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Background: Decisions regarding mode of delivery in the context of a prior cesarean birth is complicated because both trial of labor after cesarean and elective repeat cesarean birth have risks and benefits., Purpose: The objective of this study was to understand the perspective of women and obstetricians in Coatepeque, Guatemala, to guide the development of a decision aid about mode of birth for women with a history of prior cesarean., Methods: We conducted in-depth semi-structured interviews with obstetricians at Coatepeque Hospital and women at the Center for Human Development in the southwest Trifinio region of Guatemala in February 2020. Using qualitative content analysis, we recorded, transcribed, translated, and analyzed qualitative data for the meaning of themes and concepts exploring the acceptability of counseling with a decision aid regarding mode of delivery., Results: A total of 30 qualitative interviews were conducted with women and physicians. Three themes emerged from the qualitative interviews: Having a decision aid for women with a prior cesarean birth will be useful and helpful. Content of the decision aid should include benefits and risks for women and babies as well as figures. Women described the need of tailoring the content surrounding family's role in their decisions. They felt that a trusted provider from the healthcare system should facilitate the use of the decision aid for counseling., Conclusions: These findings emphasize the support and need for innovative approaches to patient education around mode of delivery after a prior cesarean in the southwest region in Guatemala. There is a need to improve the educational information given to women regarding their mode of delivery after a cesarean birth. Finally, an effective decision aid needs to be tailored to not only the women's needs but also the engagement of the family unit for its successful implementation., Competing Interests: The authors have no relationships to disclose that may be deemed to influence the objectivity of this paper and its review. The authors report no commercial associations, either directly or through immediate family, in areas such as expert testimony, consulting, honoraria, stock holdings, equity interest, ownership, patent-licensing situations or employment that might pose a conflict of interest to this analysis. Additionally, the authors have no conflicts such as personal relationships or academic competition to disclose. The findings presented in this paper represent the views of the named authors only, and not the views of their institutions or organizations. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (© 2024 Jimenez-Zambrano, Avery, Feller, Rivera, Marchin, Bolaños, Asturias, Rodas and Harrison.)

Multivalent pneumococcal vaccines have been developed successfully to combat invasive pneumococcal diseases (IPD) and reduce the associated healthcare burden. These vaccines employ pneumococcal capsular polysaccharides (PnPs), either conjugated or unconjugated, as antigens to provide serotype-specific protection. Pneumococcal capsular polysaccharides used for vaccine often contain residual levels of cell wall polysaccharides (C-Ps), which can generate a non-serotype specific immune response and complicate the desired serotype-specific immunity. Therefore, the C-P level in a pneumococcal vaccine needs to be controlled in the vaccine process and the anti C-P responses need to be dialed out in clinical assays. Currently, two types of cell-wall polysaccharide structures have been identified: a mono-phosphocholine substituted cell-wall polysaccharide C-Ps1 and a di-phosphocholine substituted C-Ps2 structure. In our effort to develop a next-generation novel pneumococcal conjugate vaccine (PCV), we have generated a monoclonal antibody (mAb) specific to cell-wall polysaccharide C-Ps2 structure. An antibody-enhanced HPLC assay (AE-HPLC) has been established for serotype-specific quantification of pneumococcal polysaccharides in our lab. With the new anti C-Ps2 mAb, we herein extend the AE-HPLC assay to the quantification and identification of C-Ps2 species in pneumococcal polysaccharides used for vaccines.

The development of mRNA vaccines has increased rapidly since the COVID-19 pandemic. As one of the critical attributes, understanding mRNA lipid nanoparticle (LNP) stability is critical in the vaccine product development. However, the correlation between LNPs' physiochemical characteristics and their potency still remains unclear. The lack of regulatory guidance on the specifications for mRNA LNPs is also partially due to this underexplored relationship. In this study, we performed a three-month stability study of heat-stressed mRNA LNP samples. The mRNA LNP samples were analyzed for their mRNA degradation, LNP particle sizes, and mRNA encapsulation efficiency. In vitro cell potency was also evaluated and correlated with these above-mentioned physiochemical characterizations. The mRNA degradation-cell potency correlation data showed two distinct regions, indicating a critical cut-off size limit for mRNA degradation. The same temperature dependence was also observed in the LNP size-cell potency correlation.

Objectives:  To demonstrate the safety of direct oral anticoagulants in relation to intracranial bleeding (ICB), we compared the number of patients taking anticoagulants in all cases of hospitalization and cases of hospitalization for ICB over time in Germany. We analyzed the intrahospital mortality of ICB cases in relation to long-term use of anticoagulants (LUAs).We performed a retrospective registry analysis of nationwide German hospitalizations including all hospital admissions and admission for ICB in patients aged ≥60 years in the period from 2006 to 2020 and separated for LUAs., Results:  In 2006, the age-standardized rate of hospitalized male patients with LUAs was 7.3% and that of female patients was 5.6%. In 2020, the rates increased to 22.0 and 17.7% for male and female patients, respectively. Among patients hospitalized for ICB in 2006, 7.0 and 5.6% were male and female patients with LUAs, respectively. In 2020, the rate increased to 13.7% for males and 10.8% for females.In 2006, age-standardized mortality rates of male and female patients with ICB without LUAs were 24.1 and 23.9%, respectively. In 2020, the rate slightly decreased to 22.7% in males, but it remained almost unchanged in females at 23.8%. In the cases with LUA, the mortality rate decreased from 30.1 to 24.3% in males and from 28.4 to 24.2% in females in the same period., Conclusion:  LUA seems to be safe because there is a slower increase of the rate of LUAs in ICB cases than in generally hospitalized cases in the period from 2006 to 2020. In addition, mortality in ICB cases with LUA tends to decrease compared to cases without LUA., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Aim: The aim of this study was to define determinants of length of hospital stay (LOS) longer than mean and recurrence of infection (ROI) after complete healing of patients with deep sternal wound infections (DSWI)., Patients and Methods: In this observational study, we included 303 patients (155 females and 148 males, with mean age of 68 years) treated from 2016 to 2020 at the Department of Plastic Surgery of the HELIOS Klinik Krefeld, Germany. All patients received extensive necrosectomy, repetitive negative pressure therapy periods, and final transplantation of a pectoral musculocutaneous flap. In the German diagnosis-related group (DRG)-system, the mean inpatient LOS depends on the number of surgical procedures and is longer in those with four or more surgical procedures (DRG IO2B) and shorter in those with fewer procedures (DRGs I02C and I02D). The determinants which have a significant effect on LOS longer than mean and ROI after complete healing were identified by estimating a logistic regression model. The effect of the different calculated determinants was quantified as odds ratio. To measure the discriminant ability of the model between patients, we determined a receiver operating characteristic curve. The fit of the model was quantified by comparing predicted probabilities of the model with empirical probabilities of the data. The goodness of fit was then measured by applying the Hosmer-Lemeshow test., Results: Among patients in DRG IO2B ( n  = 246), the variable clopidogrel and therapeutic anticoagulation was the most important determinant for a longer LOS, with an odds ratio of 5.83 (95% CI = 0.83/40.80). Female sex and renal insufficiency also prolonged LOS. Applying this analysis to the patients with group DRG groups I02C and I02D ( n  = 57), none of these parameters were predictive. The variable immunosuppression was the most important determinant for ROI ( n  = 49) (OR = 4.67; 95% CI = 1.01/21.52). Body mass index also played a role, but with a much smaller influence., Conclusion: There are specific risk factors for LOS longer than mean and ROI in patients with DSWI that can be identified on admission. Addressing these risk factors, if possible, could reduce the rate of patients with LOS longer than mean and ROI., Competing Interests: None declared., (Thieme. All rights reserved.)

