMI, weight, obese, chubby, and no communication (which only occurred in LI visits). The pediatrician communicated child overweight in 81% of visits, a weight-management plan in 50%, a culturally relevant dietary recommendation in 42%, a recommendation for a follow-up visit in 65%, and nutrition referral in 50%. Growth charts were used in 62% of visits but significantly less often in LI (13%) versus language-congruent (83%) visits (P < .001). Many overweight Latino children do not receive direct communication of overweight, culturally sensitive dietary advice, or follow-up visits. LI is associated with a lower likelihood of growth chart use. During primary care visits with overweight Latino children, special attention should be paid to directly communicating child overweight, formulating culturally sensitive weight-management plans, and follow-up. With LEP families, vigilance is needed in providing a trained interpreter and using growth charts.


Gestational intake of methyl donors and global LINE-1 DNA methylation in maternal and cord blood: prospective results from a folate-replete population.
Maternal diet affects offspring DNA methylation in animal models, but evidence from humans is limited. We investigated the extent to which gestational intake of methyl donor nutrients affects global DNA methylation in maternal and umbilical cord blood. Among mother-infant pairs in Project Viva, a folate-replete US population, we estimated maternal intakes of vitamin B12, betaine, choline, folate, cadmium, zinc and iron periconceptionally and during the second trimester. We examined associations of these nutrients with DNA methylation, measured as %5-methyl cytosines (%5mC) in Long Interspersed Nuclear Element-1 (LINE-1), in first trimester (n = 830) and second trimester (n = 671) maternal blood and in cord blood at delivery (n = 516). Cord blood methylation was higher for male than female infants {mean [standard deviation (SD)] 84.8 [0.6] vs. 84.4 [0.7]%}. In the multivariable-adjusted model, maternal intake of methyl donor nutrients periconceptionally and during the second trimester of pregnancy was not positively associated with first trimester, second trimester or cord blood LINE-1 methylation. Periconceptional betaine intake was inversely associated with cord blood methylation [regression coefficient = -0.08% (95% confidence interval (CI): -0.14,-0.01)] but this association was attenuated after adjustment for dietary cadmium, which itself was directly associated with first trimester methylation and inversely associated with cord blood methylation. We also found an inverse association between periconceptional choline [-0.10%, 95% CI: -0.17,-0.03 for each SD (~63 mg/day)] and cord blood methylation in males only. In this folate-replete population, we did not find positive associations between intake of methyl donor nutrients during pregnancy and DNA methylation overall, but among males, higher early pregnancy intakes of choline were associated with lower cord blood methylation.


Safety and immunogenicity of a self-amplifying RNA vaccine against COVID-19: COVAC1, a phase I, dose-ranging trial.
Lipid nanoparticle (LNP) encapsulated self-amplifying RNA (saRNA) is a novel technology formulated as a low dose vaccine against COVID-19. A phase I first-in-human dose-ranging trial of a saRNA COVID-19 vaccine candidate LNP-nCoVsaRNA, was conducted at Imperial Clinical Research Facility, and participating centres in London, UK, between 19th June to 28th October 2020. Participants received two intramuscular (IM) injections of LNP-nCoVsaRNA at six different dose levels, 0.1-10.0μg, given four weeks apart. An open-label dose escalation was followed by a dose evaluation. Solicited adverse events (AEs) were collected for one week from enrolment, with follow-up at regular intervals (1-8 weeks). The binding and neutralisation capacity of anti-SARS-CoV-2 antibody raised in participant sera was measured by means of an anti-Spike (S) IgG ELISA, immunoblot, SARS-CoV-2 pseudoneutralisation and wild type neutralisation assays. (The trial is registered: ISRCTN17072692, EudraCT 2020-001646-20). 192 healthy individuals with no history or serological evidence of COVID-19, aged 18-45 years were enrolled. The vaccine was well tolerated with no serious adverse events related to vaccination. Seroconversion at week six whether measured by ELISA or immunoblot was related to dose (both p<0.001), ranging from 8% (3/39; 0.1μg) to 61% (14/23; 10.0μg) in ELISA and 46% (18/39; 0.3μg) to 87% (20/23; 5.0μg and 10.0μg) in a post-hoc immunoblot assay. Geometric mean (GM) anti-S IgG concentrations ranged from 74 (95% CI, 45-119) at 0.1μg to 1023 (468-2236) ng/mL at 5.0μg (p<0.001) and was not higher at 10.0μg. Neutralisation of SARS-CoV-2 by participant sera was measurable in 15% (6/39; 0.1μg) to 48% (11/23; 5.0μg) depending on dose level received. Encapsulated saRNA is safe for clinical development, is immunogenic at low dose levels but failed to induce 100% seroconversion. Modifications to optimise humoral responses are required to realise its potential as an effective vaccine against SARS-CoV-2. This study was co-funded by grants and gifts from the Medical Research Council UKRI (MC_PC_19076), and the National Institute Health Research/Vaccine Task Force, Partners of Citadel and Citadel Securities, Sir Joseph Hotung Charitable Settlement, Jon Moulton Charity Trust, Pierre Andurand, Restore the Earth.


Novel sialic acid derivatives lock open the 150-loop of an influenza A virus group-1 sialidase.
Influenza virus sialidase has an essential role in the virus' life cycle. Two distinct groups of influenza A virus sialidases have been established, that differ in the flexibility of the '150-loop', providing a more open active site in the apo form of the group-1 compared to group-2 enzymes. In this study we show, through a multidisciplinary approach, that novel sialic acid-based derivatives can exploit this structural difference and selectively inhibit the activity of group-1 sialidases. We also demonstrate that group-1 sialidases from drug-resistant mutant influenza viruses are sensitive to these designed compounds. Moreover, we have determined, by protein X-ray crystallography, that these inhibitors lock open the group-1 sialidase flexible 150-loop, in agreement with our molecular modelling prediction. This is the first direct proof that compounds may be developed to selectively target the pandemic A/H1N1, avian A/H5N1 and other group-1 sialidase-containing viruses, based on an open 150-loop conformation of the enzyme.


