Bone mineral density of the lumbar spine in women with endometriosis.
Young women with endometriosis have reduced cortical and trabecular bone mineral density of the wrist compared with age-matched controls. This conclusion was based on 41 subjects from one geographical location. The purpose of this study was to test this finding in a larger, more geographically diverse population. One hundred women with laparoscopically proven endometriosis were enrolled in this study for the evaluation of the efficacy of nafarelin, a gonadotropin-releasing hormone agonist. Patients were recruited from nine investigators across the United States and Canada, and bone mineral density of the lumbar spine was obtained at baseline, with 6 Hologic QDR (Hologic Inc., Waltham, MA) and a Lunar DPX (Lunar Radiation Corp., Madison, WI) instrument. The age of the women was 30.3 +/- 5.8 years (mean +/- SD); 91% were white. Bone mineral density of the lumbar spine was 1.1 +/- 0.11 g/cm2 (n = 85 Hologic QDR) and 1.2 +/- 0.93 g/cm2 (n = 15 Lunar DPX). Hologic bone mineral density was 104.8 +/- 11.0 and Lunar bone mineral density was 103.4% +/- 7.8% of normal values for age. To conclude, in a population based cross-sectional study of patients with endometriosis, we do not observe low bone mineral density of the lumbar spine by techniques that measure a combination of cortical and trabecular bone.


Practical recommendations for the use of ACE inhibitors, beta-blockers and spironolactone in heart failure: putting guidelines into practice.
Surveys of prescribing in both hospitals and primary care have shown delays in translating improved survival data from clinical trials into clinical practice thereby denying patients the benefits of proven treatments, such as the angiotensin converting enzyme inhibitors. This may be due to unfamiliarity with clinical guidelines and concerns about adverse events. Recent trials have shown that substantial improvements in survival are associated with spironolactone and beta-blocker therapy. In order to accelerate the uptake of these treatments, and to ensure that all eligible patients should receive the most appropriate medications, a clear and concise set of clinical recommendations has been prepared by a group of clinicians with practical expertise in the management of heart failure. The objective of these recommendations is to provide practical guidance for non-specialists in order to support the implementation of evidenced-based therapy for heart failure. These practical recommendations are meant to supplement rather than replace existing guidelines.


Experimental and numerical analysis to identify the performance limiting mechanisms in solid-state lithium cells under pulse operating conditions.
Solid-state lithium batteries could reduce the safety concern due to thermal runaway while improving the gravimetric and volumetric energy density beyond the existing practical limits of lithium-ion batteries. The successful commercialisation of solid-state lithium batteries depends on understanding and addressing the bottlenecks limiting the cell performance under realistic operational conditions such as dynamic current profiles of different pulse amplitudes. This study focuses on experimental analysis and continuum modelling of cell behaviour under pulse operating conditions, with most model parameters estimated from experimental measurements. By using a combined impedance and distribution of relaxation times analysis, we show that charge transfer at both interfaces occurs between the microseconds and milliseconds timescale. We also demonstrate that a simplified set of governing equations, rather than the conventional Poisson-Nernst-Planck equations, are sufficient to reproduce the experimentally observed behaviour during pulse discharge, pulse charging and dynamic pulse. Our simulation results suggest that solid diffusion in bulk LiCoO2 is the performance limiting mechanism under pulse operating conditions, with increasing voltage loss for lower states of charge. If bulk electrode forms the positive electrode, improvement in the ionic conductivity of the solid electrolyte beyond 10-4 S cm-1 yields marginal overall performance gains due to this solid diffusion limitation. Instead of further increasing the electrode thickness or improving the ionic conductivity on their own, we propose a holistic model-based approach to cell design, in order to achieve optimum performance for known operating conditions.