Objectives: Oral anticoagulation (OAC) may have an impact on mortality in cases hospitalized for hip fracture (HF). We studied nationwide time trends of OAC prescriptions and compared time trends of inhospital mortality of HF cases with and without OAC in Germany DESIGN: Retrospective cohort study SETTING: Nationwide German hospitalization, Diagnosis-Related Groups Statistic PATIENTS/PARTICIPANTS: All hospital admissions for HF 60 years and older in the years 2006 through 2020., Intervention: Additional diagnosis with a personal history of long-term use of anticoagulants (ICD code Z92.1)., Main Outcome Measurements: Inhospital mortality RESULTS: Cases hospitalized for HF 60 years and older increased by 29.5%. In 2006, 5.6% had a documented history of long-term use of OACs. This proportion rose to 20.1% in 2020. Age-standardized hospitalization mortality in HF cases without long-term use of OACs in males decreased steadily from 8.6% (95% confidence intervals 8.2 - 8.9) in 2006 to 6.6% (6.3 - 6.9) in 2020 and in females from 5.2% (5.0 - 5.3) to 3.9% (3.7 - 4.0). Mortality of HF cases with long-term use of OACs remained unchanged: males 7.0% (5.7 - 8.2) in 2006 and 7.3% (6.7 - 7.8) in 2020, females 4.8% (4.1 - 5.4) and 5.0% (4.7 - 5.3)., Conclusion: Inhospital mortality of HF cases with and without long-term OAC show different trends. In HF cases without OAC, mortality decreased from 2006 to 2020. In cases with OAC such a decrease could not be observed., Competing Interests: Declaration of Competing Interest The authors have no relevant financial or non-financial interests to disclose., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Light-manipulating materials are discovered in the eyeglitter of pelagic crustaceans.

Vat photopolymerization (VP) is a high-throughput additive manufacturing modality that also offers exceptional feature resolution and surface finish; however, the process is constrained by a limited selection of processable photocurable resins. Low resin viscosity (<10 Pa·s) is one of the most stringent process-induced constraints on resin processability, which in turn limits the mechanical performance of printed resin systems. Recently, the authors created a VP-processable photosensitive latex resin, where compartmentalization of the high molecular weight polymer chains into discrete particles resulted in the decoupling of viscosity from molecular weight. However, the monomers used to form the hydrogel green body resulted in decreased ultimate material properties due to the high cross-link density. Herein, we report a novel scaffold that allows for facile UV-based AM and simultaneously enhances the final part's material properties. This is achieved with a chemically labile acetal-containing cross-linker in conjunction with N-vinylpyrrolidone, which forms a glassy polymer after photocuring. Subsequent reactive extraction cleaves the cross-links and liberates the glassy polymer, which provides mechanical reinforcement of the geometrically complex VP-printed elastomer. With only a 0.1 wt % loading of photoinitiator, G '/ G '' crossover times of less than 1 s and green body plateau moduli nearing 10 5 Pa are obtained. In addition, removal of the hydrophilic and thermally labile scaffold results in decreased water uptake and increased thermal stability of the final printed part. Ultimate strain and stress values of over 650% and 8.5 MPa, respectively, are achieved, setting a new benchmark for styrene-butadiene VP elastomers.

Background: The decision regarding delivery in the context of a prior cesarean birth is complex because both trial of labor after cesarean and elective repeat cesarean birth have risks and benefits., Purpose: Our research objective was to understand the perspective of women and obstetricians regarding factors influencing mode of birth for women with a history of prior cesarean., Methods: In February 2020, qualitative data was collected at Coatepeque Hospital in Coatepeque, Guatemala. In-depth interviews were conducted with obstetricians and women at the Center for Human Development in the Southwest Trifinio region. Interviews were recorded, transcribed, translated, and analyzed using conceptual content analysis of key informant interviews to analyze the meaning of themes and concepts related to mode of delivery for women with a history of prior cesarean birth., Results: Women described feeling conflicted about their preferences on the location and attendant of their future births, but suggested that the hospital setting, and physician providers were more capable of managing complications. Physicians felt trial of labor after cesarean was the safer option but described multiple reasons that made repeat cesarean birth the more common mode of birth., Conclusions: There is a need for innovative approaches to patient messaging and education around mode of delivery after a prior cesarean in the Southwest Region in Guatemala. Findings from this study underscore the need to improve the quality and dissemination of the educational information given, medical history collected during prenatal care, and pain control during labor. Finally, there is a need for obstetric training to support vaginal birth in the facility setting for the successful implementation of evidence-based practices around trial of labor after cesarean at Coatepeque Hospital., Competing Interests: Conflict of Interest The authors have no relationships to disclose that may be deemed to influence the objectivity of this paper and its review. The authors report no comercial associations, either directly or through immediate family, in areas such as expert testimony, consulting, honoraria, stock holdings, equity interest, ownership, patent-licensing situations or employment that might pose a conflict of interest to this analysis. Additionally, the authors have no conflicts such as personal relationships or academic competition to disclose. The findings presented in this paper represent the views of the named authors only, and not the views of their institutions or organizations.