More negative self-esteem and inferior coping strategies among patients diagnosed with IBS compared with patients without IBS--a case-control study in primary care.
Irritable Bowel Syndrome (IBS) is a chronic, relapsing gastrointestinal disorder, that affects approximately 10% of the general population and the majority are diagnosed in primary care. IBS has been reported to be associated with altered psychological and cognitive functioning such as mood disturbances, somatization, catastrophizing or altered visceral interoception by negative emotions and stress. The aim was to investigate the psychosocial constructs of self-esteem and sense of coherence among IBS patients compared to non-IBS patients in primary care. A case-control study in primary care setting among IBS patients meeting the ROME III criteria (n = 140) compared to controls i.e. non-IBS patients (n = 213) without any present or previous gastrointestinal complaints. The data were collected through self-reported questionnaires of psychosocial factors. IBS-patients reported significantly more negative self-esteem (p < 0.001), lower scores for positive self-esteem (p < 0.001), and lower sense of coherence (p < 0.001) than the controls. The IBS-cases were also less likely to report 'good' health status (p < 0.001) and less likely to report a positive belief in the future (p < 0.001). After controlling for relevant confounding factors in multiple regressions, the elevation in negative self-esteem among IBS patients remained statistically significant (p = 0.02), as did the lower scores for sense of coherence among IBS cases (p = 0.04). The more frequently reported negative self-esteem and inferior coping strategies among IBS patients found in this study suggest the possibility that psychological therapies might be helpful for these patients. However these data do not indicate the causal direction of the observed associations. More research is therefore warranted to determine whether these psychosocial constructs are more frequent in IBS patients.


Proline racemases: insights into Trypanosoma cruzi peptides containing D-proline.
Trypanosoma cruzi proline racemases (TcPRAC) are homodimeric enzymes that interconvert the L and D-enantiomers of proline. At least two paralogous copies of proline racemase (PR) genes are present per parasite haploid genome and they are differentially expressed during T. cruzi development. Non-infective epimastigote forms that overexpress PR genes differentiate more readily into metacyclic infective forms that are more invasive to host cells, indicating that PR participates in mechanisms of virulence acquisition. Using a combination of biochemical and enzymatic methods, we show here that, in addition to free D-amino acids, non-infective epimastigote and infective metacyclic parasite extracts possess peptides composed notably of D-proline. The relative contribution of TcPRAC to D-proline availability and its further assembly into peptides was estimated through the use of wild-type parasites and parasites over-expressing TcPRAC genes. Our data suggest that D-proline-bearing peptides, similarly to the mucopeptide layer of bacterial cell walls, may be of benefit to T. cruzi by providing resistance against host proteolytic mechanisms.


ENPP1 K121Q Genotype Not Associated with Coronary Artery Calcification in Korean Patients with Type 2 Diabetes Mellitus.
Ectonucleotide pyrophosphatase/phosphodiesterase-1 (ENPP1) generates inorganic pyrophosphate, a solute that serves as an essential physiological inhibitor of calcification. Inactivating mutations of ENPP1 are associated with generalized calcification in infancy and an increased risk of developing type 2 diabetes mellitus (T2DM). We hypothesized that the ENPP1 K121Q variant may be associated with increased coronary artery calcification in T2DM patients. The study subjects were aged 34 to 85 years and showed no evidence of clinical cardiovascular disease prior to recruitment. A total of 140 patients with T2DM were assessed for their coronary artery calcium (CAC) scores and ENPP1 K121Q polymorphisms were identified. The prevalence of subjects carrying the KQ genotype was 12.9% (n = 18). There were no 121QQ homozygotes. Patients with the KQ genotype did not show a significantly higher CAC score (122 vs. 18; P = 0.858). We matched each patient with the KQ genotype to a respective control with the KK genotype by gender, age, and duration of diabetes. When compared to matched controls, we observed no significant difference in CAC score (P = 0.959). The ENPP1 K121Q polymorphism does not appear to be associated with coronary artery calcification in patients with T2DM.


A novel α-conopeptide Eu1.6 inhibits N-type (CaV2.2) calcium channels and exhibits potent analgesic activity.
We here describe a novel α-conopeptide, Eu1.6 from Conus eburneus, which exhibits strong anti-nociceptive activity by an unexpected mechanism of action. Unlike other α-conopeptides that largely target nicotinic acetylcholine receptors (nAChRs), Eu1.6 displayed only weak inhibitory activity at the α3β4 and α7 nAChR subtypes and TTX-resistant sodium channels, and no activity at TTX-sensitive sodium channels in rat dorsal root ganglion (DRG) neurons, or opiate receptors, VR1, KCNQ1, L- and T-type calcium channels expressed in HEK293 cells. However, Eu1.6 inhibited high voltage-activated N-type calcium channel currents in isolated mouse DRG neurons which was independent of GABAB receptor activation. In HEK293 cells expressing CaV2.2 channels alone, Eu1.6 reversibly inhibited depolarization-activated Ba2+ currents in a voltage- and state-dependent manner. Inhibition of CaV2.2 by Eu1.6 was concentration-dependent (IC50 ~1 nM). Significantly, systemic administration of Eu1.6 at doses of 2.5-5.0 μg/kg exhibited potent analgesic activities in rat partial sciatic nerve injury and chronic constriction injury pain models. Furthermore, Eu1.6 had no significant side-effect on spontaneous locomotor activity, cardiac and respiratory function, and drug dependence in mice. These findings suggest α-conopeptide Eu1.6 is a potent analgesic for the treatment of neuropathic and chronic pain and opens a novel option for future analgesic drug design.