A neutron irradiation-induced displacement damage of indium vacancies in α-In2Se3 nanoflakes.
The discovery of layered two-dimensional (2D) ferroelectric materials has promoted the development of miniaturized and highly integrated ferroelectric electronics. The 2D ferroelectric materials can be applied in a radiation environment, in which the effect of radiation on these materials should be considered. However, the effects of radiation on 2D ferroelectric materials may be entirely different from those on traditional ferroelectric materials. Ionization effect-induced domain switching can be recovered by applying an external electric field, whereas the displacement effect initiated by radiation particles produces crystal structure damage. The displacement damage that is extremely difficult to recover may have a negative impact on the application of 2D ferroelectric materials in a radiation environment. In this study, the effect of displacement induced by neutron irradiation on the promising α-In2Se3 nanoflakes was investigated. Neutron irradiation (1 MeV) with a fluence of 1014 cm-2 was used for avoiding ionization effects in a certain range. Although the topography of α-In2Se3 does not change underneutron irradiation, vacancies have been proved to be induced by neutron irradiation; furthermore, it has been identified that the vacancies mostly originate from the loss of In atoms. The out-of-plane (OOP) and in-plane (IP) domain structures of the α-In2Se3 nanoflakes with a few layers only slighlty change. In addition, the polarization of the irradiated nanoflakes could still be reversed. All these findings show that although the vacancies may influence the band structure and polarizaiton values of α-In2Se3, the ferroelectric performance may have a strong resistance to neutron irradiation. Therefore, our investigation implies that α-In2Se3 is an excellent 2D ferroelectric material for application in radiation-resistant electronic devices in the future.


Nanoparticle-coated separators for lithium-ion batteries with advanced electrochemical performance.
We report a simple, scalable approach to improve the interfacial characteristics and, thereby, the performance of commonly used polyolefin based battery separators. The nanoparticle-coated separators are synthesized by first plasma treating the membrane in oxygen to create surface anchoring groups followed by immersion into a dispersion of positively charged SiO(2) nanoparticles. The process leads to nanoparticles electrostatically adsorbed not only onto the exterior of the surface but also inside the pores of the membrane. The thickness and depth of the coatings can be fine-tuned by controlling the ζ-potential of the nanoparticles. The membranes show improved wetting to common battery electrolytes such as propylene carbonate. Cells based on the nanoparticle-coated membranes are operable even in a simple mixture of EC/PC. In contrast, an identical cell based on the pristine, untreated membrane fails to be charged even after addition of a surfactant to improve electrolyte wetting. When evaluated in a Li-ion cell using an EC/PC/DEC/VC electrolyte mixture, the nanoparticle-coated separator retains 92% of its charge capacity after 100 cycles compared to 80 and 77% for the plasma only treated and pristine membrane, respectively.


Distance learning and patient safety: Report and evaluation of an online patient safety course.
Patient safety is a critical topic in health care globally, with implications for nurses, physicians, administrators, and most importantly, patients and their well-being. Online distance learning (ODL) is widely accepted among most disciplines in higher education and has been used to promote patient safety knowledge among health care students and professionals in diverse contexts. This article reports on an online Nursing and Patient Safety course developed in 2012 by the University of Miami School of Nursing and Health Studies in conjunction with the Pan American Health Organization and the International Network for Nursing and Patient Safety. The study's objectives are to describe the implementation of an international ODL program to enhance patient safety knowledge in nurses and nursing students, and to examine the participants' assessments of this online approach as an effective learning tool. Most participants who completed the Nursing and Patient Safety ODL course reported being satisfied with the course content and experience, and demonstrated increased knowledge on patient safety, as measured by post-module quizzes and self-report. Limitations of the study include the lack of a comparison group, disparity in the number of participants across the course's language formats (English, Portuguese, Spanish), and the large number of participants who registered for but did not complete the course. Future research should identify obstacles to course completion, explore participants' awareness of patient safety issues and perceived need for more instruction, and look at ways to disseminate the course to the broadest international population of nurses and nursing students.