Nitrous oxides (N 2 O) emissions contribute to climate change and stratospheric ozone depletion. Wastewater treatment is an important, yet likely underestimated, source of N 2 O emissions, as recent, long-term monitoring campaigns have demonstrated. However, the available data are insufficient to representatively estimate countrywide emission due to the brevity of most monitoring campaigns. This study showed that the emission estimates can be significantly improved using an advanced approach based on multiple continuous, long-term monitoring campaigns. In monitoring studies on 14 full-scale wastewater treatment plants (WWTPs), we found a strong variability in the yearly emission factors (EFs) (0.1 to 8% of the incoming nitrogen load) which exhibited a good correlation with effluent nitrite. But countrywide data on nitrite effluent concentrations is very limited and unavailable for emission estimation in many countries. Hence, we propose a countrywide emission factor calculated from the weighted EFs of three WWTP categories (carbon removal, EF: 0.1-8%, nitrification only: 1.8%, and full nitrogen removal: 0.9%). However, EF of carbon removal WWTPs are still highly uncertain given the expected variability in performance. The newly developed approach allows representative, country-specific estimations of the N 2 O emissions from WWTP. Applied to Switzerland, the estimations result in an average EF of 0.9 to 3.6% and total emissions of 410 to 1690 tN 2 O-N/year, which corresponds to 0.3-1.4% of the total greenhouse gas emissions in Switzerland. Our results demonstrate that better data availability and an improved understanding of long-term monitoring campaigns is crucial to improve current emission estimations. Finally, our results confirm several measures to mitigate N 2 O emissions from wastewater treatment; year-round denitrification, limiting nitrite accumulation, and stringent control of sludge age in carbon removal plants., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 The Authors. Published by Elsevier Ltd.)

Objective: Our objective was to observe the prevalence of postpartum contraceptive use in a population of rural women in Southwest Guatemala by type, and to determine characteristics associated with long-acting reversible contraceptive (LARC) use and sterilization., Methods: We conducted a secondary analysis of prospectively collected quality improvement data from a cohort of postpartum women. We compared women intending to use or already using contraception to those not intending to utilize a method; bivariate comparisons were used to determine if there were differences in characteristics between these groups. If differences occurred (p < 0.2), those covariates were included in multivariable regression analyses to determine characteristics associated with use, and then specifically with LARC use and sterilization., Results: In a cohort of 424 women who were surveyed between 2015-2017, the average age was 23 years old, and the prevalence of use or plan to use postpartum contraception was 87.5%. Women with a parity of 2 - 3 were 10% more likely to use any form of postpartum birth control (RR 1.1, CI [1.01, 1.2]) compared to primiparous women. Women who were married were also more likely to use a postpartum method (RR > 10, CI [>10,>10]). The prevalence of LARC use was low (4.0%), and women were more likely to choose this method if they were employed (RR 3.5 CI [1.1, 11.3]).Regarding sterilization, women with a parity of greater than one compared to primiparous women had an increased likelihood of sterilization (RR 3.6 CI [2.5,4.9]); each year a woman aged was associated with a 10% increased likelihood of postpartum sterilization (RR 1.1 CI [1.01,1.08]). Women were also more likely to choose sterilization if delivered by a skilled birth attendant (RR 1.8 CI [1.1,2.9]) or by cesarean birth (RR 2.1 CI [1.4,3.1])., Conclusion: In this cohort, married women of higher parity were more likely to use postpartum contraception, with employed women more likely to use a LARC method. Older women of higher parity who were delivered by a skilled attendant by cesarean birth were the most likely to pursue sterilization., Competing Interests: Conflict of Interest The authors have no relationships to disclose that may be deemed to influence the objectivity of this paper and its review. The authors report no commercial associations, either directly or through immediate family, in areas such as expert testimony, consulting, honoraria, stock holdings, equity interest, ownership, patent-licensing situations or employment that might pose a conflict of interest to this analysis. Additionally, the authors have no conflicts such as personal relationships or academic competition to disclose. The findings presented in this paper represent the views of the named authors only, and not the views of their institutions or organizations.