Polarization rotator-splitters in standard active silicon photonics platforms.
We demonstrate various silicon-on-insulator polarization management structures based on a polarization rotator-splitter that uses a bi-level taper TM0-TE1 mode converter. The designs are fully compatible with standard active silicon photonics platforms with no new levels required and were implemented in the IME baseline and IME-OpSIS silicon photonics processes. We demonstrate a polarization rotator-splitter with polarization crosstalk < -13 dB over a bandwidth of 50 nm. Then, we improve the crosstalk to < -22 dB over a bandwidth of 80 nm by integrating the polarization rotator-splitter with directional coupler polarization filters. Finally, we demonstrate a polarization controller by integrating the polarization rotator-splitters with directional couplers, thermal tuners, and PIN diode phase shifters.


Role of the 4-phosphopantetheinyl transferase of Trichoderma virens in secondary metabolism and induction of plant defense responses.
Trichoderma virens is a ubiquitous soil fungus successfully used in biological control due to its efficient colonization of plant roots. In fungi, 4-phosphopantetheinyl transferases (PPTases) activate enzymes involved in primary and secondary metabolism. Therefore, we cloned the PPTase gene ppt1 from T. virens and generated PPTase-deficient (?ppt1) and overexpressing strains to investigate the role of this enzyme in biocontrol and induction of plant defense responses. The ?ppt1 mutants were auxotrophic for lysine, produced nonpigmented conidia, and were unable to synthesize nonribosomal peptides. Although spore germination was severely compromised under both low and high iron availability, mycelial growth occurred faster than the wild type, and the mutants were able to efficiently colonize plant roots. The ?ppt1 mutants were unable of inhibiting growth of phytopathogenic fungi in vitro. Arabidopsis thaliana seedlings co-cultivated with wild-type T. virens showed increased expression of pPr1a:uidA and pLox2:uidA markers, which correlated with enhanced accumulation of salicylic acid (SA), jasmonic acid, camalexin, and resistance to Botrytis cinerea. Co-cultivation of A. thaliana seedlings with ?ppt1 mutants compromised the SA and camalexin responses, resulting in decreased protection against the pathogen. Our data reveal an important role of T. virens PPT1 in antibiosis and induction of SA and camalexin-dependent plant defense responses.


Internal jugular vein cannulation: A comparison of three techniques.
Ultrasound-guided internal jugular vein (IJV) cannulation is known for increasing success rate and decreasing rate of complications. The ultrasound image can be used as a real time image during cannulation or to prelocate the IJV before attempting cannulation. This study compares both the ultrasound-guided technique with the classical anatomical landmark technique (central approach) for right IJV cannulation in terms of success rate, complications, and time for cannulation. A prospective, randomized, observational study was conducted at a tertiary care hospital. One hundred twenty patients requiring IJV cannulation were included in this study and were randomly allocated in three groups. Number of attempts, success rate, venous access time, catheterization time, and complications were observed in each group. Statistical analysis was performed using STATA-9 software. Demographic data were compared using one-way analysis of variance (ANOVA). Nonparametric data were compared using the Kruskall-Wallis test, and multiple comparisons were done applying The Mann-Whitney test for individual pairs of groups. Nominal data were compared by applying the Chi-square test and Fisher exact test. Successful cannulation (≤3 attempt) was achieved in 90.83% of patients without any statistical significant difference between the groups. Venous access time and catheterization time was found to be significantly less in both the ultrasound groups than the anatomical land mark group. Number of attempts and success in first attempt was similar between the groups. Both the ultrasound techniques are found to be better than the anatomical landmark technique. Further, ultrasound-guided prelocation was found to be as effective as ultrasound guided real-time imaging technique for right IJV cannulation.


Melittin suppresses tumor progression by regulating tumor-associated macrophages in a Lewis lung carcinoma mouse model.
Tumor-associated macrophages (TAM) are a major component of tumor stroma. It has been reported that TAMs have M2-like phenotype and facilitate tumor progression by promoting angiogenesis and immunosuppression. Melittin, a major polypeptide of bee venom, has been widely studied as an anti-cancer drug due to its cytotoxicity to malignant cells. However, very little is known regarding the effect of melittin on immune cells in the tumor microenvironment. This study focuses on the effect of melittin on TAMs in a Lewis lung carcinoma mouse model. Melittin inhibited the rapid tumor growth compared to the control in vivo. Melittin increased the M1/M2 ratio of TAMs by selectively reducing the number of CD206+ M2-like TAMs while not altering the population of CD86+ M1-like TAMs. Melittin also preferentially binds to M2 macrophages, and this binding was not associated with phagocytosis. Gene and protein expression of vascular endothelial growth factor (Vegf) and mannose receptor C type 1 (Mrc1/CD206) was reduced in M2-like bone marrow-derived macrophages by melittin treatment, but there was no significant change in the gene level of Vegf and FMS-like tyrosine kinase 1 (Flt1/VEGFR1) in tumor cells in vitro. Additionally, the levels of VEGF and CD31, markers of angiogenesis, were significantly decreased by melittin treatment in tumor tissues. This study revealed a novel role for melittin in tumor treatment and suggested that melittin could be a promising therapeutic agent for targeting M2-like TAMs.


The role of perceived partner alliance on the efficacy of CBT-I: preliminary findings from the Partner Alliance in Insomnia Research Study (PAIRS).
Despite cognitive behavioral therapy for insomnia (CBT-I) being effective, barriers to adherence have been documented. Perceived partner alliance has been shown to influence adherence and treatment outcome across a range of other health conditions. The present study examined patients' perceptions regarding the role of their partner in CBT-I and the impact of perceived partner alliance on treatment outcome. Twenty-one patients were interviewed, following CBT-I, to examine the areas where partners were thought to influence the process of CBT-I. The majority of statements made during interviews explicitly mentioned a partner's influence (65%). Additionally, the production of more positive partner statements was associated with better treatment outcome (using the Insomnia Severity Index). The integration of perceived partner alliance into CBT-I is discussed.


