The 12-in-1 procedure for the treatment of congenital idiopathic clubfoot.
The purpose of this study was to assess the long-term results of an extended soft tissue release in a single procedure, for the treatment of congenital idiopathic clubfoot. Seventeen patients with 22 congenital idiopathic clubfeet were treated surgically with the 12-in-1 procedure. The majority of cases were grade III (severe) deformities. The procedure consisted of dividing or lengthening 12 elements of the posterior, medial, and plantar side of the foot. The mean follow-up period was 11 years (range, 7-18 years). Revision surgery was required within 1 to 3.5 years of the initial procedure in four cases (residual deformity), whereas in another patient, bilateral camptodactyly was corrected 11 years postoperatively. At the time of the most recent follow-up, and after the revision procedures in patients with residual or recurrent deformities, results were excellent in 8 and good in 14 cases. The long-term follow-up results of the 12-in-1 procedure are encouraging for the treatment of idiopathic congenital clubfoot.


Family Structure Transitions and Child Development: Instability, Selection, and Population Heterogeneity.
A growing literature documents the importance of family instability for child wellbeing. In this article, we use longitudinal data from the Fragile Families and Child Wellbeing Study to examine the impacts of family instability on children's cognitive and socioemotional development in early and middle childhood. We extend existing research in several ways: (1) by distinguishing between the number and types of family structure changes; (2) by accounting for time-varying as well as time-constant confounding; and (3) by assessing racial/ethnic and gender differences in family instability effects. Our results indicate that family instability has a causal effect on children's development, but the effect depends on the type of change, the outcome assessed, and the population examined. Generally speaking, transitions out of a two-parent family are more negative for children's development than transitions into a two-parent family. The effect of family instability is stronger for children's socioemotional development than for their cognitive achievement. For socioemotional development, transitions out of a two-parent family are more negative for white children, whereas transitions into a two-parent family are more negative for Hispanic children. These findings suggest that future research should pay more attention to the type of family structure transition and to population heterogeneity.


Measurement of colonic mucosal concentrations of 5-aminosalicylic acid is useful for estimating its therapeutic efficacy in distal ulcerative colitis: comparison of orally administered mesalamine and sulfasalazine.
Oral 5-aminosalicylic acid (5-ASA) preparations have been used frequently in the treatment of ulcerative colitis. However, there have been few reports investigating the relationship between colonic mucosal concentrations of 5-ASA and its clinical efficacy when oral sulfasalazine or 5-ASA compounds were administered. The aim of this study is to compare the mucosal concentrations of 5-ASA ensured by sulfasalazine or mesalamine, and to define the clinical significance of the measurement of 5-ASA concentrations in the treatment of distal ulcerative colitis. Biopsies were taken from the rectum and sigmoid colon of the oral sulfasalazine group (n = 13) and the slow-release 5-ASA (mesalamine) group with (n = 5) or without (n = 11) rectal administration of 5-ASA. High-pressure liquid chromatography was used to measure the tissue concentrations of 5-ASA and its metabolites. We compared the 5-ASA concentrations of the sulfasalazine group with the mesalamine group. Furthermore, we analyzed the relationship between tissue 5-ASA concentrations and the Disease Activity Index (DAI). The concentrations of 5-ASA and acetyl-5-ASA in the sulfasalazine group were higher than those in the group taking oral mesalamine alone (p < 0.01). The concentration of 5-ASA was much higher in the patients who received oral and rectal mesalamine in an enema than in the patients who had oral mesalamine alone. There was a significant inverse correlation between the DAI and concentrations of 5-ASA in the rectum (r = 0.712, p < 0.001). We demonstrated that the colonic mucosal concentration of 5-ASA was significantly higher in the sulfasalazine group than in the mesalamine group. Furthermore, the concentrations of mucosal 5-ASA may be a good marker for the estimation of its efficacy in the treatment of ulcerative colitis.


Nanotopological plate stimulates osteogenic differentiation through TAZ activation.
The topographical environment, which mimics the stem cell niche, provides mechanical cues to regulate the differentiation of mesenchymal stem cells (MSC). Diverse topographical variations have been engineered to investigate cellular responses; however, the types of mechanical parameters that affect cells, and their underlying mechanisms remain largely unknown. In this study, we screened nanotopological pillars with size gradient to activate transcriptional coactivator with PDZ binding motif (TAZ), which stimulates osteogenesis of MSC. We observed that a nanotopological plate, 70 nm in diameter, significantly induces osteogenic differentiation with the activation of TAZ. TAZ activation via the nanotopological plate was mediated by actin polymerization and Rho signaling, as evidenced by the cytosolic localization of TAZ under F-actin or Rho kinase inhibitor. The FAK and MAPK pathways also play a role in TAZ activation by the nanotopological plate because the inhibitor of ERK and JNK blocked nanopattern plate induced osteogenic differentiation. Taken together, these results indicate that nanotopology regulates cell differentiation through TAZ activation.


First Report of Gray Mold Caused by Botrytis cinerea on Greenhouse-Grown Zucchini in Korea.
In the winter of 2011, greenhouse-grown zucchini (Cucurbita pepo) in Andong City, Korea, showed severe disease symptoms on fruits and dying leaves of zucchini plants that resembled gray mold disease with about 20% yield loss. Symptoms included extensive growth of mycelia and gray conidia on stem and fruit lesions. Lesions expanded rapidly under cool, humid conditions. As the disease progressed, leaves, stems, and fruits became necrotic and were covered by an abundant, soft, gray, sporulating mycelium. Diseased fruit tissue was excised and surface sterilized by immersion in 2% NaOCl for 1 min, placed on PDA (potato dextrose agar), and incubated at 22°C. Fungal colonies were initially white and became gray to brown after 72 h. Analysis of light micrographs showed the presence of elliptical conidia on PDA that was 7.5 to 16.0 μm long and 5 to 10.5 μm wide. In culture, a few, black, small and large irregular sclerotia were produced. Microsclerotia were round, spherical or irregular in shape, and ranged from 1.0 to 3.3 and 1.2 to 3.4 mm (width and length). Conidiophores were slender and branched with enlarged apical cells bearing smooth, ash-colored conidia. These morphological characteristics identified the fungus as Botrytis cinerea (1). The internal transcribed spacer (ITS) region of rDNA was amplified using the ITS1 (forward) and ITS4 (reverse) primer set (ITS1: 5'-TCCGTAGGTGAACCTGCGG-3', ITS4: 5'-TCCTCCGCTTATTGATATGC-3') and sequenced (2). BLAST analysis of the PCR product showed that the sequence had 100% identity with the nucleotide sequences for B. cinerea. Pathogenicity tests were performed by placing mycelium fragments (1 cm2) of PDA cultures on zucchini fruits. Controls were treated with PDA alone. Five replicates for the inoculated and control plants were used. All fruits were covered with plastic bags and incubated in a growth chamber to maintain 90 to 100% relative humidity at 22°C. Typical symptoms appeared 2 to 6 days after inoculation. The inoculated plants developed typical gray mold symptoms with gray sporulating lesions, while controls remained healthy with no lesions. B. cinerea reisolated from the inoculated tissues was morphologically identical to the original isolates. In a cold outside (below 0°C), wet greenhouse, plants are likely to be exposed to resident Botrytis populations and if the gray mold disease occurs, it can spread on zucchini plants very fast, in 2 days to a week inside a 100 m2 greenhouse. Therefore, gray mold disease could have a significant impact on greenhouse production of zucchini. To our knowledge, this is the first report of B. cinerea causing gray mold of greenhouse-grown zucchini in Korea. References: (1) H. L. Barnett and B. B. Hunter. Illustrated Genera of Imperfect Fungi. Burgess Publishing Company, Minneapolis, MN, 1972. (2) T. J. White et al. PCR Protocols. Academic Press, Inc., New York, 1990.


WUS and STM homologs are linked to the expression of lateral dominance in the acaulescent Streptocarpus rexii (Gesneriaceae).
Acaulescent species of Streptocarpus Lindl. show unusual patterns of growth, characterized by anisocotyly (i.e. the unequal growth of cotyledons after germination) and lack of a conventional embryonic shoot apical meristem (SAM). A SAM-like structure appears during post-embryonic development on the axis of the continuously growing cotyledon. Since we have shown previously that KNOX genes are involved in this unusual morphology of Streptocarpus rexii, here we investigated the expression pattern of WUSCHEL (WUS), which is also required for the indeterminacy of the SAM, but is expressed independently from KNOX in Arabidopsis thaliana. In A. thaliana WUSCHEL is involved in the maintenance of the stem cell fate in the organizing centre. The expression pattern of the WUS ortholog in S. rexii (SrWUS) strongly deviates from that of the model plant, suggesting a fundamentally different spatial and temporal regulation of signalling involved in meristem initiation and maintenance. In S. rexii, exogenous application of growth regulators, i.e. gibberellin (GA(3)), cytokinin (CK) and a gibberellin biosynthesis inhibitor (PAC), prevents anisocotyly and relocates meristematic cells to a position of conventional SAMs; this coincides with a re-localization of the two main pathways controlling meristem formation, the SrWUS and the KNOX pathways. Our results suggest that the establishment of a hormone imbalance in the seedlings is the basis of anisocotyly, causing a lateral dominance of the macrocotyledon over the microcotyledon. The peculiar morphogenetic program in S. rexii is linked to this delicate hormone balance and is the result of crosstalk between endogenous hormones and regulatory genes.


Dynamically crosslinked polymer nanocomposites to treat multidrug-resistant bacterial biofilms.
Multidrug-resistant biofilms are highly resistant to current antimicrobial therapies. We have developed an antimicrobial platform that integrates the bacteria-killing phytochemical carvacrol into dynamically crosslinked polymer nanocomposites (DCPNs). Taking advantage of a reversibly crosslinked Schiff-base scaffold throughout the engineered emulsions, DCPNs exhibited long-term shelf-life and good stability in serum, while readily disassembling in acidic microenvironments. Furthermore, we demonstrated that DCPNs efficiently penetrate the biofilm matrix, eradicating both Gram-negative/positive bacteria enclosed within. Moreover, DCPNs showed no observable toxicity to fibroblast mammalian cells with the same antimicrobial concentrations necessary to eradicate MDR biofilms. Given their potent antimicrobial and stimuli-responsive dissociation characteristics in a biofilm setting, DCPNs are a suitable therapeutic platform for combating MDR bacterial infections.