Objective: Osteoarthritis (OA) is a progressive degenerative disease of the articular cartilage caused by an unbalanced activity of proteases, cytokines and other secreted proteins. Since heparan sulfate (HS) determines the activity of many extracellular factors, we investigated its role in OA progression., Methods: To analyze the role of the HS level, OA was induced by anterior cruciate ligament transection (ACLT) in transgenic mice carrying a loss-of-function allele of Ext1 in clones of chondrocytes (Col2-rtTA-Cre;Ext1 e2fl/e2fl ). To study the impact of the HS sulfation pattern, OA was surgically induced in mice with a heterozygous (Ndst1 +/- ) or chondrocyte-specific (Col2-Cre;Ndst1 fl/fl ) loss-of-function allele of the sulfotransferase Ndst1. OA progression was evaluated using the OARSI scoring system. To investigate expression and activity of cartilage degrading proteases, femoral head explants of Ndst1 +/- mutants were analyzed by qRT-PCR, Western Blot and gelatin zymography., Results: All investigated mouse strains showed reduced OA scores (Col2-rtTA-Cre;Ext1 e2fl/e2fl : 0.83; 95% HDI 0.72-0.96; Ndst1 +/- : 0.83, 95% HDI 0.74-0.9; Col2-Cre;Ndst1 fl/fl : 0.87, 95% HDI 0.76-1). Using cartilage explant cultures of Ndst1 animals, we detected higher amounts of aggrecan degradation products in wildtype samples (NITEGE 4.24-fold, 95% HDI 1.05-18.55; VDIPEN 1.54-fold, 95% HDI 1.54-2.34). Accordingly, gelatin zymography revealed lower Mmp2 activity in mutant samples upon RA-treatment (0.77-fold, 95% HDI: 0.60-0.96). As expression of major proteases and their inhibitors was not altered, HS seems to regulate cartilage degeneration by affecting protease activity., Conclusion: A decreased HS content or a reduced sulfation level protect against OA progression by regulating protease activity rather than expression., Competing Interests: Conflict of interest The authors declare no conflicts of interest., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Inter-professional collaboration is acknowledged as essential for quality patient-care. However, little is known about receptiveness to inter-professional feedback in the postgraduate training. This study explores, in light of social identity theory, the perceptions of residents, supervising physicians and allied health care professionals regarding inter-professional feedback in the context of workplace-based assessment., Methods: For 6 months, residents in Diabetology at the University Hospital of Bern performed formative workplace-based assessments under direct observation of a supervising physician and an allied health care professional. Feedback from both observers was given to the resident after every assessment. Subsequently, focus group discussions were conducted to collect the participants' perceptions of inter- and intra-professional feedback. Transcripts were analyzed qualitatively using a thematic analysis approach., Results: We identified four main themes: (1) Identity and hierarchy; (2) Interdependence of feedback source and feedback content; (3) Impact on collaboration and patient-care; (4) Logistical and organizational requirements. While different social identities are the source of inter-professional hierarchies, they did not impede the receptiveness to feedback. Perceived trustworthiness of the feedback was attributed with more importance than professional affiliations, whereas intra-professional hierarchies between physicians led to the perception of a more summative nature of the feedback and rather impeded receptiveness. According to the participants, inter-professional feedback raised awareness of the working reality of other team members and had a positive impact on communication between the different professional groups. Moreover, participants reported positive response from patients regarding the inter-professional collaboration they experienced. Considerable organizational effort is required to enable the parallel observation of a resident's consultation by a supervising physician and an allied health care professional., Conclusions: Feedback from allied health care professionals can be a valuable learning resource for residents, given its role outside the sometimes conflicting area of intra-professional hierarchies. Inter-professional feedback in the context of workplace-based assessment carries the potential to strengthen collaboration between the different professional groups.

Purpose: Congenital hypogonadotropic hypogonadism (CHH), a rare genetic disease caused by gonadotropin-releasing hormone deficiency, can also be part of complex syndromes (e.g., CHARGE syndrome). CHD7 mutations were reported in 60% of patients with CHARGE syndrome, and in 6% of CHH patients. However, the definition of CHD7 mutations was variable, and the associated CHARGE signs in CHH were not systematically examined., Methods: Rare sequencing variants (RSVs) in CHD7 were identified through exome sequencing in 116 CHH probands, and were interpreted according to American College of Medical Genetics and Genomics guidelines. Detailed phenotyping was performed in CHH probands who were positive for CHD7 RSVs, and genotype-phenotype correlations were evaluated., Results: Of the CHH probands, 16% (18/116) were found to harbor heterozygous CHD7 RSVs, and detailed phenotyping was performed in 17 of them. Of CHH patients with pathogenic or likely pathogenic CHD7 variants, 80% (4/5) were found to exhibit multiple CHARGE features, and 3 of these patients were reclassified as having CHARGE syndrome. In contrast, only 8% (1/12) of CHH patients with nonpathogenic CHD7 variants exhibited multiple CHARGE features (P = 0.01)., Conclusion: Pathogenic or likely pathogenic CHD7 variants rarely cause isolated CHH. Therefore a detailed clinical investigation is indicated to clarify the diagnosis (CHH versus CHARGE) and to optimize clinical management.

We report on the case of a 25-year-old man with pituitary germinoma. The patient had noticed polydipsia, reduced sexual function, and loss of body hair. Laboratory investigations confirmed panhypopituitarism including diabetes insipidus. Magnetic resonance imaging of the brain showed a 14×8.4 mm enhancing lesion of the pituitary stalk and histopathology of the neurosurgical biopsy confirmed pituitary germinoma. The patient was treated with 3 cycles of chemotherapy, consisting of 150 mg/m 2 etoposide and 75 mg/m 2 cisplatin, with the administration of intrathecal 12.5 mg methotrexate, on day one, alternating every 10 to 11 days with 1 mg/m 2 vincristine, 1,000 mg/m 2 methotrexate on day 1 and 30 mg/m 2 bleomycin on day 2. MRI scans showed lasting complete remission more than a year after completion of chemotherapy. Intracranial germinomas are exquisitely sensitive to radiation. However, due to concerns of side-effects (radiation-associated tumour, relapse outside the radiation field, mental and pituitary hormonal dysfunction), and after discussing both approaches carefully with the patient, the decision was made to treat his pituitary germinoma with chemotherapy alone. Further studies should address the question as to whether a modulated approach, using radiotherapy only as a salvage in patients with relapse, might result in a better overall outcome, given the potentially harmful long-term side-effects of radiotherapy to the brain., (Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

This paper aims to compare the metabolic effects of glucose-fructose co-ingestion (GLUFRU) with glucose alone (GLU) in exercising individuals with type 1 diabetes mellitus. Fifteen male individuals with type 1 diabetes (HbA1c 7.0% ± 0.6% (53 ± 7 mmol/mol)) underwent a 90 min iso-energetic continuous cycling session at 50% VO 2max while ingesting combined glucose-fructose (GLUFRU) or glucose alone (GLU) to maintain stable glycaemia without insulin adjustment. GLUFRU and GLU were labelled with 13 C-fructose and 13 C-glucose, respectively. Metabolic assessments included measurements of hormones and metabolites, substrate oxidation, and stable isotopes. Exogenous carbohydrate requirements to maintain stable glycaemia were comparable between GLUFRU and GLU ( p = 0.46). Fat oxidation was significantly higher (5.2 ± 0.2 vs. 2.6 ± 1.2 mg·kg -1 ·min -1 , p < 0.001) and carbohydrate oxidation lower (18.1 ± 0.8 vs. 24.5 ± 0.8 mg·kg -1 ·min -1 p < 0.001) in GLUFRU compared to GLU, with decreased muscle glycogen oxidation in GLUFRU (10.2 ± 0.9 vs. 17.5 ± 1.0 mg·kg -1 ·min -1 , p < 0.001). Lactate levels were higher (2.2 ± 0.2 vs. 1.8 ± 0.1 mmol/L, p = 0.012) in GLUFRU, with comparable counter-regulatory hormones between GLUFRU and GLU ( p > 0.05 for all). Glucose and insulin levels, and total glucose appearance and disappearance were comparable between interventions. Glucose-fructose co-ingestion may have a beneficial impact on fuel metabolism in exercising individuals with type 1 diabetes without insulin adjustment, by increasing fat oxidation whilst sparing glycogen.