Experimental mouse models of T cell-dependent inflammatory bowel disease.
Inflammatory bowel diseases (IBD) represent idiopathic chronic inflammatory disorders of the intestinal tract that are associated with aberrant immune responses against intestinal bacteria. Here, we describe two T cell-dependent models of experimental murine IBD. In the "T cell transfer" model, lymphopenic (scid or Rag (-/-) ) mice develop colitis upon adoptive transfer of naïve CD4(+) T cells. This model has also been extensively employed to identify mechanisms through which CD4(+)CD25(+) regulatory T cells suppress intestinal inflammation in vivo. We also describe a model of T cell-dependent IBD in immunocompetent mice, induced by infection with the intestinal bacterium Helicobacter hepaticus and concomitant treatment with a blocking αIL-10R mAb, which leads to the development of chronic inflammation of the caecum and colon (typhlocolitis). Both models reproduce many facets of human IBD pathology, including epithelial hyperplasia, goblet cell depletion, and leukocyte infiltration. These models provide reliable and tractable systems for the analyses of the induction and regulation of chronic inflammation in the gut.


Impact of serum total cholesterol on the incidence of gastric cancer in a population-based prospective study: the Hisayama study.
The results of prospective studies that have examined the association between serum cholesterol levels and the incidence of gastric cancer remain controversial. To examine this issue in a general population, a total of 2,604 subjects aged 40 years or older were followed up prospectively for 14 years. During the follow-up period, gastric cancer developed in 97 subjects. The age- and sex-adjusted incidence of gastric cancer by quartiles of serum cholesterol level, namely, <4.06, 4.06-5.32, 5.33-6.04 and >or=6.05 mmol/L, were 3.9, 3.3, 3.1 and 2.1 per 1,000 person-years, respectively. The risk of gastric cancer increased with decreasing cholesterol level (age- and sex-adjusted hazard ratio [HR], 1.22; 95% confidence interval [CI], 1.01-1.49; p = 0.04 for a decrease of 1 mmol/L in serum cholesterol level). This inverse association remained unchanged even after adjustment for other confounding factors, namely, Helicobacter pylori infection, atrophic gastritis, family history of malignant neoplasm, smoking habits, body mass index, hemoglobin A1c, white blood cell count and dietary factors (adjusted HR, 1.28; 95% CI, 1.03-1.58; p = 0.02). This association was significant for intestinal-type gastric cancers, but not for diffuse-type. As regards cancer stage, the inverse cholesterol-cancer association was marginally significant for early gastric cancer after multivariate-adjustment (adjusted HR, 1.25; 95% CI, 0.97-1.61; p = 0.09), but was not for advanced gastric cancer probably due to the small number of cases. In conclusion, our findings suggest that low serum cholesterol levels are an independent risk factor for developing gastric cancer, especially intestinal-type gastric cancer.


Design and Rationale for a Phase III, Randomized, Placebo-controlled Trial of Durvalumab With or Without Tremelimumab After Concurrent Chemoradiotherapy for Patients With Limited-stage Small-cell Lung Cancer: The ADRIATIC Study.
Limited-stage (LS) small-cell lung cancer (SCLC) remains an area of high unmet medical need. The standard-of-care therapy comprises curative-intent platinum-based chemotherapy with concurrent radiotherapy (cCRT), which can be followed by prophylactic brain irradiation and then observation. However, most patients will relapse. Durvalumab (antiprogrammed cell death ligand-1) has enhanced the efficacy outcomes after cCRT for patients with unresectable, stage III non-small-cell lung cancer. Recently, durvalumab combined with platinum-etoposide demonstrated a significant survival benefit compared with platinum-etoposide as first-line treatment of patients with extensive-stage SCLC and has also shown antitumor activity as monotherapy and combined with tremelimumab (anticytotoxic T-lymphocyte-associated antigen-4) in pretreated patients with extensive-stage SCLC. ADRIATIC, a phase III, randomized, double-blind, placebo-controlled, multicenter, global study (ClinicalTrials.gov identifier, NCT03703297), is designed to investigate the efficacy of durvalumab, with or without tremelimumab, as consolidation therapy for patients with LS-SCLC without disease progression after cCRT. Approximately 600 patients with documented histologic or cytologic LS-SCLC, World Health Organization/Eastern Cooperative Oncology Group performance status 0 or 1, and no progression after 4 cycles of cCRT will be randomized (1:1:1) to treatment (durvalumab 1500 mg plus placebo every 4 weeks [q4w] for 4 cycles, followed by durvalumab 1500 mg q4w; durvalumab 1500 mg plus tremelimumab 75 mg q4w for 4 cycles, followed by durvalumab 1500 mg q4w; or dual placebo q4w for 4 cycles, followed by single placebo q4w) within 1 to 42 days of completing cCRT, stratified by stage and receipt of prophylactic brain irradiation. The primary endpoints are progression-free survival and overall survival. The secondary endpoints are overall survival and progression-free survival rates, objective response rate, and safety and tolerability. Recruitment began in September 2018.


Mode analysis and prism coupling for multilayered optical waveguides.
Recursion relationships are developed which generate the characteristic mode equations for both free and prism-loaded optical waveguides composed of N arbitrary dielectric layers. The solutions of these equations allow the computation of the effective mode-propagation coefficients and, in the case of prism loading, leakage rates and coupling efficiencies for arbitrary gap shape and coupling strength. As an illustration four specific prism/waveguide couplers with linearly tapered gaps are numerically analyzed. Two of these are single-layer waveguides (N = 1), and the other two are multilayered waveguides (N = 19) with n(i) chosen to simulate exponential index gradients. Results obtained from the present theory in the weak coupling limit are shown to agree with those obtained in previous work.