Placebo in sports nutrition: a proof-of-principle study involving caffeine supplementation.
We investigated the effects of supplement identification on exercise performance with caffeine supplementation. Forty-two trained cyclists (age 37 ± 8 years, body mass [BM] 74.3 ± 8.4 kg, height 1.76 ± 0.06 m, maximum oxygen uptake 50.0 ± 6.8 mL/kg/min) performed a ~30 min cycling time-trial 1 h following either 6 mg/kgBM caffeine (CAF) or placebo (PLA) supplementation and one control (CON) session without supplementation. Participants identified which supplement they believed they had ingested ("caffeine", "placebo", "don't know") pre- and post-exercise. Subsequently, participants were allocated to subgroups for analysis according to their identifications. Overall and subgroup analyses were performed using mixed-model and magnitude-based inference analyses. Caffeine improved performance vs PLA and CON (P ≤ 0.001). Correct pre- and post-exercise identification of caffeine in CAF improved exercise performance (+4.8 and +6.5%) vs CON, with slightly greater relative increases than the overall effect of caffeine (+4.1%). Performance was not different between PLA and CON within subgroups (all P > 0.05), although there was a tendency toward improved performance when participants believed they had ingested caffeine post-exercise (P = 0.06; 87% likely beneficial). Participants who correctly identified placebo in PLA showed possible harmful effects on performance compared to CON. Supplement identification appeared to influence exercise outcome and may be a source of bias in sports nutrition.


A bioinspired multi-modal flying and walking robot.
With the aim to extend the versatility and adaptability of robots in complex environments, a novel multi-modal flying and walking robot is presented. The robot consists of a flying wing with adaptive morphology that can perform both long distance flight and walking in cluttered environments for local exploration. The robot's design is inspired by the common vampire bat Desmodus rotundus, which can perform aerial and terrestrial locomotion with limited trade-offs. Wings' adaptive morphology allows the robot to modify the shape of its body in order to increase its efficiency during terrestrial locomotion. Furthermore, aerial and terrestrial capabilities are powered by a single locomotor apparatus, therefore it reduces the total complexity and weight of this multi-modal robot.


Successful Surgical Management of Palatogingival Groove Using Platelet-rich Fibrin and Guided Tissue Regeneration: A Novel Approach.
Palatogingival groove also known as radicularlingual groove is a developmental anomaly involving the lingual surface of the maxillary incisors. They are inconspicuous, funnel-shaped, extend for varying distances on root surface and occur due to infolding of the hertwigs epithelial root sheath. This encourages adherence of microorganisms and plaque to levels significant for pathological changes resulting in endodontic and periodontal lesions. The variations in anatomy of the tooth as a cause of pulp necrosis in teeth of anterior maxillary segment should be considered by the clinician when other etiological factors are ruled out. Recognition of palatogingival groove is critical, especially because of its diagnostic complexity and the problems that may arise if it is not properly interpreted and treated. Regeneration is a new emerging approach in endodontics. Choukroun et al. were among the pioneers for using platelet-rich fibrin (PRF) to improve bone healing. PRF is rich in platelet cytokines and growth factors. Numerous techniques have been used to eliminate or seal the groove and regenerate endodontic and periodontal tissues. In this case report of two cases, a novel combination therapy involving ultrasonics, blend of PRF with bone graft, guided tissue regeneration membrane was used in the treatment of a palatogingival groove with an endoperio lesion to ensure arrest of disease progression and promote regeneration. The groove was cleaned and prepared ultrasonically and sealed with a bioactive dentin substitute.