NRG1 represses yeast-hypha morphogenesis and hypha-specific gene expression in Candida albicans.
We have characterized CaNrg1 from Candida albicans, the major fungal pathogen in humans. CaNrg1 contains a zinc finger domain that is conserved in transcriptional regulators from fungi to humans. It is most closely related to ScNrg1, which represses transcription in a Tup1-dependent fashion in Saccharomyces cerevisiae. Inactivation of CaNrg1 in C.albicans causes filamentous and invasive growth, derepresses hypha-specific genes, increases sensitivity to some stresses and attenuates virulence. A tup1 mutant displays similar phenotypes. However, unlike tup1 cells, nrg1 cells can form normal hyphae, generate chlamydospores at normal rates and grow at 42 degrees C. Transcript profiling of 2002 C.albicans genes reveals that CaNrg1 represses a subset of CaTup1-regulated genes, which includes known hypha-specific genes and other virulence factors. Most of these genes contain an Nrg1 response element (NRE) in their promoter. CaNrg1 interacts specifically with an NRE in vitro. Also, deletion of two NREs from the ALS8 promoter releases it from Nrg1-mediated repression. Hence, CaNrg1 is a transcriptional repressor that appears to target CaTup1 to a distinct set of virulence-related functions, including yeast-hypha morphogenesis.


Production and characterization of chitooligosaccharides by the fungal chitinase Chit42 immobilized on magnetic nanoparticles and chitosan beads: selectivity, specificity and improved operational utility.
Chitin-active enzymes are of great biotechnological interest due to the wide industrial application of chitinolytic materials. Non-stability and high cost are among limitations that hinder industrial application of soluble enzymes. Here we report the production and characterization of chitooligosaccharides (COS) using the fungal exo-chitinase Chit42 immobilized on magnetic nanoparticles and food-grade chitosan beads with an immobilization yield of about 60% using glutaraldehyde and genipin linkers. The immobilized enzyme gained operational stability with increasing temperature and acidic pH values, especially when using chitosan beads-genipin that retained more than 80% activity at pH 3. Biocatalysts generated COS from colloidal chitin and different chitosan types. The immobilized enzyme showed higher hydrolytic activity than free enzyme on chitosan, and produced COS mixtures with higher variability of size and acetylation degree. In addition, biocatalysts were reusable, easy to handle and to separate from the reaction mixture.


Prognostic factors and therapeutic options of radiotherapy in pediatric brain stem gliomas.
A retrospective analysis was made to clarify the relationship between prognosis, radiation dose and survival of brain stem gliomas. From 1983 to 1995, 22 children with brain stem tumors were treated by radiotherapy in the Veterans General Hospital-Taipei. Twelve patients had pathology proof and the remainder were diagnosed by computerized tomography and/or magnetic resonance imaging. Seven patients had postoperative radiotherapy. Fifteen patients had radiotherapy as primary management, five of whom had adjuvant chemotherapy. All patients received 4000-7060 cGy, either in conventional daily or hyperfractionated twice daily radiotherapy. Survival from date of diagnosis was calculated by the Kaplan-Meier method. Univariate analyses and multivariate analyses were calculated by the log rank test and the Cox proportional hazard model, respectively. Most patients showed improvement following treatment. The overall 2-year survival rate was 55.5% with a median survival of 27.1 months. Two-year survival for patients with primary management of operation and radiotherapy (n = 7), radiotherapy alone (n = 10) and radiotherapy with adjuvant chemotherapy (n = 5) were 66.7, 50 and 53.3%, respectively. In univariate analysis, the study revealed that the growth pattern of tumors and the simultaneous presence of cranial neuropathy and long tract sign were significant prognostic factors (P = 0.017 and 0.036). A trend of better outcome with radiation dose > 6600 cGy and the hyperfractionation scheme was also noted in our study (P = 0.0573 and 0.0615). However, only the hyperfractionation scheme was also noted in our study (P = 0.0573 and 0.0615). However, only the hyperfractionation scheme showed significance in multivariate analyses (P = 0.0355). Survival was not significantly affected by age, gender or method of diagnosis. Radiotherapy appears to be an effective treatment modality of brain stem tumors. Patients with both cranial neuropathy and long tract signs had a poorer outcome. Hyperfractionated radiotherapy may give better local control and lead to better survival.


Crystal structures of Moorella thermoacetica cyanuric acid hydrolase reveal conformational flexibility and asymmetry important for catalysis.
An ancient enzyme family responsible for the catabolism of the prebiotic chemical cyanuric acid (1,3,5-triazine-2,4,6-triol) was recently discovered and is undergoing proliferation in the modern world due to industrial synthesis and dissemination of 1,3,5-triazine compounds. Cyanuric acid has a highly stabilized ring system such that bacteria require a unique enzyme with a novel fold and subtle active site construction to open the ring. Each cyanuric acid hydrolase monomer consists of three isostructural domains that coordinate and activate the three-fold symmetric substrate cyanuric acid for ring opening. We have now solved a series of X-ray structures of an engineered, thermostable cyanuric acid ring-opening enzyme at 1.51 ~ 2.25 Å resolution, including various complexes with the substrate, a tight-binding inhibitor, or an analog of the reaction intermediate. These structures reveal asymmetric interactions between the enzyme and bound ligands, a metal ion binding coupled to conformational changes and substrate binding important for enzyme stability, and distinct roles of the isostructural domains of the enzyme. The multiple conformations of the enzyme observed across a series of structures and corroborating biochemical data suggest importance of the structural dynamics in facilitating the substrate entry and the ring-opening reaction, catalyzed by a conserved Ser-Lys dyad.


Planned delivery for pre-eclampsia between 34 and 37 weeks of gestation: the PHOENIX RCT.
In women with late preterm pre-eclampsia (i.e. at 34+0 to 36+6 weeks' gestation), the optimal delivery time is unclear because limitation of maternal-fetal disease progression needs to be balanced against infant complications. The aim of this trial was to determine whether or not planned earlier initiation of delivery reduces maternal adverse outcomes without substantial worsening of perinatal or infant outcomes, compared with expectant management, in women with late preterm pre-eclampsia. We undertook an individually randomised, triple non-masked controlled trial in 46 maternity units across England and Wales, with an embedded health economic evaluation, comparing planned delivery and expectant management (usual care) in women with late preterm pre-eclampsia. The co-primary maternal outcome was a maternal morbidity composite or recorded systolic blood pressure of ≥ 160 mmHg (superiority hypothesis). The co-primary short-term perinatal outcome was a composite of perinatal deaths or neonatal unit admission (non-inferiority hypothesis). Analyses were by intention to treat, with an additional per-protocol analysis for the perinatal outcome. The primary 2-year infant neurodevelopmental outcome was measured using the PARCA-R (Parent Report of Children's Abilities-Revised) composite score. The planned sample size of the trial was 900 women; the trial is now completed. We undertook two linked substudies. Between 29 September 2014 and 10 December 2018, 901 women were recruited; 450 women [448 women (two withdrew consent) and 471 infants] were allocated to planned delivery and 451 women (451 women and 475 infants) were allocated to expectant management. The incidence of the co-primary maternal outcome was significantly lower in the planned delivery group [289 (65%) women] than in the expectant management group [338 (75%) women] (adjusted relative risk 0.86, 95% confidence interval 0.79 to 0.94; p = 0.0005). The incidence of the co-primary perinatal outcome was significantly higher in the planned delivery group [196 (42%) infants] than in the expectant management group [159 (34%) infants] (adjusted relative risk 1.26, 95% confidence interval 1.08 to 1.47; p = 0.0034), but indicators of neonatal morbidity were similar in both groups. At 2-year follow-up, the mean PARCA-R scores were 89.5 points (standard deviation 18.2 points) for the planned delivery group (290 infants) and 91.9 points (standard deviation 18.4 points) for the expectant management group (256 infants), both within the normal developmental range (adjusted mean difference -2.4 points, 95% confidence interval -5.4 to 0.5 points; non-inferiority p = 0.147). Planned delivery was significantly cost-saving (-£2711, 95% confidence interval -£4840 to -£637) compared with expectant management. There were nine serious adverse events in the planned delivery group and 12 in the expectant management group. In women with late preterm pre-eclampsia, planned delivery reduces short-term maternal morbidity compared with expectant management, with more neonatal unit admissions related to prematurity but no indicators of greater short-term neonatal morbidity (such as need for respiratory support). At 2-year follow-up, around 60% of parents reported follow-up scores. Average infant development was within the normal range for both groups; the small between-group mean difference in PARCA-R scores is unlikely to be clinically important. Planned delivery was significantly cost-saving to the health service. These findings should be discussed with women with late preterm pre-eclampsia to allow shared decision-making on timing of delivery. Limitations of the trial include the challenges of finding a perinatal outcome that adequately represented the potential risks of both groups and a maternal outcome that reflects the multiorgan manifestations of pre-eclampsia. The incidences of maternal and perinatal primary outcomes were higher than anticipated on the basis of previous studies, but this did not limit interpretation of the analysis. The trial was limited by a higher loss to follow-up rate than expected, meaning that the extent and direction of bias in outcomes (between responders and non-responders) is uncertain. A longer follow-up period (e.g. up to 5 years) would have enabled us to provide further evidence on long-term infant outcomes, but this runs the risk of greater attrition and increased expense. We identified a number of further questions that could be prioritised through a formal scoping process, including uncertainties around disease-modifying interventions, prognostic factors, longer-term follow-up, the perspectives of women and their families, meta-analysis with other studies, effect of a similar intervention in other health-care settings, and clinical effectiveness and cost-effectiveness of other related policies around neonatal unit admission in late preterm birth. The trial was prospectively registered as ISRCTN01879376. This project was funded by the National Institute for Health and Care Research ( NIHR ) Health Technology Assessment programme and will be published in Health Technology Assessment. See the NIHR Journals Library website for further project information.