Effect of an alkyl substituent and spacer length in benzene-centered tripodal diglycolamides on the sequestration of minor actinides.
Three benzene-centered tripodal diglycolamide (Bz-T-DGA) ligands, where diglycolamide (DGA) moieties are tethered to the central benzene ring through a methylene spacer and having either a hydrogen atom (LI) or an isopentyl group (LII) attached to the N-atom, and DGA moieties attached via an ethylene spacer and having an isopentyl group attached to the N-atom (LIII), were studied for their complexation and extraction abilities towards trivalent actinides and lanthanides. The distribution ratio of Am(iii) and Eu(iii) with 1 mmol L-1 ligand in 5% iso-decanol/n-dodecane followed the order: LII > LIII > LI. The substitution of the H atom with the isopentyl group on the N-atom of the DGA moieties resulted in two orders of magnitude enhancement in the extraction ability of the ligand. On the other hand, increase in the spacer length between the benzene ring and the DGA moieties resulted in several fold reduction in the extraction ability of the ligand. Spectroscopic studies with Eu3+ ions in acetonitrile also confirmed the metal/ligand complex formation constant in the order: LII > LIII > LI. Luminescence decay lifetimes of Eu3+/ligand complexes confirmed the absence of water molecules and that all the primary coordination sites of the metal ion are occupied by the ligands.


Outcomes of cholecystectomy in US heart transplant recipients.
The aim of this study was to evaluate outcomes and predictors of in-hospital mortality after cholecystectomy in heart transplant (HTx) recipients. There is a paucity of data on outcomes after cholecystectomy in HTx recipients. The Nationwide Inpatient Sample (NIS) database was used to identify HTx recipients who underwent cholecystectomy between 1998 and 2008. Multivariate logistic regression analysis was constructed using clinically relevant covariates (age, gender, Charlson comorbidity index, race, admission acuity, complicated gallstone disease, hospital teaching status, and open versus laparoscopic approach) to identify predictors of in-hospital mortality. A total of 1687 HTx recipients underwent cholecystectomy (open n = 420; laparoscopic n = 1267) during the study period. Mean age was 57.1 ± 12.5 years, and there were 1230 (72.9%) males. The majority of patients had acute cholecystitis (n = 1218; 72.2%) and were admitted urgently/emergently (n = 1028; 60.9%). Overall inpatient mortality occurred in 37 (2.2%) patients, with a higher mortality rate in open cholecystectomy compared with laparoscopic (6.2% vs. 0.9%; P = 0.009), and in urgent/emergent versus elective cases (3.6% vs. 0%; P = 0.04). Open or urgent/emergent cholecystectomies also had higher overall complication and respiratory failure rates as compared with laparoscopic or elective cases. Predictors of inpatient mortality in multivariable analysis included urgent/emergent admission, open cholecystectomy, and complicated gallstone disease (each P < 0.05). This is the largest reported study to date of cholecystectomy in HTx recipients. HTx patients appear to be at increased risk of inpatient mortality and morbidity after cholecystectomy as compared with the general population, and this rate is particularly high in those with a nonelective admission who undergo open cholecystectomy for complicated gallstone disease. Therefore, strong consideration should be given to prophylactic cholecystectomy in HTx recipients with asymptomatic and uncomplicated gallstone disease.


Repeated porphyrin lipoprotein-based photodynamic therapy controls distant disease in mouse mesothelioma via the abscopal effect.
While photodynamic therapy (PDT) can induce acute inflammation in the irradiated tumor site, a sustained systemic, adaptive immune response is desirable, as it may control the growth of nonirradiated distant disease. Previously, we developed porphyrin lipoprotein (PLP), a ∼20 nm nanoparticle photosensitizer, and observed that it not only efficiently eradicated irradiated primary VX2 buccal carcinomas in rabbits, but also induced regression of nonirradiated metastases in a draining lymph node. We hypothesized that PLP-mediated PDT can induce an abscopal effect and we sought to investigate the immune mechanism underlying such a response in a highly aggressive, dual subcutaneous AE17-OVA+ mesothelioma model in C57BL/6 mice. Four cycles of PLP-mediated PDT was sufficient to delay the growth of a distal, nonirradiated tumor four-fold relative to controls. Serum cytokine analysis revealed high interleukin-6 levels, showing a 30-fold increase relative to phosphate-buffered solution (PBS) treated mice. Flow cytometry revealed an increase in CD4+ T cells and effector memory CD8+ T cells in non-irradiated tumors. Notably, PDT in combination with PD-1 antibody therapy prolonged survival compared to monotherapy and PBS. PLP-mediated PDT shows promise in generating a systemic immune response that can complement other treatments, improving prognoses for patients with metastatic cancers.


Bayesian methods in palliative care research: cancer-induced bone pain.
To show how a simple Bayesian analysis method can be used to improve the evidence base in patient populations where recruitment and retention are challenging. A Bayesian conjugate analysis method was applied to binary data from the Thermal testing in Bone Pain (TiBoP) study: a prospective diagnostic accuracy/predictive study in patients with cancer-induced bone pain (CIBP). This study aimed to evaluate the clinical utility of a simple bedside tool to identify who was most likely to benefit from palliative radiotherapy (XRT) for CIBP. Recruitment and retention of patients were challenging due to the frail population, with only 27 patients available for the primary analysis. The Bayesian method allowed us to make use of prior work done in this area and combine it with the TiBoP data to maximise the informativeness of the results. Positive and negative predictive values were estimated with greater precision, and interpretation of results was facilitated by use of direct probability statements. In particular, there was only 7% probability that the true positive predictive value was above 80%. Several advantages of using Bayesian analysis are illustrated in this article. The Bayesian method allowed us to gain greater confidence in our interpretation of the results despite the small sample size by allowing us to incorporate data from a previous similar study. We suggest that this method is likely to be useful for the analysis of small diagnostic or predictive studies when prior information is available.