Aims/hypothesis: To investigate exercise-related fuel metabolism in intermittent high-intensity (IHE) and continuous moderate intensity (CONT) exercise in individuals with type 1 diabetes mellitus., Methods: In a prospective randomised open-label cross-over trial twelve male individuals with well-controlled type 1 diabetes underwent a 90 min iso-energetic cycling session at 50% maximal oxygen consumption ([Formula: see text]), with (IHE) or without (CONT) interspersed 10 s sprints every 10 min without insulin adaptation. Euglycaemia was maintained using oral (13)C-labelled glucose. (13)C Magnetic resonance spectroscopy (MRS) served to quantify hepatocellular and intramyocellular glycogen. Measurements of glucose kinetics (stable isotopes), hormones and metabolites complemented the investigation., Results: Glucose and insulin levels were comparable between interventions. Exogenous glucose requirements during the last 30 min of exercise were significantly lower in IHE (p = 0.02). Hepatic glucose output did not differ significantly between interventions, but glucose disposal was significantly lower in IHE (p < 0.05). There was no significant difference in glycogen consumption. Growth hormone, catecholamine and lactate levels were significantly higher in IHE (p < 0.05)., Conclusions/interpretation: IHE in individuals with type 1 diabetes without insulin adaptation reduced exogenous glucose requirements compared with CONT. The difference was not related to increased hepatic glucose output, nor to enhanced muscle glycogen utilisation, but to decreased glucose uptake. The lower glucose disposal in IHE implies a shift towards consumption of alternative substrates. These findings indicate a high flexibility of exercise-related fuel metabolism in type 1 diabetes, and point towards a novel and potentially beneficial role of IHE in these individuals., Trial Registration: ClinicalTrials.gov NCT02068638 FUNDING: Swiss National Science Foundation (grant number 320030&#95;149321/) and R&A Scherbarth Foundation (Switzerland).

Scope: The pharmacokinetics, bioavailability, and regional brain distribution of polyphenols from apple-grape seed extract (AGSE) mixture and bilberry extract were studied after 3 weeks of dosing in weanling pigs., Materials and Methods: Weanling piglets were treated for 3 weeks with extracts of (AGSE) or bilberry extracts, using a physiological (27.5 mg/kg) or supplement (82.5 mg/kg) dose. A 24-h pharmacokinetic study was conducted and brain tissue was harvested. Major flavan-3-ol and flavonol metabolites including catechin-O-β-glucuronide, epicatechin-O-β-glucuronide, 3'O-methyl-catechin-O-β-glucuronide, 3'O-methyl-epicatechin-O-β-glucuronide, quercetin-O-β-glucuronide, and O-methyl-quercetin-O-β-glucuronide were analyzed in plasma, urine, and regional brain extracts from AGSE groups. Anthocyanidin-O-galactosides and O-glucosides of delphinidin (Del), cyanidin (Cyn), petunidin (Pet), peonidin (Peo), and malvidin (Mal) were analyzed in plasma, urine, and brain extracts from bilberry groups., Conclusion: Significant plasma dose-dependence was observed in flavan-3-ol metabolites of the AGSE group and in Mal, Del and Cyn galactosides and Pet, Peo, and Cyn glucosides of the bilberry groups. In the brain, a significant dose dependence was found in the cerebellum and frontal cortex in all major flavan-3-ol metabolites. All anthocyanidin glycosides, except for delphinidin, showed a dose-dependent increase in the cerebellum., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Dysregulation of the CXCR4/CXCL12 axis, relevant in melanoma progression, activates cell cycle progression and migration via stimulation of the MAPK pathway. We sought to ascertain the cooperativity of the CXCR4/CXCL12 axis with established prognosticators and BRAF status in melanoma. Samples (n = 107) of primary cutaneous melanoma were assessed for protein expression of CXCR4 and CXCL12, and molecular analyses were performed to ascertain BRAF status. Univariate analyses of CXCR4 protein showed that the proportion of CXCR4 positives was greater in melanomas with absence of mitoses (P < .0001), absence of ulceration (P = .0008), and absence of regression (P = .02). Patients presenting at shallower stages (American Joint Committee on Cancer [AJCC] 1-2) exhibited a larger proportion of CXCR4 positives (76.9%, P < .0001 and 69.0%, P = .008), whereas those at deeper stages (AJCC 3-4) exhibited a larger proportion of negatives (75.0%, P = .004 and 66.7%, P = .22). In a multivariate analysis, lower odds of CXCR4 protein expression were associated with AJCC stage 3 (odds ratio [OR]=0.16, P = .01), AJCC stage 4 (OR=0.17, P = .04), and mitoses (OR=0.21, P = .01). Univariate analyses of CXCL12 protein showed that the proportion of CXCL12 negatives was significantly smaller in melanomas with depth of at least 1 mm, absence of ulceration, and absence of vascular invasion (P < .0001 for all). CXCR4 and CXCL12 appear to be biomarkers associated with established prognosticators of good and poor clinical outcome, respectively, in primary cutaneous melanoma. A BRAF mutation does not appear to be associated with CXCR4/CXCL12 axis upregulation in primary cutaneous melanoma., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Reading fluency has been identified as a key component in effective literacy instruction (National Reading Panel, 2000). Instruction in reading fluency has been shown to lead to improvements in reading achievement. Reading fluency instruction is most commonly associated with guided repeated oral reading instruction. In the present retrospective study we examine the effects of a computer-based silent reading fluency instructional system called Reading Plus (Taylor Associates, Winooski, Vermont, USA) on the reading comprehension and overall reading achievement of a large corpus of students in an urban school setting. Findings indicate that the program resulted in positive, substantial, and significant improvements in reading comprehension and overall reading achievement on a criterion referenced reading test for Grades 5, 6, 7, 8, and 9 and on a norm-referenced test of reading achievement for Grades 4, 5, 6, 7, 8 and 10. Moreover, mean gains made by students in the Reading Plus intervention were greater than mean gains for all students at the state and district level. The findings were generally positive for all subpopulations studied, including special education and regular education students. Qualitative reports from teachers who participated in the study were also supportive of the program. Implications for the study are explored for particular subgroups of students and for the role of fluency instruction with struggling adolescent readers.