Management, asthma control and quality of life in Swedish adolescents with asthma.
In Sweden, paediatricians or general practitioners treat most adolescents with asthma. This study compares management, treatment goals and quality of life for adolescents aged 15-18 y in paediatric or primary care. A random sample of patients answered a disease-specific and a quality-of-life (MiniAQLQ) questionnaire. The 146 adolescents in paediatric care had more years with asthma, better continuity of annual surveillance, higher use of inhaled steroids and a stated better knowledge of their asthma than the 174 patients in primary care. No difference could be detected in asthma control or quality of life. Of all 320 adolescents, approximately 20% had woken at night due to asthma symptoms during the last week. About 15% had made unscheduled, urgent care visits and a third had used short-acting beta-agonist relievers more than twice a week. Quality-of-life scores were high and similar in both settings. Swedish adolescents with asthma are managed and treated somewhat differently in paediatric and primary care but with equal and, for the most part, satisfying results. The difference between the two settings probably reflects both differences in severity of asthma and different treatment traditions. For all adolescents, better fulfilment of goals regarding symptoms and exacerbations would be desirable, whereas a good quality of life including normal physical activity seems to have been achieved.


Blood Biomarker Profiling and Monitoring for High-Performance Physiology and Nutrition: Current Perspectives, Limitations and Recommendations.
Blood test data were traditionally confined to the clinic for diagnostic purposes, but are now becoming more routinely used in many professional and elite high-performance settings as a physiological profiling and monitoring tool. A wealth of information based on robust research evidence can be gleaned from blood tests, including: the identification of iron, vitamin or energy deficiency; the identification of oxidative stress and inflammation; and the status of red blood cell populations. Serial blood test data can be used to monitor athletes and make inferences about the efficacy of training interventions, nutritional strategies or indeed the capacity to tolerate training load. Via a profiling and monitoring approach, blood biomarker measurement combined with contextual data has the potential to help athletes avoid injury and illness via adjustments to diet, training load and recovery strategies. Since wide inter-individual variability exists in many biomarkers, clinical population-based reference data can be of limited value in athletes, and statistical methods for longitudinal data are required to identify meaningful changes within an athlete. Data quality is often compromised by poor pre-analytic controls in sport settings. The biotechnology industry is rapidly evolving, providing new technologies and methods, some of which may be well suited to athlete applications in the future. This review provides current perspectives, limitations and recommendations for sports science and sports medicine practitioners using blood profiling and monitoring for nutrition and performance purposes.


Human chorionic gonadotrophin and weight loss. A double-blind, placebo-controlled trial.
Low-dose human chorionic gonadotrophin (HCG) combined with a severe diet remains a popular treatment for obesity, despite equivocal evidence of its effectiveness. In a double-blind, placebo-controlled study, the effects of HCG on weight loss were compared with placebo injections. Forty obese women (body mass index greater than 30 kg/m2) were placed on the same diet supplying 5,000 kJ per day and received daily intramuscular injections of saline or HCG, 6 days a week for 6 weeks. A psychological profile, hunger level, body circumferences, a fasting blood sample and food records were obtained at the start and end of the study, while body weight was measured weekly. Subjects receiving HCG injections showed no advantages over those on placebo in respect of any of the variables recorded. Furthermore, weight loss on our diet was similar to that on severely restricted intake. We conclude that there is no rationale for the use of HCG injections in the treatment of obesity.


The ontogeny and evolution of sex-biased gene expression in Drosophila melanogaster.
Sexually dimorphic phenotypes are thought to largely result from sex differences in gene expression, and genes with sex-biased expression have been well characterized in adults of many species. Although most sexual dimorphisms manifest in adults, many result from sex-specific developmental trajectories, implying that juveniles may exhibit significant levels of sex-biased expression. However, it is unclear how much sex-biased expression occurs before reproductive maturity and whether preadult sex-biased genes should exhibit the same evolutionary dynamics observed for adult sex-biased genes. In order to understand the continuity, or lack thereof, and evolutionary dynamics of sex-biased expression throughout the life cycle, we examined sex-biased genes in pre-gonad tissue of two preadult stages and compared them with the adult gonad of Drosophila melanogaster. We found that the majority of the genome is sex-biased at some point in the life cycle, with some genes exhibiting conserved sex-biased expression and others displaying stage-specific sex bias. Our results also reveal a far more complex pattern of evolution for sex-biased genes throughout development. The most rapid evolutionary divergence occurred in genes expressed only in larvae within each sex, compared with continuously expressed genes. In females-but not males-this pattern appeared to be due to relaxed purifying selection in larva-limited genes. Furthermore, genes that retained male bias throughout life evolved more rapidly than stage-specific male-biased genes, due to stronger purifying selection in stage-specific genes. However, female-biased genes that were specific to larvae evolved most rapidly, a pattern that could not be definitively attributed to differences in adaptive evolution or purifying selection, suggesting that pleiotropic constraints on protein-coding sequences can arise when genes are broadly expressed across developmental stages. These results indicate that the signature of sex-specific selection can be detected well before reproductive maturity and is strongest during development.


Subtype-specific mutation of PPP2R1A in endometrial and ovarian carcinomas.
PPP2R1A mutations have recently been described in 3/42 (7%) of clear cell carcinomas of the ovary. PPP2R1A encodes the α-isoform of the scaffolding subunit of the serine/threonine protein phosphatase 2A (PP2A) holoenzyme. This putative tumour suppressor complex is involved in growth and survival pathways. Through targeted sequencing of PPP2R1A, we identified somatic missense mutations in 40.8% (20/49) of high-grade serous endometrial tumours, and 5.0% (3/60) of endometrial endometrioid carcinomas. Mutations were also identified in ovarian tumours at lower frequencies: 12.2% (5/41) of endometrioid and 4.1% (2/49) of clear cell carcinomas. No mutations were found in 50 high-grade and 12 low-grade serous carcinomas. Amino acid residues affected by these mutations are highly conserved across species and are involved in direct interactions with regulatory B-subunits of the PP2A holoenzyme. PPP2R1A mutations in endometrial high-grade serous carcinomas are a frequent and potentially targetable feature of this disease. The finding of frequent PPP2R1A mutations in high-grade serous carcinoma of the endometrium but not in high-grade serous carcinoma of the ovary provides clear genetic evidence that these are distinct diseases.


New-onset IgG autoantibodies in hospitalized patients with COVID-19.
COVID-19 is associated with a wide range of clinical manifestations, including autoimmune features and autoantibody production. Here we develop three protein arrays to measure IgG autoantibodies associated with connective tissue diseases, anti-cytokine antibodies, and anti-viral antibody responses in serum from 147 hospitalized COVID-19 patients. Autoantibodies are identified in approximately 50% of patients but in less than 15% of healthy controls. When present, autoantibodies largely target autoantigens associated with rare disorders such as myositis, systemic sclerosis and overlap syndromes. A subset of autoantibodies targeting traditional autoantigens or cytokines develop de novo following SARS-CoV-2 infection. Autoantibodies track with longitudinal development of IgG antibodies recognizing SARS-CoV-2 structural proteins and a subset of non-structural proteins, but not proteins from influenza, seasonal coronaviruses or other pathogenic viruses. We conclude that SARS-CoV-2 causes development of new-onset IgG autoantibodies in a significant proportion of hospitalized COVID-19 patients and are positively correlated with immune responses to SARS-CoV-2 proteins.


Uterine preservation vs hysterectomy in pelvic organ prolapse surgery: a systematic review with meta-analysis and clinical practice guidelines.
We aimed to systematically review the literature on apical pelvic organ prolapse surgery with uterine preservation compared with prolapse surgeries including hysterectomy and provide evidence-based guidelines. The sources for our data were MEDLINE, Cochrane, and clinicaltrials.gov databases from inception to January 2017. We accepted randomized and nonrandomized studies of uterine-preserving prolapse surgeries compared with those involving hysterectomy. Studies were extracted for participant information, intervention, comparator, efficacy outcomes, and adverse events, and they were individually and collectively assessed for methodological quality. If 3 or more studies compared the same surgeries and reported the same outcome, a meta-analysis was performed. We screened 4467 abstracts and identified 94 eligible studies, 53 comparing uterine preservation to hysterectomy in prolapse surgery. Evidence was of moderate quality overall. Compared with hysterectomy plus mesh sacrocolpopexy, uterine preservation with sacrohysteropexy reduces mesh exposure, operative time, blood loss, and surgical cost without differences in prolapse recurrence. Compared with vaginal hysterectomy with uterosacral suspension, uterine preservation in the form of laparoscopic sacrohysteropexy improves the C point and vaginal length on the pelvic organ prolapse quantification exam, estimated blood loss, postoperative pain and functioning, and hospital stay, but open abdominal sacrohysteropexy worsens bothersome urinary symptoms, operative time, and quality of life. Transvaginal mesh hysteropexy (vs with hysterectomy) decreases mesh exposure, reoperation for mesh exposure, postoperative bleeding, and estimated blood loss and improves posterior pelvic organ prolapse quantification measurement. Transvaginal uterosacral or sacrospinous hysteropexy or the Manchester procedure compared with vaginal hysterectomy with native tissue suspension both showed improved operative time and estimated blood loss and no worsening of prolapse outcomes with uterine preservation. However, there is a significant lack of data on prolapse outcomes >3 years after surgery, the role of uterine preservation in obliterative procedures, and longer-term risk of uterine pathology after uterine preservation. Uterine-preserving prolapse surgeries improve operating time, blood loss, and risk of mesh exposure compared with similar surgical routes with concomitant hysterectomy and do not significantly change short-term prolapse outcomes. Surgeons may offer uterine preservation as an option to appropriate women who desire this choice during apical prolapse repair.


Defined PEG smears as an alternative approach to enhance the search for crystallization conditions and crystal-quality improvement in reduced screens.
The quest for an optimal limited set of effective crystallization conditions remains a challenge in macromolecular crystallography, an issue that is complicated by the large number of chemicals which have been deemed to be suitable for promoting crystal growth. The lack of rational approaches towards the selection of successful chemical space and representative combinations has led to significant overlapping conditions, which are currently present in a multitude of commercially available crystallization screens. Here, an alternative approach to the sampling of widely used PEG precipitants is suggested through the use of PEG smears, which are mixtures of different PEGs with a requirement of either neutral or cooperatively positive effects of each component on crystal growth. Four newly defined smears were classified by molecular-weight groups and enabled the preservation of specific properties related to different polymer sizes. These smears not only allowed a wide coverage of properties of these polymers, but also reduced PEG variables, enabling greater sampling of other parameters such as buffers and additives. The efficiency of the smear-based screens was evaluated on more than 220 diverse recombinant human proteins, which overall revealed a good initial crystallization success rate of nearly 50%. In addition, in several cases successful crystallizations were only obtained using PEG smears, while various commercial screens failed to yield crystals. The defined smears therefore offer an alternative approach towards PEG sampling, which will benefit the design of crystallization screens sampling a wide chemical space of this key precipitant.