The PPD-specific T-cell clonal response in UK and Malawian subjects following BCG vaccination: a new repertoire evolves over 12 months.
Mycobacterium bovis bacille Calmette Guerin vaccination protects against pulmonary tuberculosis in the United Kingdom but not in Malawi. We investigated whether a difference in the clonal T-cell response to BCG vaccination might account for this. The results of clonal analysis were compared to those obtained by skin testing and in a whole blood interferon gamma assay. Pre-vaccination antigen specific T-cell clones were detected, but the majority of clones present 12 months after vaccination were not present earlier. The magnitude of the clonal response did not correlate well with results of the other assays. These data indicate that single assays may not be reliable and that a stable memory T-cell repertoire is slow to develop.


Enzymatically Degradable Polyester-Based Adhesives.
A designed 3,4-dihydroxyphenylalanine (DOPA) mimetic enzymatic degradable synthetic adhesive with good adhesion to soft tissue and metals made by a simple two-step reaction is presented in this article. This adhesive has degradable polycaprolactone-type of repeat units together with glycidyl methacrylate (GMA) and oligo(ethylene glycol) methacrylate (OEGMA) on the polymer backbone. Radical initiated copolymerization of 2-methylene-1,3-dioxepane (MDO), glycidyl methacrylate (GMA) and OEGMA followed by immobilization of catechol group on epoxy rings of GMA provided the adhesive material. Fe(acac)3 was proved to be the most effective cross-linking agent with lap shear strength of 13.13 ± 1.74 kPa and 218.4 ± 16.0 kPa on soft tissue (porcine skin) and metal (aluminum), respectively. The cross-linked adhesive showed good adhesion stability in pH 7 PBS buffer at 37 °C for at least 1 week. Because of the high adhesive strength, enzymatic degradability, and low toxicity, the material is a promising candidate for future studies as medical glue.


A conserved motif for the transport of G protein-coupled receptors from the endoplasmic reticulum to the cell surface.
The structural determinants for the export trafficking of G protein-coupled receptors are poorly defined. In this report, we determined the role of carboxyl termini (CTs) of alpha2B-adrenergic receptor (AR) and angiotensin II type 1A receptor (AT1R) in their transport from the endoplasmic reticulum (ER) to the cell surface. The alpha2B-AR and AT1R mutants lacking the CTs were completely unable to transport to the cell surface and were trapped in the ER. Alanine-scanning mutagenesis revealed that residues Phe436 and Ile433-Leu444 in the CT were required for alpha2B-AR export. Insertion or deletion between Phe436 and Ile443-Leu444 as well as Ile443-Leu444 mutation to FF severely disrupted alpha2B-AR transport, indicating there is a defined spatial requirement, which is essential for their function as a single motif regulating receptor transport from the ER. Furthermore, the carboxyl-terminally truncated as well as Phe436 and Ile443-Leu444 mutants were unable to bind ligand and the alpha2B-AR CT conferred its transport properties to the AT1R mutant without the CT in a Phe436-Ile443-Leu444-dependent manner. These data suggest that the Phe436 and Ile443-Leu444 may be involved in both proper folding and export from the ER of the receptor. Similarly, residues Phe309 and Leu316-Leu317 in the CT were identified as essential for AT1R export. The sequence F(X)6LL (where X can be any residue, and L is leucine or isoleucine) is highly conserved in the membrane-proximal CTs of many G protein-coupled receptors and may function as a common motif mediating receptor transport from the ER to the cell surface.


Hip resurfacing: a 40-year perspective.
Saving bone by resurfacing the femoral head is not a new concept and the appeal for this type of hip replacement has remained despite the difficulties to find a bearing material suitable for this procedure. In this article, the unique experience of a surgeon who has been performing hip resurfacing since its early development is presented, along with a comparative analysis of the performance of successive designs. The overall 10-year Kaplan-Meier survivorship of the early designs with polyethylene bearings did not exceed 62% while that of the current Conserve®Plus metal-on-metal hybrid design implanted with second generation surgical technique is in excess of 92%. Further exceptional, in the 10-year survivorship, 99.7% has been achieved with femoral size of 46 mm and good bone quality. Cementless acetabular components provide better enduring fixation than cemented designs. Metal-on-metal is currently and fortunately the only highly successful bearing material that can combine low wear rates and the manufacturing of a thin acetabular component to preserve bone and still accommodate the large femoral head of a hip resurfacing. The adverse local tissue reactions (ALTR) associated with metal-on-metal devices are not a bearing material issue per se but one of the device design and surgical technique. Almost all of ALTR and the rare events of systemic toxicity are due to abnormal wear patterns which can be prevented by proper acetabular component design and precise socket orientation in both the coronal and sagittal planes. Further improvements of the long-term durability with hip resurfacing can be anticipated with the use of recently developed trabecular bone-like tantalum or titanium porous coatings and with proper training of the surgeons interested in performing hip resurfacing arthroplasty.