We report the expression of three visual opsins in the retina of the little brown bat (Myotis lucifugus, Vespertilionidae). Gene sequences for a rod-specific opsin and two cone-specific opsins were cloned from cDNA derived from bat eyes. Comparative sequence analyses indicate that the two cone opsins correspond to an ultraviolet short-wavelength opsin (SWS1) and a long-wavelength opsin (LWS). Immunocytochemistry using antisera to visual opsins revealed that the little brown bat retina contains two types of cone photoreceptors within a rod-dominated background. However, unlike other mammalian photoreceptors, M. lucifugus cones and rods are morphologically indistinguishable by light microscopy. Both photoreceptor types have a thin, elongated outer segment. Using microspectrophotometry we classified the absorption spectrum for the ubiquitous rods. Similar to other mammals, bat rhodopsin has an absorption peak near 500 nm. Although we were unable to confirm a spectral range, cellular and molecular analyses indicate that M. lucifugus expresses two types of cone visual pigments located within the photoreceptor layer. This study provides important insights into the visual capacity of a nocturnal microchiropteran species.

Ectopic thyroid tissue in the submandibular space with the thyroid gland in its normal location is an extremely rare phenomenon. We present a case of a 75-year-old woman who had painless swelling in the left submandibular space and was referred to our hospital with the suspicion of having a malignant tumor originating from the submandibular gland. Histologic examination showed normal follicular thyroid tissue without any sign of malignancy. In general there are 3 explanations for the presence of ectopic thyroid tissue found in the submandibular region: (1) displacement during the course of embryonal development, (2) spread of tissue during surgery on a normally located thyroid gland, and (3) metastasis of a highly differentiated papillary thyroid carcinoma. We reviewed the literature with respect to the embryological background and the clinical management of such cases.

An automated optical flow cell multichannel immunosensor for the detection and identification of toxins, viruses and bacterial particles is presented. A solid phase ELISA, based on a peroxidase label for signal generation and on fused silica capillaries as a support for immobilized antibodies, has been employed for analyte detection and identification. The sensing and signal transducing component of the sensor consists of a light-emitting diode and a photodetector. The device is fitted with three channels allowing the simultaneous detection of three agents. An integrated flow injection analysis system ensures automation of the assay cycles. Data on the detection of the bacterial toxin staphylococcal enterotoxin B (SEB), the bacteriophage M13 as a viral agent, and Escherichia coli as a bacterial agent are presented.

The influence of platelet specific and HLA antibodies was investigated on primary hemostasis by the in vitro bleeding test (IVBT) (Thrombostat 4000). Seven of 12 plasmas with HPA-1a (P1A1) antibodies and two with antibodies against glycoprotein Ib/IX significantly inhibited the IVBT of normal, cross-match-positive donor blood. This correlated with a significant increase of GMP-140 (CD 62) on the platelets, determined by flow cytometry. These results agree with the literature showing both activation and inhibition of platelet function by platelet specific antibodies. On the other hand, HLA antibodies showed a similar platelet activation (shortening of occlusion time and decrease in blood volume in the IVBT, increase of CD 62 expression) as plasma samples of polytransfused thrombocytopenic patients without HLA antibodies. It can be concluded that neither an activating nor an inhibitory effect of HLA antibodies on platelet function is significant in vivo. The IVBT seems not to be suited for compatibility testing.

The influence of platelet-specific and HLA antibodies on primary hemostasis was investigated by the in vitro bleeding test (IVBT). Seven of 12 plasmas with HPA-1a (PLA1) antibodies and two with antibodies against glycoprotein Ib/IX significantly inhibited the IVBT of normal cross-match-positive donor blood. This correlated with an increase of GMP-140 on the platelets determined by flow cytometry. Therefore the inhibition of the IVBT was interpreted to be due to rapid platelet activation by platelet-specific antibodies followed by an irreversible loss of function. In contrast, with HLA antibodies neither activation nor inhibition of the platelet function could be proven.

Lidocaine has been widely investigated as a local anaesthetic and cardiac antiarrhythmic agent. Articaine is the mostly used local anaesthetic agent in German dentistry. Blood levels of local anaesthetic agents after application in dentistry have been measured only in peripheral venous blood. Concentrations in the target region near the pain receptor have not been investigated. Therefore it seemed worth to compare the concentration of lidocaine and articaine in the upper and the lower jaw after extraction of a tooth as well as the penetration and distribution of the drug in the tissue and bone of the jaw. For this purpose a method for withdrawing blood from the alveolus after extraction of a tooth was developed. First patients were submitted to submucous injections of lidocaine (2.3 ml 2%) into the upper jaw and to mandibular block injection of lidocaine (2.0 ml 2%) into the lower jaw. Correlation between blood levels of lidocaine and the type of anaesthesia as well as the location of the extracted teeth were found. In the upper jaw very high concentrations of both anaesthetics were found and the blood levels of lidocaine in the region of incisors were higher compared to those in the region of molars. In the lower jaw the blood levels of lidocaine were on average ten times lower than in the upper jaw and the highest values were found in the region of molars. Secondly, blood samples were withdrawn from the alveolus of the upper molars 3 to 23 min after submucous injection of articaine (2.0 ml 4%) or identical injection of lidocaine (2.0 ml 2%).(ABSTRACT TRUNCATED AT 250 WORDS)

This study was undertaken to develop a time- and cost-effective method for the detection of articaine and articainic acid in alveolus blood by high-performance liquid chromatography with a simple method of sample pretreatment. To overcome the problem of very rapid hydrolysis a method for controlling hydrolysis in vitro after blood sampling was developed. Blood samples were withdrawn from the alveolus of the upper molars 2-14 min after submucous injection of articaine (2.0 ml 4%) or identical injection of lidocaine (2.0 ml 2%). The higher blood levels found for articaine correspond to the higher concentration of the drug in the injection solution. A relationship between the serum concentration of articaine and lidocaine, respectively, and the time between injection and blood sampling could be established.