Intracellular pH and electrolytes in human skeletal muscle during adrenaline and insulin infusions.
There is evidence that both beta-adrenergic stimulation and insulin are of importance in controlling intracellular pH. Therefore we have investigated the influence of intravenous infusion of adrenaline or insulin glucose (euglycaemic clamp) on pH and electrolyte composition in resting skeletal muscle (m. quadriceps femoris) and arterial blood in six healthy subjects. A decrease in the arterial potassium concentration was observed during infusion of adrenaline and is in conformity with previous studies. Both adrenaline and insulin infusions resulted in an increased lactate content of muscle and blood, indicating an enhanced glycolysis. The intracellular concentrations of K+, Na+, Mg2+ and H+, however, remained unchanged during the adrenaline infusions as well as during infusions of insulin. It is concluded that increasing the plasma adrenaline and insulin concentrations to levels well above the physiological range (adrenaline) or in the upper physiological range (insulin) does not affect the concentrations of electrolytes and hydrogen ions in resting human muscle to any appreciable extent.


Placental and uterine pathology in women undergoing peripartum hysterectomy.
To estimate if peripartum hysterectomies performed for intractable uterine atony have pathologic findings consistent with infection more often than those hysterectomies performed for other indications. This is a retrospective cohort study of all consecutive peripartum hysterectomies at our institution from 1988 to 2009. Scheduled cesarean hysterectomies were excluded. Maternal, fetal, and pathologic data were obtained by medical record review. Pathologic evaluation was performed for each specimen per a standardized protocol. Patients undergoing hysterectomy for uterine atony were compared with those requiring hysterectomy for another indication. Pearson's χ and Student's t test were used for analysis. Of 324,654 deliveries during the study period, 558 (1.7%) women underwent emergent peripartum hysterectomies; 190 (34%) were for intractable uterine atony. Those requiring hysterectomy for uterine atony were more likely to be at term (87% compared with 62%), have clinical chorioamnionitis (19% compared with 6%), and have longer labors (8 hours compared with 2.5 hours). Certain placental pathologic findings were significantly more common in the atony group, including chorioamnionitis, umbilical vasculitis, chorionic plate vasculitis, and funisitis. Acute endometritis and cervicitis were also more common in the atony group. Conversely, abnormal placental implantation (37% compared with 8%) and leiomyomas (21% compared with 8%) were significantly more common in the group requiring hysterectomy for other indications. Patients requiring emergent peripartum hysterectomies as a result of intractable uterine atony are more likely to have clinical and pathologic findings consistent with acute inflammation and infection. II.


Diaphragmatic paralysis due to Lyme disease.
Lyme disease is a tick-borne spirochaete infection which, in a proportion of patients, can lead to neuropathy. This article describes a case of diaphragmatic paralysis due to Lyme disease. A 39-yr-old male presented to the hospital because of an acute left facial palsy. Six weeks prior to admission he had developed a circular rash on his left flank during a camping holiday. He also complained of shortness of breath and arthralgia for 1 week. His chest radiograph demonstrated a raised right hemi-diaphragm. Diaphragmatic paralysis was confirmed by fluoroscopy (a positive sniff test). Serology revealed evidence of recent infection by Borrelia burgdorferi. On the basis of the patient's clinical presentation, a recent history of erythema migrans, and positive Lyme serology, a diagnosis of neuroborreliosis was made. He received oral doxycycline therapy (200 mg x day(-1)) for three weeks. Facial and diaphragmatic palsies resolved within eight weeks. On the basis of this case, a diagnosis of Lyme disease should be considered in patients from endemic regions with otherwise unexplained phrenic nerve palsy.


Genomic analysis reveals a point mutation in the two-component sensor gene graS that leads to intermediate vancomycin resistance in clinical Staphylococcus aureus.
Methicillin-resistant Staphylococcus aureus (MRSA), once restricted to hospitals, is spreading rapidly through the wider community. Resistance to vancomycin, the principal drug used to treat MRSA infections, has only recently emerged, is mainly low level, and characteristically appears during vancomycin therapy (vancomycin-intermediate S. aureus [VISA] and hetero-resistant VISA). This phenomenon suggests the adaptation of MRSA through mutation, although defining the mutations leading to resistance in clinical isolates has been difficult. We studied a vancomycin-susceptible clinical MRSA isolate (MIC of 1 microg/ml) and compared it with an isogenic blood culture isolate from the same patient, despite 42 days of vancomycin treatment (MIC of 4 microg/ml). A whole-genome sequencing approach allowed the nearly complete assembly of the genome sequences of the two isolates and revealed only six nucleotide substitutions in the VISA strain compared with the parent strain. One mutation occurred in graS, encoding a putative two-component regulatory sensor, leading to a change from a polar to a nonpolar amino acid (T136I) in the conserved histidine region of the predicted protein. Replacing the graS allele of the vancomycin-susceptible parent strain with the graS allele from the VISA derivative resulted in increased vancomycin resistance at a level between those of the vancomycin-susceptible S. aureus and VISA clinical isolates, confirming a role for graRS in VISA. Our study suggests that MRSA is able to develop clinically significant vancomycin resistance via a single point mutation, and the two-component regulatory system graRS is a key mediator of this resistance. However, additional mutations are likely required to express the full VISA phenotype.


Photonic hybrid state entanglement swapping using cat state superpositions.
We propose the use of hybrid entanglement in an entanglement swapping protocol, as means of distributing a Bell state with high fidelity to two parties. The hybrid entanglement used in this work is described as a discrete variable (Fock state) and a continuous variable (cat state super- position) entangled state. We model equal and unequal levels of photonic loss between the two propagating continuous variable modes, before detecting these states via a projective vacuum-one-photon measurement, and the other mode via balanced homodyne detection. We investigate homodyne measurement imperfections, and the associated success probability of the measurement schemes chosen in this protocol. We show that our entanglement swapping scheme is resilient to low levels of photonic losses, as well as low levels of averaged unequal losses between the two propagating modes, and show an improvement in this loss resilience over other hybrid entanglement schemes using coherent state superpositions as the propagating modes. Finally, we conclude that our protocol is suitable for potential quantum networking applications which require two nodes to share entanglement separated over a distance of 5 -- 10 km , when used with a suitable entanglement purification scheme.


Sleep-wake disturbances and quality of life in patients with advanced lung cancer.
To examine the scope and severity of subjective sleep-wake disturbances in patients with lung cancer and compare them to a group of healthy adults who were similar in age, gender, and race, and to examine the impact of sleep-wake disturbances on measures of health-related quality of life (QOL). Descriptive, comparative. University-based and private urban ambulatory care clinics. 43 patients with advanced non-small cell or small cell lung cancer and 36 healthy adults. All participants were cognitively intact, and none had any known neurologic disorder, polysomnographically diagnosed sleep disorder, mood or anxiety disorders, or cerebral metastasis. Questionnaires, interview, and medical record review. Nocturnal sleep (quality, quantity, and disturbance), daytime sleepiness, and health-related QOL (physical, mental). Patients with lung cancer had poor perceived nocturnal sleep quality and excessive daytime sleepiness that differed significantly from the comparison group. Sleep disturbances in the group with lung cancer were characterized by breathing difficulty, cough, nocturia, and frequent awakenings. Sleep-wake disturbances were significantly associated with poorer health-related QOL after controlling for group. Excessive daytime sleepiness was associated most often with decreases in mental health, whereas poor nocturnal sleep was associated most often with decreases in physical health. Findings suggest that sleep-wake disturbances are common in patients with lung cancer and that the disturbances are significantly associated with health-related QOL. Patients with lung cancer may be at risk for sleep-disordered breathing. The magnitude of nocturnal sleep disturbance and daytime sleepiness identified in this study reinforces the importance of ongoing screening and effective intervention for sleep-wake disturbances in patients with lung cancer.


Heat shock protein 70 is induced in mouse human colon tumor xenografts after sublethal radiofrequency ablation.
Radiofrequency ablation (RFA) destroys tumor cells by generating high temperatures through ionic vibration. Tumor recurrence may be a direct function of sublethal temperature. Further, a set of proteins called heat shock proteins (HSPs) can be synthesized under heat stress to facilitate recovery of tumor cells from heat damage. Subcutaneous xenografts were induced in nude mice by injection with HT29 human colon cancer cells. The tumors were exposed surgically and subjected to RFA. The tumors were randomly assigned to achieve a target tumor temperature of 42 degrees C, 45 degrees C, or 50 degrees C. Total RNA and cell lysates were isolated from tumor tissues and subjected to reverse transcription-polymerase chain reaction and Western blot analyses, respectively, at various time points after treatments for assessing HSP expression. For in vitro experiments, HT29 cells were subjected to variable temperatures, and HSP expression was assayed. During a 50-day follow-up, the recurrence rates were 0% at 50 degrees C, 30% at 45 degrees C, and 100% at 42 degrees C. The messenger RNA and protein levels of HSP90 and HSP27 remained unchanged after RFA at 45 degrees C; however, HSP70 was induced at 4 and 10 hours after RFA. In vitro HT29 culture cells subjected to a heated water bath exhibited a cellular sensitivity to heat and change of HSP expression similar to those in tumor xenografts subjected to RFA. Our data establish the requisite heat parameters during RFA for human colon tumors in vitro and in vivo. Because HSP70 plays an important role in protecting cell death from a variety of stresses, HSP70 could be a potential target for enhancing the efficacy of RFA.


The effect of e-health contents on health science students' attitude toward the efficiency of health ICT in care provision.
This study aimed to examine the effects of e-health education content on the attitude of undergraduate health science students towards the efficiency of health ICT in healthcare provision. A cross-sectional survey design was used. Participants were Health Sciences students attending The University of Sydney. Students were divided into three groups: junior students enrolled in a subject with non e-health content; senior students enrolled in a subject with non e-health content; and students enrolled in a subject with e-health content. Students' attitude towards the efficiency of ICT in healthcare provision was measured by a modified version of the Information Technology Attitude Scales for Health (ITASH). Students enrolled in the subject with e-health content had a significantly higher average baseline attitude score than the other two groups (T198=-3.47, p=0.001; T93=-2.43, p=0.017). The repeat measures analysis yielded a result with significant interaction between survey time and student group (F2, 267=4.99, p=0.007) suggesting that changes of score was dependent on student group status. Subjects rich in e-health content significantly enhanced student attitudes, even with a group of students with a rather positive initial attitude. To facilitate the uptake and utilisation of health ICT by the future health workforce, it is important for tertiary educational institutes to provide students with sufficient exposure to specific health-related ICT training, via specifically designed subjects delivering both generic and specific e-health content.