Rapamycin pharmacokinetic and pharmacodynamic relationships in osteosarcoma: a comparative oncology study in dogs.
Signaling through the mTOR pathway contributes to growth, progression and chemoresistance of several cancers. Accordingly, inhibitors have been developed as potentially valuable therapeutics. Their optimal development requires consideration of dose, regimen, biomarkers and a rationale for their use in combination with other agents. Using the infrastructure of the Comparative Oncology Trials Consortium many of these complex questions were asked within a relevant population of dogs with osteosarcoma to inform the development of mTOR inhibitors for future use in pediatric osteosarcoma patients. This prospective dose escalation study of a parenteral formulation of rapamycin sought to define a safe, pharmacokinetically relevant, and pharmacodynamically active dose of rapamycin in dogs with appendicular osteosarcoma. Dogs entered into dose cohorts consisting of 3 dogs/cohort. Dogs underwent a pre-treatment tumor biopsy and collection of baseline PBMC. Dogs received a single intramuscular dose of rapamycin and underwent 48-hour whole blood pharmacokinetic sampling. Additionally, daily intramuscular doses of rapamycin were administered for 7 days with blood rapamycin trough levels collected on Day 8, 9 and 15. At Day 8 post-treatment collection of tumor and PBMC were obtained. No maximally tolerated dose of rapamycin was attained through escalation to the maximal planned dose of 0.08 mg/kg (2.5 mg/30 kg dog). Pharmacokinetic analysis revealed a dose-dependent exposure. In all cohorts modulation of the mTOR pathway in tumor and PBMC (pS6RP/S6RP) was demonstrated. No change in pAKT/AKT was seen in tumor samples following rapamycin therapy. Rapamycin may be safely administered to dogs and can yield therapeutic exposures. Modulation pS6RP/S6RP in tumor tissue and PBMCs was not dependent on dose. Results from this study confirm that the dog may be included in the translational development of rapamycin and potentially other mTOR inhibitors. Ongoing studies of rapamycin in dogs will define optimal schedules for their use in cancer and evaluate the role of rapamycin use in the setting of minimal residual disease.


Birthweight distribution in ART singletons resulting from embryo culture in two different culture media compared with the national population.
Is there a difference in birthweight distribution in ART singletons born after IVF culture in two different culture media? There is no effect of culture media on both crude and adjusted birthweight distributions in ART singletons from nulliparous mothers. Studies on human ART singletons have reported a difference in birthweight in singletons following IVF culture in different culture media. However, other studies comparing different culture media have not shown any significant differences in birthweight. This study was a retrospective comparison of birthweights in IVF/ICSI singletons conceived after fresh embryo transfer following embryo culture in Cook or Medicult medium and in a national cohort of naturally conceived singletons in nulliparous women. The study compares four independent groups consisting of singletons in nulliparous women from Cook-d2: 2-day culture in Cook medium at Rigshospitalet (n = 974), Medicult-d2: 2-day culture in Medicult EmbryoAssist medium at Rigshospitalet (n = 147), Medicult-d3: 3-day culture in Medicult EmbryoAssist medium with and without added GM-CSF (n = 204), and DK: pregnancies from the Danish birth registry (n = 106842). The study compares the birthweights of singletons from nulliparous women in the four independent groups mentioned above; Cook-d2: Medicult-d2: Medicult-d3: and DK. In addition, distributions of large and small for gestational age infants were compared between the groups and a multiple linear regression analysis was used to determine which factors determined birthweight. We found no significant difference in the crude birthweight distributions between singletons born after culture in Cook-d2 or Medicult-groups. Singleton girls from the Cook-d2 group weighed 3302 ± 28 g, versus 3252 ± 76 in the Medicult-d2 group (difference 50 g; P = 0.547). Singleton boys from the Cook-d2 group weighed 3430 ± 27 g, versus 3354 ± 56 in the Medicult-d2 group (difference 76 g; P = 0.279). In the background population, mean birthweights for singleton girls and boys were 3383 ± 2.4 g and 3494 ± 2.5 g, respectively. The mean birthweights of girls, 3315 ± 61 g, and boys, 3383 ± 64 g, in the Medicult-d3 group were not significantly different from that in the Medicult-d2 group. When pooling data from all culture media groups, we found the same slightly lower mean birthweight in IVF/ICSI singletons when compared with the national birth cohort as has been previously reported (Cook-d2 + Medicult-d2 + d3 versus birth cohort; girls: P < 0.001, boys: P < 0.001). We also pooled data on boys and girls and calculated the mean birthweight for the Cook-d2, Medicult-d2 and Medicult-d3 groups and found no significant differences. The retrospective design and the inherent risk of confounding factors is a limitation. Selection bias cannot be excluded as the embryos cultured in Cook-d2 and Medicult-d2 were from single centre studies while data in Medicult-D3 group were derived from a multicentre study. This large cohort of singletons born after IVF/ICSI shows no difference in crude mean birthweight after culture in two different culture media, indicating that if such a difference exists, this must be specific for certain culture media. As expected we found a slightly lower mean birthweight in ART compared with naturally conceived singletons. This suggests that parental characteristics or IVF technique related factors other than type of culture medium may influence the birthweight in ART singletons. No external funding was used for this study. No conflicts of interest are declared.


Spatial analysis and correlates of county-level diabetes prevalence, 2009-2010.
Information on the relationship between diabetes prevalence and built environment attributes could allow public health programs to better target populations at risk for diabetes. This study sought to determine the spatial prevalence of diabetes in the United States and how this distribution is associated with the geography of common diabetes correlates. Data from the Centers for Disease Control and Prevention and the US Census Bureau were integrated to perform geographically weighted regression at the county level on the following variables: percentage nonwhite population, percentage Hispanic population, education level, percentage unemployed, percentage living below the federal poverty level, population density, percentage obese, percentage physically inactive, percentage population that cycles or walks to work, and percentage neighborhood food deserts. We found significant spatial clustering of county-level diabetes prevalence in the United States; however, diabetes prevalence was inconsistently correlated with significant predictors. Percentage living below the federal poverty level and percentage nonwhite population were associated with diabetes in some regions. The percentage of population cycling or walking to work was the only significant built environment-related variable correlated with diabetes, and this association varied in magnitude across the nation. Sociodemographic and built environment-related variables correlated with diabetes prevalence in some regions of the United States. The variation in magnitude and direction of these relationships highlights the need to understand local context in the prevention and maintenance of diabetes. Geographically weighted regression shows promise for public health research in detecting variations in associations between health behaviors, outcomes, and predictors across geographic space.