Blood levels of local anesthetic agents after application in dentistry have been determined only in peripheral venous blood. A method of withdrawing blood from the alveolus after extraction of a tooth was developed. With a new simple gas chromatographic method with a low detection limit, concentration of lidocaine was determined. A correlation between the blood levels of lidocaine and the type of anesthesia and the localization of the extracted teeth was found.

The pharmacokinetics of the muscarinolytic drug AWD 26-06 was investigated in two subjects after a single dose of 50 and 100 mg, respectively, and with six subjects after repeated dosage. The half time (t1/2) is 2.4 and 2.6 h, respectively, the height of the concentration maximum (Cmax) 500 and 1400 ng.ml-1, respectively, and the area under the curve (AUC) 2155 and 4334 ng.ml-1.h, respectively. The repeated dosage (25 mg every 8 h for 7 d) showed a small increase of the serum level. The t1/2 and the mean residence time (MRT) at the 1st and the 8th d are 2.6 h (range: 1.8-2.9 h) and 4 h (range: 2.7-5.8 h), respectively. The point (tmax) and the Cmax were not different at the 1st and 8th d: mean tmax (1st d) 1.1 h (range: 1.0-1.5 h), mean tmax (8th d) 0.9 h (range: 0.75-1.0 h); Cmax (1st d) 227 ng.ml-1 (range: 160-320 ng.ml-1), Cmax (8th d) 282 ng.ml-1 (range: 168-320 ng.ml-1). There were also no differences for the AUC0-t at the 1st and 8th d (1st d) 815 ng.ml-1.h (range: 610-1134 ng.ml-1.h). The simulation of the serum level by means of the data from the single dose were established by this investigation. Typical subjective muscarinolytic symptoms (e.g. dryness of the mouth, diminution of accommodation) were observed after the 2nd/3rd dosage. These signs diminished 24-36 h after discontinuation of the dosage. The parameter ALAT, proteins of plasma, and blood cell count were not changed at the end of therapy in comparison to the beginning.

The interaction of diclofenac as a pure substance was investigated without and with concomitant administration of food in 8 healthy, male volunteers (age: 23-29 years, body weight: 60-87 kg). Diclofenac was given as a pure substance by means of a rapid dissolving capsule in a dose of 50 mg. Paracetamol (1.5 g), a marker of gastric emptying rate, was administered simultaneously with diclofenac in order to elucidate the influence of gastric emptying rate on diclofenac absorption. The bioavailability was determined according to the time (tmax) of the concentration maximum in plasma (Cmax) and the area under the curve (AUC). Food significantly delays tmax of diclofenac (without food: [mean +/- SD] 0.8 +/- 0.5 h, range: 0.5 +/- 2 h; with food: 2.4 +/- 0.9 h, range: 1.5-4 h) and diminishes Cmax (without food: 1,125 +/- 765 ng/ml, range: 95-2,100 ng/ml; with food: 434 +/- 151 ng/ml, range: 250-555 ng/ml). The AUC is not influenced (without food: 1,217 +/- 368 ng/ml x h; with food: 1,037 +/- 267 ng/ml x h). The bioavailability of paracetamol is unchanged. It is concluded that the diminishing of Cmax and the delay of tmax of diclofenac are possibly the consequence of an interaction with food and not of the delayed gastric emptying per se.

Theophylline concentrations in serum between 10 to 20 micrograms/ml cannot be obtained with usual dosage of theophylline in children with individual very short elimination half time of theophylline. Multiple corrections of dosage and repeated controls of theophylline concentrations in serum are necessary for empirical adjustment of individual optimal dosage. Pharmacokinetic investigations were made to shorten this management. 12 patients with bronchial asthma, 6 to 18 years of age, received 1.5 to 3 tablets of Aminophyllin under conditions of steady state. Blood samples were taken up to 6 hours after oral application. As a result of statistical analysis we found that the biological half time of theophylline could be determined from 2 to 3 blood samples. Estimation of optimal individual dosage is possible by simple mathematical pharmacokinetic formulas.

The tolerability of the compound AWD 26-06 (which is to classify as a M1-antagonist in consequence of the pharmacological investigations) was investigated in 11 healthy male persons with increasing dosage from 5 to 150 mg. Dryness of the mouth and scratch in the throat were observed by a dosage of 50 mg onwards, a diminuation of the flow of saliva and the accommodation were observed by a dosage of 100 and 150 mg, respectively. The frequency of the heart, but not the blood pressure, is increased by 150 mg of AWD 26-06. The influence on the secretion of the gastric juice was investigated in normal conditions and after stimulation by Pentagastrin with a dosage of AWD 26-06 of 25 mg in comparison with a placebo on 7 healthy male persons. The volume of gastric juice was diminished by 35% in all fractions, but the secretion of HCl, measured as basal acid output and peak acid output, was diminished in 5 of the 7 persons by 20%. A further investigation in order to check the therapeutic effect in patients with ulcus ventriculi and ulcus duodeni, respectively, is necessary and useful.