[Factors Associated with Sexual Risk Behaviour Among Young People in Catalonia].
Sexual behavior in young people is influenced by external factors that may increase their vulnerability. to describe sexual behavior and other indicators of sexual and reproductive health among young people (16 to 24 years) in Catalonia and to identify factors associated with sexual risk behaviors. Cross-sectional study in 2012 carried out by an online survey from a panel of population (n=800). Factors associated with not using a condom at last sexual intercourse were evaluated using multivariate logistic regression models. 76.1% of boys and 83.3% of girls reported having had complete sexual intercourse (p=0.012). The proportion of boys and girls who reported casual partners was 39.7% and 22.5%, respectively. 31.4% of boys and 10.3% of girls reported having contacted partners through Internet. Not using a condom at first sexual intercourse showed significant association with reporting not using a condom in the last sexual intercourse, for both, boys (OR= 2.50) and girls (OR= 3.18). Having contacted partners through the Internet (OR=2.29) was associated with this risky sexual behavior in boys, and having used the emergency contraception 3 or more times (OR=3.38) was associated in girls. There are differences in the sexual behavior of young people by sex, being condom use at first sexual relationship a good predictor of condom use at last sexual intercourse. Boys show a higher number of casual partners than girls, as well as a higher use of the Internet to contact sexual partners.


Selectivity of Electrochemical Ion Insertion into Manganese Dioxide Polymorphs.
The ion insertion redox chemistry of manganese dioxide has diverse applications in energy storage, catalysis, and chemical separations. Unique properties derive from the assembly of Mn-O octahedra into polymorphic structures that can host protons and nonprotonic cations in interstitial sites. Despite many reports on individual ion-polymorph couples, much less is known about the selectivity of electrochemical ion insertion in MnO2. In this work, we use density functional theory to holistically compare the electrochemistry of AxMnO2 (where A = H+, Li+, Na+, K+, Mg2+, Ca2+, Zn2+, Al3+) in aqueous and nonaqueous electrolytes. We develop an efficient computational scheme demonstrating that Hubbard-U correction has a greater impact on calculating accurate redox energetics than choice of exchange-correlation functional. Using PBE+U, we find that for nonprotonic cations, ion selectivity depends on the oxygen coordination environments inside a polymorph. When H+ is present, however, the driving force to form hydroxyl bonds is usually stronger. In aqueous electrolytes, only three ion-polymorph pairs are thermodynamically stable within water's voltage stability window (Na+ and K+ in α-MnO2, and Li+ in λ-MnO2), with all other ion insertion being metastable. We find Al3+ may insert into the δ, R, and λ polymorphs across the full 2-electron redox of MnO2 at high voltage; however, electrolytes for multivalent ions must be designed to impede the formation of insoluble precipitates and facilitate cation desolvation. We also show that small ions coinsert with water in α-MnO2 to achieve greater coordination by oxygen, while solvation energies and kinetic effects dictate water coinsertion in δ-MnO2. Taken together, these findings explain reports of mixed ion insertion mechanisms in aqueous electrolytes and highlight promising design strategies for safe, high energy density electrochemical energy storage, desalination batteries, and electrocatalysts.


Biomechanical evaluation of three fixation methods in a feline transverse patella fracture model.
This study aimed to compare the biomechanical properties of three stabilisation techniques in feline patella transverse fractures and select the strongest method with potentially minimal complications. Patella fracture was simulated in 27 feline cadaveric pelvic limbs (mean weight of the cadavers 3.78 kg), and the limbs were randomly grouped to be stabilised with one of the three stabilisation methods. The modified tension band wiring technique with a single Kirschner wire (0.9 mm) and figure-of-eight wiring (20 G) was applied to group 1 (n = 9). Group 2 (n = 9) was stabilised with a combination of circumferential and figure-of-eight wiring techniques with orthopaedic wire (20 G). Group 3 (n = 9) was stabilised with the same technique as group 2, but with #2 FiberWire. The knee joints were positioned and fixed in the neutral standing angle (135°) and tested by applying tensile force. The loads at gap formations of 1, 2 and 3 mm were recorded, and the maximum failure load was measured in each group. In all the loads at displacement (1, 2 and 3 mm), group 3 was significantly stronger than groups 1 and 2, respectively (P <0.017). Group 3 (261.0 ± 52.8 N) showed significantly stronger fixation in the maximum load compared with group 1 (172.9 ± 45.6 N) (P <0.017). No significant difference was observed between groups 1 and 2 (204.9 ± 68.4 N) or between groups 2 and 3. This study shows that the combination of circumferential and figure-of-eight techniques with FiberWire is more resistant to displacement than metal wire in this ex vivo feline patella fracture model.


SMI of Bcl-2 TW-37 is active across a spectrum of B-cell tumors irrespective of their proliferative and differentiation status.
The Bcl-2 family of proteins is critical to the life and death of malignant B-lymphocytes. Interfering with their activity using small-molecule inhibitors (SMI) is being explored as a new therapeutic strategy for treating B-cell tumors. We evaluated the efficacy of TW-37, a non-peptidic SMI of Bcl-2 against a range spectrum of human B-cell lines, fresh patient samples and animal xenograft models. Multiple cytochemical and molecular approaches such as acridine orange/ethidium bromide assay for apoptosis, co-immunoprecipitation of complexes and western blot analysis, caspase luminescent activity assay and apoptotic DNA fragmentation assay were used to demonstrate the effect of TW-37 on different B-cell lines, patient derived samples, as well as in animal xenograft models. Nanomolar concentrations of TW-37 were able to induce apoptosis in both fresh samples and established cell lines with IC50 in most cases of 165-320 nM. Apoptosis was independent of proliferative status or pathological classification of B-cell tumor. TW-37 was able to block Bim-Bcl-XL and Bim-Mcl-1 heterodimerization and induced apoptosis via activation of caspases -9, -3, PARP and DNA fragmentation. TW-37 administered to tumor-bearing SCID mice led to significant tumor growth inhibition (T/C), tumor growth delay (T-C) and Log10kill, when used at its maximum tolerated dose (40 mg/kg x 3 days) via tail vein. TW-37 failed to induce changes in the Bcl-2 proteins levels suggesting that assessment of baseline Bcl-2 family proteins can be used to predict response to the drug. These findings indicate activity of TW-37 across the spectrum of human B-cell tumors and support the concept of targeting the Bcl-2 system as a therapeutic strategy regardless of the stage of B-cell differentiation.


Sulfonolipids as novel metabolite markers of Alistipes and Odoribacter affected by high-fat diets.
The gut microbiota generates a huge pool of unknown metabolites, and their identification and characterization is a key challenge in metabolomics. However, there are still gaps on the studies of gut microbiota and their chemical structures. In this investigation, an unusual class of bacterial sulfonolipids (SLs) is detected in mouse cecum, which was originally found in environmental microbes. We have performed a detailed molecular level characterization of this class of lipids by combining high-resolution mass spectrometry and liquid chromatography analysis. Eighteen SLs that differ in their capnoid and fatty acid chain compositions were identified. The SL called "sulfobacin B" was isolated, characterized, and was significantly increased in mice fed with high-fat diets. To reveal bacterial producers of SLs, metagenome analysis was acquired and only two bacterial genera, i.e., Alistipes and Odoribacter, were revealed to be responsible for their production. This knowledge enables explaining a part of the molecular complexity introduced by microbes to the mammalian gastrointestinal tract and can be used as chemotaxonomic evidence in gut microbiota.


eIF5 has GDI activity necessary for translational control by eIF2 phosphorylation.
In protein synthesis initiation, the eukaryotic translation initiation factor (eIF) 2 (a G protein) functions in its GTP-bound state to deliver initiator methionyl-tRNA (tRNA(i)(Met)) to the small ribosomal subunit and is necessary for protein synthesis in all cells. Phosphorylation of eIF2 [eIF2(alphaP)] is critical for translational control in diverse settings including nutrient deprivation, viral infection and memory formation. eIF5 functions in start site selection as a GTPase accelerating protein (GAP) for the eIF2.GTP.tRNA(i)(Met) ternary complex within the ribosome-bound pre-initiation complex. Here we define new regulatory functions of eIF5 in the recycling of eIF2 from its inactive eIF2.GDP state between successive rounds of translation initiation. First we show that eIF5 stabilizes the binding of GDP to eIF2 and is therefore a bi-functional protein that acts as a GDP dissociation inhibitor (GDI). We find that this activity is independent of the GAP function and identify conserved residues within eIF5 that are necessary for this role. Second we show that eIF5 is a critical component of the eIF2(alphaP) regulatory complex that inhibits the activity of the guanine-nucleotide exchange factor (GEF) eIF2B. Together our studies define a new step in the translation initiation pathway, one that is critical for normal translational controls.