The Impact of Diabetes Mellitus on Vascular Biomarkers in Patients with End-Stage Renal Disease.
Diabetes mellitus (DM) is the most common cause of end-stage renal disease (ESRD) and an important risk factor for cardiovascular (CV) disease. We investigated the impact of DM on subclinical CV damage by comprehensive screening protocol in ESRD patients. Echocardiography, coronary computed tomography angiogram, 24-h ambulatory blood pressure monitoring, and central blood pressure with pulse wave velocity (PWV) were performed in 91 ESRD patients from the Cardiovascular and Metabolic disease Etiology Research Center-HIgh risk cohort. The DM group (n=38) had higher systolic blood pressure than the non-DM group (n=53), however, other clinical CV risk factors were not different between two groups. Central aortic systolic pressure (148.7±29.8 mm Hg vs. 133.7±27.0 mm Hg, p= 0.014), PWV (12.1±2.7 m/s vs. 9.4±2.1 m/s, p<0.001), and early mitral inflow to early mitral annulus velocity (16.7±6.4 vs. 13.7±5.9, p=0.026) were higher in the DM group. Although the prevalence of coronary artery disease (CAD) was not different between the DM and the non-DM group (95% vs. 84.4%, p=0.471), the severity of CAD was higher in the DM group (p=0.01). In multivariate regression analysis, DM was an independent determinant for central systolic pressure (p=0.011), PWV (p<0.001) and the prevalence of CAD (p=0.046). Diabetic ESRD patients have higher central systolic pressure and more advanced arteriosclerosis than the non-DM control group. These findings suggest that screening for subclinical CV damage may be helpful for diabetic ESRD patients.


Insights into mechanochemical reactions at the molecular level: simulated indentations of aspirin and meloxicam crystals.
Although solvent-free mechanochemical synthesis continues to gain ever greater importance, the molecular scale processes that occur during such reactions remain largely uncharacterised. Here, we apply computational modelling to indentations between particles of crystals of aspirin and meloxicam under a variety of conditions to mimic the early stages of their mechanochemical cocrystallisation reaction. The study also extends to the effects of the presence of small amounts of solvent. It is found that, despite the solid crystalline nature of the reactants and the presence of little or no solvent, mixing occurs readily at the molecular level even during relatively low-energy collisions. When indented crystals are subsequently drawn apart, a connective neck formed by a mixture of the reactant molecules is observed, suggesting plastic-like behaviour of the reacting materials. Overall the work reveals some striking new insights including (i) relatively facile mixing of crystals under solvent-free conditions, (ii) no appreciable local temperature increases, (iii) localised amorphisation at the contact region and neck of the reacting crystals, and (iv) small amounts of solvent have relatively little effect during this early stage of the reaction, suggesting that their accelerating effect on the reaction may be exerted at later stages.


A qualitative and quantitative analysis of autologous human multipotent adult stem cells derived from three anatomic areas by marrow aspiration: tibia, anterior ilium, and posterior ilium.
The purpose of this article was to compare the yields of stromal multipotent stem cells (CD34+ and CD105+) and hematopoetic multipotent stem cells (CD44+) obtained from different areas via bone marrow aspiration (BMA). Sixty 60-mL bone marrow aspirates were taken from the tibial plateau, the anterior ilium, and the posterior ilium using a single point-of-care BMA technique and a single BMA concentration (BMAC) device. A 1-mL portion of each sample was used to determine CD stem cell concentrations and the nucleated cell count. The remaining BMA was centrifuged to separate the more mature red blood cell precursors from the stem cells and then concentrate the latter into a BMAC. The BMAC yield of 10 mL was analyzed with flow cytometry and nucleated cell counts to derive a concentration factor for the BMAC. The yield of total nucleated cells was equal between the anterior and posterior ilium and more than twice that obtained from the tibial plateau. The CD44+ and CD105+ cell yields were also nearly equal between the anterior and posterior ilium but more than twice that of the tibial plateau; however, the ratios between the three different stem cell types in BMAC obtained from the different areas suggest varying potentials for tissue development. The ilium is the preferred donor site for obtaining autologous stem cells at the point of care. The tibial plateau yielded only half as much bone marrow multipotent/progenitor stem cells as did the anterior and posterior ilium. The composition of the BMAC from each site suggests that the potential for differentiation into various cell types changes depending on the source of bone marrow, but that BMAC represents 6.5 ± 1.0 concentration factor from BMA.


Nicotine-induced relaxation in isolated canine cerebral arteries.
Nicotine in concentrations ranging from 5 times 10- minus 6 to 10- minus 4 M caused a transient relaxation in strips of isolated canine basilar, middle cerebral and posterior cerebral arteries contracted with prostaglandin F2a (PGF). Transmural neural stimulation did not produce changes in the tension of these arteries. Tyramine contracted the arterial strips. Relaxation induced by nicotine was markedly attenuated by hexamethonium (10- minus 5 M), cocaine (10- minus 5M), bretylium (2 times 10- minus 5 M), sotalol (5 times 10- minus 5 M), propranolol (10- minus 6 M) and removal of Ca-++ from the bathing media. Relaxation was not significantly influenced by atropine, physostigmine, ouabain, tetrodotoxin, aminophylline and sotalol (10- minus 5 M). In cerebral arterial strips, the addition of K-+ also elicited a transient relaxation which was abolished by treatment with ouabain but not with other blocking agents. In mesenteric arterial strips, nicotine caused a transient contraction as did transmural stimulation. The nicotine-induced contraction was markedly attenuated or completely abolished by hexamethonium, cocaine, bretylium and phentolamine and also high concentration of sotalol (5 times 10- minus 5 M), and propranolol. Tetrodotoxin did not affect the contractile response to nicotine but did abolish the response to transmural stimulation. It is strongly suggested that relaxation induced by nicotine in cerebral arterial strips is the result of a specific action on nicotinic receptors as is the contraction observed in mesenteric arteries. It appears that beta adrenergic and cholinergic mechanisms do not play major roles in the genesis of nicotine-induced relaxation nor does it appear that an electrogenic Na-+ pump mechanism is involved.