The biliary elimination of the beta-1-receptor blocking agent talinolol was investigated after intravenous administration of 30 mg in 6 patients with a T-tube drain after cholecystectomy. Serum concentration decreased in a biexponential manner with a median terminal half-life time of 4.4 h (range: 3.0-6.2 h). In some patients a second peak of the serum level was found. Concentration-time curves in bile paralleled serum profiles. The bile:serum concentration ratio (b:s-ratio) ranged from 24 to 98. The biliary clearance amounted to 43 ml/h.kg (range: 13-212 ml/h.kg). The median of the amount of talinolol eliminated by bile was 2.8 mg (range: 1.1-7.4 mg). It is concluded that talinolol undergoes an enterohepatic circulation. However, the amount eliminated cannot provide a sufficient explanation for the second peak, observed in some patients.

The in vitro liberation and the bioavailability (BV) of dipyridamole (D) in three different brands (A, B, C) were determined in a three way cross-over study on 12 healthy subjects. Also, the pharmacokinetics of D given intravenously was investigated. The in vitro liberation of B is only to be achieved by repeated touching. The tmax for the preparations, expressed as mean +/- s mean amounts as follows: A: 0.8 +/- 0.06; B: 1.1 +/- 0.1; C: 0.8 +/- 0.09 hours and is in the case of B significantly different (p less than 0.05) from the others. The cmax values (A: 1.01 +/- 0.25; B: 1.16 +/- 0.15; C: 1.51 +/- 0.3 mumol X l-1) and the AUC values (A: 3.8 +/- 0.9; B: 3.1 +/- 0.5; C: 3.8 +/- 0.7 mumol X h X l-1) are not different. The absolute BV of D is 27 +/- 5.5% (range: 11-44%) independent of the used brand. In 4 subjects a second tmax at the 4th-6th hour is to be observed irrespective of the way of dosing. An enterohepatic circulation is assumed. It is concluded that the determination of the in vitro liberation is a necessary and useful parameter, but cannot be used alone for characterization of the BV in every case, as e.g., for problem drugs.

The equilibration of drug concentrations between blood plasma (unbound part) and saliva was studied for selected drugs with different physicochemical properties: Quinidine, sulfamerazine, paracetamol, diazepam and ethanol. From these and other experimental results it is suggested: 1. The concentration ratio between saliva and blood plasma (unbound) can only equal one for basic drugs with a pK a lower than 5.5 and acid drugs with a pK a higher than 8.5 and for pH indifferent drugs. 2. The drug must have a sufficient permeation ability through lipid membranes, valuable by the lipid water partition coefficient.

The activities of the following enzymes in soybean roots were determined at early times after infection of the roots with zoospores of an incompatible or a compatible race of Phytophthora megasperma f.sp. glycinea: dimethylallyl-diphosphate : 3,6a,9-trihydroxypterocarpan dimethylallyltransferase (prenyltransferase), an enzyme specific for glyceollin biosynthesis; NADPH-cytochrome reductase and hydroxymethylglutaryl-CoA reductase, enzymes related to the glyceollin pathway; and isocitrate dehydrogenase. Already at 4 h after infection there was a higher activity of the prenyltransferase in the incompatible interaction than in the compatible interaction, and enzyme activity in the incompatible interaction increased considerably between 4 and 8 h after infection. In the compatible interaction prenyltransferase activity was only slightly higher than in uninfected roots. The activity of the other enzymes in infected roots was not significantly different from that in the uninfected roots. No qualitative differences could be detected between the two-dimensional patterns of unlabelled proteins or proteins labelled with L-[35S]methionine of infected and uninfected roots at early times after infection. We conclude from these and earlier results (A. Bonhoff et al. (1986) Arch. Biochem. Biophys. 246, 149-154) that infection of the soybean roots with an incompatible race of the fungus leads to selective induction of the phytoalexin pathway and presumably to induction of other as yet unknown defense mechanisms.

From the research results given we may conclude that the flicker fusion frequency is reduced not only by tranquillisers but also by neuroleptic drugs. The records obtained of the effect of the dosage can be seen as a measure of the efficiency of this method. It should be established by means of similar experiments, by including additional substances, in which regions of the cortico-retinal system the site of action should be presumed to be.

After administration of easily soluble or ready dissolved lithium salts two phases can be defined in the changes of the blood level, and three in the case of lithium salts with a lesser solubility in water. The first phase from the time 0 to tmax is denoted by a massive invasion into the blood, this is counteracted by the beginnings of absorption into the tissue and elimination through the kidneys. In the second phase the absorption into the blood is returned to a constant even distribution; the absorption in the tissue and renal excretion rise notably. When the distribution is completed, the renal excretion is dominant. The kinetics of lithium are independent of the salt used. The salt, however, because of its solubility in oral administration can influence the absorption kinetics, tmax and the absolute blood level. By using Li2CO3 with a suitable speed of solubility a depot effect can be shown.

The bioavailability of griseofulvin in three different brands, two microfine forms (Gricin = G, Likuden = L), and one ultramicrofine form (Gris-PEG = GP), was determined in plasma and urine in six healthy volunteers in a crossover study and compared with in vitro liberation data. GP shows a higher AUCo infinity (140 +/- 24 mumol . h . l-1) and Cmax (4.5 +/- 0.1 mumol . h-1) than the microsize brands of griseofulvin (AUCo infinity:58 +/- 7, and 45 +/- 6 mumol . h . l-1; Cmax:1.7 +/- 0.2, and 1.5 +/- 0.2 mumol . l-1; G and L, resp.), but the same tmax at the third hour. There results correspond with the in vitro liberation data. Contradictory results of the bioavailability are found by determining the amount of 6-Demethylgriseofulvin eliminated in urine. The elimination of this main metabolite after dosing with L is lower (0.18 +/- 0.02 mmol) than those of the other two brands, which do not differ (0.31 +/- 0.04; 0.32 +/- 0.02 mmol, G and GP, resp.). It is concluded that the determination of bioavailability only by means of the eliminated amount of a metabolite in urine may produce false results.

The erroneous tendency to set pharmacokinetics and biotransformation of drugs in man against results obtained in animals as a different homogenous group is discussed. Species differences have mainly a quantitative character, such as the body weight to surface ratio, organ weight to body weight ratio, presence of differing fat deposits, etc. Qualitative differences are not so common. The great importance of a better knowledge of these problems for the prediction of drug effects in man from results obtained in animals is emphasized.