Gimme that old time religion: the influence of the healthcare belief system of chiropractic's early leaders on the development of x-ray imaging in the profession.
Chiropractic technique systems have been historically documented to advocate overutilization of radiography. Various rationales for this have been explored in the literature. However, little consideration has been given to the possibility that the healthcare belief system of prominent early chiropractors may have influenced the use of the diagnostic modality through the years. The original rationale was the visualisation of chiropractic subluxations, defined as bones slightly out of place, pressing on nerves, and ultimately causing disease. This paradigm of radiography has survived in parts of the chiropractic profession, despite lacking evidence of clinical validity. The purpose of this paper is to compare the characteristics of the chiropractic technique systems that have utilised radiography for subluxation detection with the characteristics of religion, and to discover potential historical links that may have facilitated the development of those characteristics. Twenty-three currently or previously existing technique systems requiring radiography for subluxation analysis were found using a search of the internet, books and consultation with experts. Evidence of religiosity from the early founders' writings was compared with textbooks, published papers, and websites of subsequently developed systems. Six criteria denoting religious thinking were developed using definitions from various sources. They are: supernatural concepts, claims of supremacy, rules and rituals, sacred artefacts, sacred stories, and special language. All of these were found to a greater or lesser degree in the publicly available documents of all the subluxation-based chiropractic x-ray systems. The founders and early pioneers of chiropractic did not benefit from the current understanding of science and research, and therefore substituted deductive and inductive reasoning to arrive at conclusions about health and disease in the human body. Some of this thinking and rationalisation demonstrably followed a religion-like pattern, including BJ Palmer's use of radiography. Although access to scientific methods and research education became much advanced and more accessible during the past few decades, the publicly available documents of technique systems that used radiography for chiropractic subluxation detection examined in this paper employed a historically derived paradigm for radiography that displayed characteristics in common with religion.


p53-independent apoptosis during mammary tumor progression in C3(1)/SV40 large T antigen transgenic mice: suppression of apoptosis during the transition from preneoplasia to carcinoma.
Alterations in apoptosis and associated mechanisms during mammary tumor progression were investigated in transgenic mice expressing the SV40 large T antigen (T(AG)) driven by the rat prostatic steroid-binding protein C3(1) 5'-flanking region. Apoptosis levels, assessed by in situ end labeling, were low in normal mammary epithelial cells, highest in atypical hyperplasias (preneoplastic lesions), and less pronounced in adenocarcinomas. Preneoplastic cells maintain the ability to undergo apoptosis as a mechanism of tumor growth suppression, but this critical control of apoptosis is lost as these lesions progress to carcinomas. These alterations in apoptosis occur during mammary tumor progression in mice containing wild-type p53+/+ genotype as well as in mice with the p53-/- genotype. Thus, apoptosis in this tumor model occurs through a p53-independent mechanism. Because other studies have demonstrated p53-dependent apoptosis in T(AG)-induced choroid plexus tumors of transgenic mice, we propose that the role of p53 in apoptosis may be tissue-specific. In addition, bcl-2 protein was not expressed in any mammary lesions. SV40 T(AG) expression, which correlated with the nuclear p53 protein at all stages of tumor progression, was low in normal mammary epithelial cells, moderately high in atypical hyperplasias, and strongly expressed in adenocarcinomas. No p53 mutations were found at any stage of mammary adenocarcinoma development, suggesting that tumor progression does not require a dominantly acting p53 mutation in this transgenic model. p2l(Waf1/Cip1), a cyclin-dependent kinase inhibitor, was expressed in normal mammary tissue but was not detected in the mammary carcinomas, despite high nuclear accumulation of wild-type p53 protein, suggesting functional loss of p53 due to binding of SV40 T(AG), to p53. These findings suggest that suppression of apoptosis during the transition from atypical hyperplasia to adenocarcinoma appears to be a critical event for mammary cancer development in C3(1)/T(AG) transgenic mice and occurs by p53- and bcl-2-independent pathways.


Deciding when to stop: efficient experimentation to learn to predict drug-target interactions.
Active learning is a powerful tool for guiding an experimentation process. Instead of doing all possible experiments in a given domain, active learning can be used to pick the experiments that will add the most knowledge to the current model. Especially, for drug discovery and development, active learning has been shown to reduce the number of experiments needed to obtain high-confidence predictions. However, in practice, it is crucial to have a method to evaluate the quality of the current predictions and decide when to stop the experimentation process. Only by applying reliable stopping criteria to active learning can time and costs in the experimental process actually be saved. We compute active learning traces on simulated drug-target matrices in order to determine a regression model for the accuracy of the active learner. By analyzing the performance of the regression model on simulated data, we design stopping criteria for previously unseen experimental matrices. We demonstrate on four previously characterized drug effect data sets that applying the stopping criteria can result in upto 40 % savings of the total experiments for highly accurate predictions. We show that active learning accuracy can be predicted using simulated data and results in substantial savings in the number of experiments required to make accurate drug-target predictions.


Improving flood risk communication by focusing on prevention-focused motivation.
This article proposes an approach to flood risk communication that gives particular emphasis to the distinction between prevention and promotion motivation. According to E. Tory Higgins, the promotion system and the prevention system are assumed to coexist in every person, but one or the other may be temporarily or chronically more accessible. These insights have far-reaching implications for our understanding of people's reasoning about risks. Flood risk communication framed in terms of prevention involves the notions of chance and harm, woven into a story about particular events that necessitate decisions to be more careful about safety issues and protect one's family and oneself from danger. The article describes how the insights worked out in practice, using a flood risk communication experiment among a sample from the general population in a highly populated river delta of the Netherlands. It had a posttest-only control group design (n = 2,302). The results showed that risk communication had a large effect on the participants' responses and that this effect was higher among chronic prevention-focused people than among others. Any information that increased the fit between a prevention-framed message and a person's chronic prevention motivation produced stronger situationally induced, prevention-focused responses. This may significantly improve communication about risks. In contrast, the notion of water city projects, featuring waterside living, had more appeal to promotion-focused people.


Presynaptic dopaminergic activity of phencyclidine in rat caudate.
This study tested the hypothesis that phencyclidine (PCP) is an indirect dopamine (DA) agonist in the caudate nucleus. Single caudate neurons in rats anesthetized with urethane were recorded extracellularly with multibarrel micropipettes. Effects of drug solutions, applied by pressure microejection, were measured as changes in spontaneous and evoked neuronal activity. Caudate neurons were classified according to their latency-to-discharge in response to supramaximal cortical stimulation. PCP inhibited the spontaneous activity of 92% of neurons with latencies less than 13 msec, while DA inhibited 87%. Both drugs inhibited evoked activity significantly less than spontaneous activity (P less than .01). Neurons with latencies greater than 13 msec were excited by DA significantly more often (45%) than by PCP (13%; P less than .05). Receptor stereospecificity is suggested by the finding that the (+)-isomer of the 3-methyl piperidine derivative of PCP was significantly more potent than the (-)-isomer for inhibition of spontaneous activity. Mg++, which blocks presynaptic release of neurotransmitter, significantly antagonized inhibitory effects of PCP on spontaneous activity, which suggests a presynaptic effect of PCP. DA, which acts postsynaptically, was much less affected by Mg++. The potency of PCP was significantly less in rats treated with reserpine or 6-hydroxydopamine than in control rats, suggesting the endogenous DA is required for the action of PCP. Fluphenazine and (+)-butaclamol, potent DA-receptor antagonists, blocked the effect of PCP, but (-)-butaclamol did not. These results support the hypothesis that PCP facilitates release and/or inhibits reuptake of DA in nerve terminals and thereby acts as an indirect DA agonist in the caudate. However, there may be a subpopulation of caudate neurons in which PCP acts by a nondopaminergic mechanism.


Daily Telephone Call During the COVID-19 Pandemic: Perceptions of Families and Providers.
In intensive care units (ICUs), the quality of communication with families is a key point in the caregiver-patient-family relationship. During the COVID-19 pandemic, hospital visits were prohibited, and many ICUs implemented a daily telephone call strategy to ensure continuity of communication with patients' families. To assess how family members and health care providers perceived this communication strategy. The study was conducted in a 45-bed ICU during the COVID-19 pandemic. Communication with families consisted of a single daily telephone call from the senior physician in charge of the patient to the patient's surrogate decision maker. Satisfaction was qualitatively assessed via an anonymous online questionnaire with open-ended questions. Participants completed 114 questionnaires. Forty-six percent of surrogate decision makers stated that the key medical messages were understandable, but 57% of other family members expressed that the frequency of information delivery was insufficient. Fifty-six percent of the physicians described the practice as functional for the organization of the unit. Among health care providers other than physicians, 55% felt that not having to interact with families decreased their emotional load and 50% mentioned saving time and the absence of task interruptions as positive aspects. Fixed-time, daily telephone calls in the ICU allowed satisfactory transmission of information between physicians and surrogate decision makers, as perceived by both parties. However, the telephone-based communication strategy could still be improved.


Alcohol Consumption, Bone Mineral Density, and Risk of Osteoporotic Fractures: A Dose-Response Meta-Analysis.
Excess alcohol consumption is known to be detrimental to human health. However, the role of light-to-moderate alcohol intake is under investigation for potential certain health benefits-mostly related to the cardiovascular system. Nevertheless, there is no univocal agreement on this matter, and research is still ongoing to clarify whether there might be other potential outcomes affected by alcohol intake. In this regard, there is evidence that excess alcohol intake may negatively influence the risk of osteoporotic fractures. However, there is no comprehensive evidence of literature assessing the role of alcohol consumption in bone mineral density (BMD) and the risk of osteoporotic fractures. Thus, the aim of this study was to quantitatively assess the dose-response relationship between alcohol intake and BMD and risk of osteoporotic fractures. The Embase and MEDLINE electronic databases were searched from their inception to December 2021 for articles providing a quantifiable measurement of alcohol consumption for at least three categories and (1) a measurement of BMD (and dispersion as continuous variables) in some area of the body or (2) risk of osteoporotic fracture provided as relative risk (RR) or hazard ratio (HR), with a 95% confidence interval (CI) as the measure of the association of each category with alcohol intake. A total of 11 studies including 46,916 individuals with BMD assessment and 8 studies including 240,871 individuals with risk of fracture analysis were included. Compared to non-drinkers, consumption of up to two standard drinks of alcohol per day was correlated with higher lumbar and femur neck BMD values, while up to one standard drink of alcohol was correlated with higher hip BMD compared to no alcohol consumption. Higher risk of hip fractures was found starting from three standard drinks of alcohol per day (RR = 1.33, 95% CI: 1.04; 1.69 for three alcoholic drinks/d, and RR = 1.59, 95% CI: 1.23; 2.05 for four alcoholic drinks/d) compared to no alcohol consumption, with no evidence of heterogeneity. Concerning the risk of any osteoporotic fractures, the risk steadily increased with higher intake of alcohol, although never reaching statistical significance. In conclusion, there is consistent evidence that increased alcohol consumption is associated with higher risk of osteoporotic hip fracture; however, the role of alcohol at lower doses is uncertain, as BMD was even higher in light drinkers compared to abstainers.


ANMS-ESNM position paper and consensus guidelines on biofeedback therapy for anorectal disorders.
Anorectal disorders such as dyssynergic defecation, fecal incontinence, levator ani syndrome, and solitary rectal ulcer syndrome are common, and affect both the adult and pediatric populations. Although they are treated with several treatment approaches, over the last two decades, biofeedback therapy using visual and verbal feedback techniques has emerged as an useful option. Because it is safe, it is commonly recommended. However, the clinical efficacy of biofeedback therapy in adults and children is not clearly known, and there is a lack of critical appraisal of the techniques used and the outcomes of biofeedback therapy for these disorders. The American Neurogastroenterology and Motility Society and the European Society of Neurogastroenterology and Motility convened a task force to examine the indications, study performance characteristics, methodologies used, and the efficacy of biofeedback therapy, and to provide evidence-based recommendations. Based on the strength of evidence, biofeedback therapy is recommended for the short-term and long-term treatment of constipation with dyssynergic defecation (Level I, Grade A), and for the treatment of fecal incontinence (Level II, Grade B). Biofeedback therapy may be useful in the short-term treatment of Levator Ani Syndrome with dyssynergic defecation (Level II, Grade B), and solitary rectal ulcer syndrome with dyssynergic defecation (Level III, Grade C), but the evidence is fair. Evidence does not support the use of biofeedback for the treatment of childhood constipation (Level 1, Grade D).


The development, design, testing, refinement, simulation and application of an evaluation framework for communities of practice and social-professional networks.
Communities of practice and social-professional networks are generally considered to enhance workplace experience and enable organizational success. However, despite the remarkable growth in interest in the role of collaborating structures in a range of industries, there is a paucity of empirical research to support this view. Nor is there a convincing model for their systematic evaluation, despite the significant potential benefits in answering the core question: how well do groups of professionals work together and how could they be organised to work together more effectively? This research project will produce a rigorous evaluation methodology and deliver supporting tools for the benefit of researchers, policymakers, practitioners and consumers within the health system and other sectors. Given the prevalence and importance of communities of practice and social networks, and the extent of investments in them, this project represents a scientific innovation of national and international significance. Working in four conceptual phases the project will employ a combination of qualitative and quantitative methods to develop, design, field-test, refine and finalise an evaluation framework. Once available the framework will be used to evaluate simulated, and then later existing, health care communities of practice and social-professional networks to assess their effectiveness in achieving desired outcomes. Peak stakeholder groups have agreed to involve a wide range of members and participant organisations, and will facilitate access to various policy, managerial and clinical networks. Given its scope and size, the project represents a valuable opportunity to achieve breakthroughs at two levels; firstly, by introducing novel and innovative aims and methods into the social research process and, secondly, through the resulting evaluation framework and tools. We anticipate valuable outcomes in the improved understanding of organisational performance and delivery of care. The project's wider appeal lies in transferring this understanding to other health jurisdictions and to other industries and sectors, both nationally and internationally. This means not merely publishing the results, but contextually interpreting them, and translating them to advance the knowledge base and enable widespread institutional and organisational application.


Minimal access to deep intracranial lesions using a serial dilatation technique: case-series and review of brain tubular retractor systems.
Surgical access to deep intracranial lesions causing the least amount of iatrogenic trauma to the surrounding brain tissue remains a challenging task. In this article, we evaluate the use of a set of sequential tubes that dilate and provide retraction of the overlying brain tissue acting as a surgical corridor for deep-seated brain lesions resection. In addition, we conducted a comprehensive review of the literature of previously described techniques using variable brain tubular retractor systems. We discuss the adaptation of a system designed for spinal use to intracranial pathologies and evaluate the outcomes for the patients involved in the study. Moreover, the advantages and limitations of the described technique were presented. Between August 2005 and 2011, a total of 30 patients with deep brain lesions were operated on using an incremental increase of tubing size for brain retraction guided by a frameless navigation device. Of these, seven cases were intraventricular, and 23 were intraparenchymal. Gross total resection was achieved in 70 % of cases, and the remaining had planned subtotal resections due to involvement of an eloquent area. In conclusion, the technique of serial dilatation of the brain tissue can be used in conjunction with a microscope or endoscope to provide satisfactory access to deep intracranial pathologies. It appears to minimize the associated retraction injury to the surrounding tissue by gradually dilating the white fiber tracts. This operative approach may be considered as an effective and safe alternative for brain tumor resections in selected cases, especially deep-seated lesions.


Evolution and isoform specificity of plant 14-3-3 proteins.
The 14-3-3 proteins, once thought of as obscure mammalian brain proteins, are fast becoming recognized as major regulators of plant primary metabolism and of other cellular processes. Their presence as large gene families in plants underscores their essential role in plant physiology. We have examined the Arabidopsis thaliana 14-3-3 gene family, which currently is the largest and most complete 14-3-3 family with at least 12 expressed members and 15 genes from the now completed Arabidopsis thaliana genome project. The phylogenetic branching of this family serves as the prototypical model for comparison with other large plant 14-3-3 families and as such may serve to rationalize clustering in a biological context. Equally important for ascribing common functions for the various 14-3-3 isoforms is determining an isoform-specific correlation with localization and target partnering. A summary of localization information available in the literature is presented. In an effort to identify specific 14-3-3 isoform location and participation in cellular processes, we have produced a panel of isoform-specific antibodies to Arabidopsis thaliana 14-3-3s and present initial immunolocalization studies that suggest biologically relevant, discriminative partnering of 14-3-3 isoforms.


Diffusion tractography of post-mortem human brains: optimization and comparison of spin echo and steady-state free precession techniques.
Diffusion imaging of post-mortem brains could provide valuable data for validation of diffusion tractography of white matter pathways. Long scans (e.g., overnight) may also enable high-resolution diffusion images for visualization of fine structures. However, alterations to post-mortem tissue (T2 and diffusion coefficient) present significant challenges to diffusion imaging with conventional diffusion-weighted spin echo (DW-SE) acquisitions, particularly for imaging human brains on clinical scanners. Diffusion-weighted steady-state free precession (DW-SSFP) has been proposed as an alternative acquisition technique to ameliorate this tradeoff in large-bore clinical scanners. In this study, both DWSE and DW-SSFP are optimized for use in fixed white matter on a clinical 3-Tesla scanner. Signal calculations predict superior performance from DW-SSFP across a broad range of protocols and conditions. DW-SE and DW-SSFP data in a whole, post-mortem human brain are compared for 6- and 12-hour scan durations. Tractography is performed in major projection, commissural and association tracts (corticospinal tract, corpus callosum, superior longitudinal fasciculus and cingulum bundle). The results demonstrate superior tract-tracing from DW-SSFP data, with 6-hour DW-SSFP data performing as well as or better than 12-hour DW-SE scans. These results suggest that DW-SSFP may be a preferred method for diffusion imaging of post-mortem human brains. The ability to estimate multiple fibers in imaging voxels is also demonstrated, again with greater success in DW-SSFP data.


Regional and age-specific patterns of pandemic H1N1 influenza virus seroprevalence inferred from vaccine clinical trials, August-October 2009.
The extent of the H1N1 pandemic has been estimated from case counts and deaths but the proportion of exposed populations with inapparent infections has not been described in detail. We analysed haemagglutination-inhibition (HI) antibody titres of pre-vaccination sera from pandemic vaccine trials conducted in six countries on four continents to provide an indication of A/CA/07/2009(H1N1)-like influenza seroprevalence in those populations. Among 7,962 subjects, ranging in age from 12 months to over 60 years, the proportions with HI antibody titres > or =40 to the H1N1pnd virus in the period from August to October 2009 were, by country: Costa Rica 26.4%, United States (US) 22.5%, Switzerland 16.9%, Germany 12.6%, Belgium 10.1%, and Japan 5.9%. Age-specific seropositivity rates in the samples were higher in children and adolescents in Costa Rica and in the US than in Europe and in Japan. The low proportion of seropositive children in Europe and Japan suggests that little local viral transmission had occurred in those regions even as late as September and October 2009, while in the US and Costa Rica, the greater proportion of previously infected children and young adults suggested that a significant number of asymptomatic infections had occurred during the first pandemic wave. Nevertheless, in all locations, the majority of the population remained susceptible to the pandemic virus at the beginning of the influenza season in the northern hemisphere, justifying the implementation of public health interventions.


Rare coding variants and X-linked loci associated with age at menarche.
More than 100 loci have been identified for age at menarche by genome-wide association studies; however, collectively these explain only ∼3% of the trait variance. Here we test two overlooked sources of variation in 192,974 European ancestry women: low-frequency protein-coding variants and X-chromosome variants. Five missense/nonsense variants (in ALMS1/LAMB2/TNRC6A/TACR3/PRKAG1) are associated with age at menarche (minor allele frequencies 0.08-4.6%; effect sizes 0.08-1.25 years per allele; P<5 × 10(-8)). In addition, we identify common X-chromosome loci at IGSF1 (rs762080, P=9.4 × 10(-13)) and FAAH2 (rs5914101, P=4.9 × 10(-10)). Highlighted genes implicate cellular energy homeostasis, post-transcriptional gene silencing and fatty-acid amide signalling. A frequently reported mutation in TACR3 for idiopathic hypogonatrophic hypogonadism (p.W275X) is associated with 1.25-year-later menarche (P=2.8 × 10(-11)), illustrating the utility of population studies to estimate the penetrance of reportedly pathogenic mutations. Collectively, these novel variants explain ∼0.5% variance, indicating that these overlooked sources of variation do not substantially explain the 'missing heritability' of this complex trait.


Population Pharmacokinetics and Exploratory Pharmacodynamics of Lorazepam in Pediatric Status Epilepticus.
Lorazepam is one of the preferred agents used for intravenous treatment of status epilepticus (SE). We combined data from two pediatric clinical trials to characterize the population pharmacokinetics of intravenous lorazepam in infants and children aged 3 months to 17 years with active SE or a history of SE. We developed a population pharmacokinetic model for lorazepam using the NONMEM software. We then assessed exploratory exposure-response relationships using the overall efficacy and safety study endpoints, and performed dosing simulations. A total of 145 patients contributed 439 pharmacokinetic samples. The median (range) age and dose were 5.4 years (0.3-17.8) and 0.10 mg/kg (0.02-0.18), respectively. A two-compartment pharmacokinetic model with allometric scaling described the data well. In addition to total body weight (WT), younger age was associated with slightly higher weight-normalized clearance (CL). The following relationships characterized the typical values for the central compartment volume (V1), CL, peripheral compartment volume (V2), and intercompartmental CL (Q), using individual subject WT (kg) and age (years): V1 (L) = 0.879*WT; CL (L/h) = 0.115*(Age/4.7)0.133*WT0.75; V2 (L) = 0.542*V1; Q (L/h) = 1.45*WT0.75. No pharmacokinetic parameters were associated with clinical outcomes. Simulations suggest uniform pediatric dosing (0.1 mg/kg, to a maximum of 4 mg) can be used to achieve concentrations of 50-100 ng/mL in children with SE, which have been previously associated with effective seizure control. The population pharmacokinetics of lorazepam were successfully described using a sparse sampling approach and a two-compartment model in pediatric patients with active SE.


Age- and gender-related prevalence of multimorbidity in primary care: the Swiss FIRE project.
General practitioners often care for patients with several concurrent chronic medical conditions (multimorbidity). Recent data suggest that multimorbidity might be observed more often than isolated diseases in primary care. We explored the age- and gender-related prevalence of multimorbidity and compared these estimates to the prevalence estimates of other common specific diseases found in Swiss primary care. We analyzed data from the Swiss FIRE (Family Medicine ICPC Research using Electronic Medical Record) project database, representing a total of 509,656 primary care encounters in 98,152 adult patients between January 1, 2009 and July 31, 2011. For each encounter, medical problems were encoded using the second version of the International Classification of primary Care (ICPC-2). We defined chronic health conditions using 147 pre-specified ICPC-2 codes and defined multimorbidity as 1) two or more chronic health conditions from different ICPC-2 rubrics, 2) two or more chronic health conditions from different ICPC-2 chapters, and 3) two or more medical specialties involved in patient care. We compared the prevalence estimates of multimorbidity defined by the three methodologies with the prevalence estimates of common diseases encountered in primary care. Overall, the prevalence estimates of multimorbidity were similar for the three different definitions (15% [95%CI 11-18%], 13% [95%CI 10-16%], and 14% [95%CI 11-17%], respectively), and were higher than the prevalence estimates of any specific chronic health condition (hypertension, uncomplicated 9% [95%CI 7-11%], back syndrome with and without radiating pain 6% [95%CI 5-7%], non-insulin dependent diabetes mellitus 3% [95%CI 3-4%]), and degenerative joint disease 3% [95%CI 2%-4%]). The prevalence estimates of multimorbidity rose more than 20-fold with age, from 2% (95%CI 1-2%) in those aged 20-29 years, to 38% (95%CI 31-44%) in those aged 80 or more years. The prevalence estimates of multimorbidity were similar for men and women (15% vs. 14%, p=0.288). In primary care, prevalence estimates of multimorbidity are higher than those of isolated diseases. Among the elderly, more than one out of three patients suffer from multimorbidity. Management of multimorbidity is a principal concern in this vulnerable patient population.


A Complex Network Perspective on Clinical Science.
Contemporary classification systems for mental disorders assume that abnormal behaviors are expressions of latent disease entities. An alternative to the latent disease model is the complex network approach. Instead of assuming that symptoms arise from an underlying disease entity, the complex network approach holds that disorders exist as systems of interrelated elements of a network. This approach also provides a framework for the understanding of therapeutic change. Depending on the structure of the network, change can occur abruptly once the network reaches a critical threshold (the tipping point). Homogeneous and highly connected networks often recover more slowly from local perturbations when the network approaches the tipping point, potentially making it possible to predict treatment change, relapse, and recovery. In this article, we discuss the complex network approach as an alternative to the latent disease model and its implications for classification, therapy, relapse, and recovery.


Effects of Health Belief Model-Based Education on Health Beliefs and Breast Self-Examination in Nursing Students.
This study was carried out to investigate the effect of an education program based on the health belief model (HBM) on nursing students' health beliefs and on their practices of breast self-examination (BSE). This research was a semi-experimental intervention study with a single group, pretest and posttest design. The sample of the research consisted of 48 students in the 3rd year of study. Data were collected before the education program and 6 months and 1 year after the training. A sociodemographic information form, the breast cancer knowledge form, the HBM scale, and the BSE proficiency rating instrument were used. Descriptive statistics and repeated measures ANOVA were used to examine the relationships among the variables. Implementing the educational program was found to be statistically insignificant for the HBM. Knowledge about breast cancer and BSE skills increased after the training. The percentage of students practicing regular BSE was determined as 14.6% before training, 45.8% after 6 months, and 28.1% after 1 year. The education provided to the students increased their HBM scores, knowledge about breast cancer, and BSE skills. However, the frequency of regular BSE was still quite low after training.


Cost-effectiveness model of adjunctive lamotrigine for the treatment of epilepsy.
To predict the cost-effectiveness of lamotrigine by evaluating the costs and health outcomes in treated patients. Lamotrigine adjunctive therapy has been found to be associated with decreased seizure frequency and severity in patients who are refractory to treatment with the older antiepileptic drugs (AEDs). We used a cost-effectiveness clinical decision analysis framework to assess the impact of these clinical benefits on patient health care use. The measure of effectiveness was seizure-free days gained. The measures of health care resource use included hospitalizations, outpatient and emergency department visits, surgery, and AEDs. Medical care use and cost estimates were derived from clinical trial data and published sources. Costs and effectiveness (incremental costs per seizure-free days gained) of lamotrigine adjunctive therapy versus older AEDs were compared in patients refractory to previous treatment during three time periods: the start-up year, the second year when decisions about surgery were made, and all subsequent years. The model predicts that use of lamotrigine would be associated with an overall reduction in use of other direct medical care resources (hospitalizations, outpatient visits, diagnostic and laboratory tests, and surgery). For a 10-year time horizon, the estimated cost-effectiveness ratio is $6.9 per seizure-free day gained. The model provides a flexible framework to analyze the effect of new antiepileptic drugs.


Ongoing epidemic of lymphogranuloma venereum in HIV-positive men who have sex with men: how symptoms should guide treatment.
Lymphogranuloma venereum (LGV) is a sexually transmitted infection (STI) caused by chlamydia trachomatis (CT) genotype L (L1, L2 and L3). Recent outbreaks of LGV in Europe and North America affected mainly men who have sex with men (MSM). Infections with CT serotypes D-K are mostly associated with mild symptoms or may be clinically silent. However, infections with L genotypes are more invasive and induce anogenital ulcer or inguinal lymphadenopathy. Between 2003 and 2013, anal or genital CT infections were diagnosed in 471 symptomatic patients attending the Infectious Diseases Center Hamburg (ICH). CT DNA was detected by PCR. CT genotyping of positive samples was performed by sequence analyses of omp1 PCR products (samples between 2003 and 2010). Samples between 2012 and 2013 were analyzed by genotype L specific real-time PCR. In total, 221 LGV patients were identified (3 in 2003; 11 in 2004; 26 in 2005; 33 in 2006; 24 in 2007; 16 in 2008; 18 in 2009; 15 in 2010; 17 in 2011; 26 in 2012 and 32 in 2013). One hundred ninety-eight of 221 (89.6%) patients with LGV were HIV-infected; 10 of 221 (4.5%) were HIV-negative, and the HIV-status unknown in 13 (5.9%). The majority of LGV positive patients (204/221; 92%) had anorectal symptoms (bloody proctitis, rectal pain, purulent or mucous discharge, tenesmus, constipation), compared to 17/221 (8%) who presented with genital symptoms as urethritis, genital ulcer or inguinal lymphadenopathy. Of 283 CT-positive patients with anorectal symptoms, genotype L was detected in 205 (72%), while non-L genotypes (D-K) were found in 78 (28%). In contrast, genotype L was found in only 6% of patients with genital symptoms (11/177), whereas 94% (166/177) were infected with non-L genotypes only. The epidemic of LGV among predominantly HIV+ MSM is ongoing. LGV might be underdiagnosed, especially in patients with anorectal symptoms. Infections with CT serotypes D-K are more often associated with urogenital symptoms or asymptomatic infection, whereas LGV genotypes are found most frequently in patients with rectal/intestinal symptoms. Anorectal CT infections in MSM should be further characterized by genotyping for LGV, as for LGV three weeks of doxycycline treatment are recommended. CT genotypes D-K generally require shorter antibiotic treatment. If CT genotyping is not available, the duration of treatment should be prolonged to three weeks empirically for CT-positive patients with anorectal or intestinal symptoms.


An evaluation of medical knowledge contained in Wikipedia and its use in the LOINC database.
The logical observation identifiers names and codes (LOINC) database contains 55 000 terms consisting of more atomic components called parts. LOINC carries more than 18 000 distinct parts. It is necessary to have definitions/descriptions for each of these parts to assist users in mapping local laboratory codes to LOINC. It is believed that much of this information can be obtained from the internet; the first effort was with Wikipedia. This project focused on 1705 laboratory analytes (the first part in the LOINC laboratory name). Of the 1705 parts queried, 1314 matching articles were found in Wikipedia. Of these, 1299 (98.9%) were perfect matches that exactly described the LOINC part, 15 (1.14%) were partial matches (the description in Wikipedia was related to the LOINC part, but did not describe it fully), and 102 (7.76%) were mis-matches. The current release of RELMA and LOINC include Wikipedia descriptions of LOINC parts obtained as a direct result of this project.


Measurements of scattering and absorption changes in muscle and brain.
Non-invasive techniques for the study of human brain function based on changes of the haemoglobin content or on changes of haemoglobin saturation have recently been proposed. Among the new methods, near-infrared transmission measurements may have significant advantages and complement well-established methods such as functional magnetic resonance imaging and positron emission tomography. Near-infrared measurements can be very fast, comparable in speed to electrophysiological measurements, bur are better localized. We will present the demonstration of measurements of millisecond signals due to brain activity in humans following stimulation of the visual cortex. However, major unresolved questions remain about the origin of the signals observed. Optical measurements on exposed cortex in animals show that both the absorption and the scattering coefficient are affected by neural activity. Model calculations show that the signals we detected may originate from rapid changes of the scattering coefficient in a region about 1 to 2 cm below the scalp. We discuss our measurement protocol, which is based on a frequency-domain instrument, and the algorithm to separate the absorption from the scattering contribution in the overall response. Our method produces excellent separation between scattering and absorption in relatively homogeneous masses such as large muscles. The extrapolation of our measurement protocol to a complex structure such as the human head is critically evaluated.