Increased plasma and renal clearance of an exchangeable pool of apolipoprotein A-I in subjects with low levels of high density lipoprotein cholesterol.
Plasma levels of HDL apo A-I are reduced in individuals with low HDL cholesterol (HDL-C) concentrations as a result of increased fractional catabolic rates (FCRs). To determine the basis for the high apo A-I FCRs, seven subjects with low HDL-C levels (31.0 +/- 4.3 mg/dl) were compared with three subjects with high HDL-C levels (72.0 +/- 4.5 mg/dl). Each subject received autologous HDL that was labeled directly by the iodine-monochloride method (whole-labeled) and autologous HDL that was labeled by exchange with homologous radiolabeled apo A-I (exchange-labeled). Blood was obtained for 2 wk, specific activities determined, and FCRs (d-1 +/- SD) estimated. In every subject, whether in the low or high HDL-C group, the exchange-labeled FCR was greater than the whole-labeled FCR. The exchange-labeled FCR was higher in the low HDL-C group (0.339 +/- 0.043) versus the high HDL-C group (0.234 +/- 0.047; P < 0.009). The whole-labeled FCR was also greater in the low HDL-C group (0.239 +/- 0.023) versus the high HDL-C group (0.161 +/- 0.064; P < 0.02). In addition, in both low and high HDL groups ultracentrifugation resulted in more radioactivity in d > 1.210 (as percentage of total plasma counts per minute) with the exchange-labeled tracer than with the whole-labeled tracer (12.55 +/- 4.95% vs. 1.02 +/- 0.38%; P < 0.003). With both HDL tracers, more radioactivity was found in d > 1.210 in the low versus the high HDL-C groups. When apo A-I catabolism was studied by perfusing isolated rabbit kidneys with whole-labeled HDL, there was twice as much accumulation (cpm/g cortex) of HDL apo A-I isolated from subjects with low HDL-C than from subjects with high HDL-C (P < 0.0025). Finally, HDL that had been isolated from subjects with high levels of HDL-C was triglyceride enriched and exposed to partially purified lipases before perfusion through kidneys. Threefold more apo A-I from modified HDL accumulated in the cortex compared with the unmodified preparation (P < 0.007). The results of these in vivo and ex vivo studies indicate that individuals with low HDL-C levels have more loosely bound, easily exchanged apo A-I and that this exchangeable apo A-I is more readily cleared by the kidney.


Evaluation of a Prognostic Homeopathic Questionnaire for Women with Premenstrual Disorders.
Validation of treatments with individually prescribed homeopathic medicines is a challenging task. A prognostic homeopathic patient questionnaire containing 140 keynote symptoms (highly characteristic of a specific homeopathic medicine) and an electronic algorithm to process the answers were used in 2 clinical studies. The algorithm outcome, based on total symptom scores, indicated 1 of 11 pre-selected homeopathic medicines for women with premenstrual syndrome and premenstrual dysphoric disorder (PMS/PMDD). Aims were (1) to estimate the prognostic values of keynote symptoms and (2) to evaluate the reliability of the homeopathic medicine ranking in the algorithm outcome. The prevalence of specific keynote symptoms was calculated in 145 women diagnosed with PMS/PMDD and in 40 included women with favorable outcomes using 1 of the 11 homeopathic medicines. Likelihood ratios (LRs) of the keynote symptoms were calculated. Pearson's correlations were calculated between 2 sets of total algorithm scores for 11 homeopathic medicines, obtained at 2 time points. (1) A positive prognostic value (LR ≥ 1.5) was found in 34 keynote symptoms with a prevalence of 10-40%, with 10 symptoms already being connected to the corresponding homeopathic medicine in the algorithm. For example, the symptom 'common cold of the nose before menstruation' indicated Magnesium carbonicum with LR = 7.47 (confidence interval (CI) 3.90-14.28). (2) Pearson's correlations for the reliability evaluation varied from 0.69 to 0.84. Recommendations can be made to improve the PMS algorithm with more accurate keynote symptoms. The prognostic questionnaire proved a reliable tool to rank 11 homeopathic medicines by total scores, based on keynote symptoms. This PMS algorithm can be used for the treatment of PMS/PMDD in clinical practice.


Electromyographical and Perceptual Responses to Different Resistance Intensities in a Squat Protocol: Does Performing Sets to Failure With Light Loads Produce the Same Activity?
This investigation examined peak motor unit activity during sets that differed in resistance (50, 70, or 90% 1 repetition maximum [1RM]). Ten resistance-trained men (age, 23 ± 3 years; height, 187 ± 7 cm; body mass, 91.5 ± 6.9 kg; squat 1RM, 141 ± 28 kg) were assessed by electromyography (EMG) on the vastus lateralis and vastus medialis muscles in a randomized within-subject experiment consisting of 2 test visits: a drop-set day and a single-set day using only the 50% of 1RM intensity performed to failure. At the start of each day, subjects performed 2 submaximal repetition sets (50% 1RM × 10 repetitions and 70% 1RM × 7 repetitions). On the drop-set day, subjects performed 3 consecutive maximal repetition sets at 90%, 70%, and 50% 1RM to failure with no rest periods in between. On the single-set day, subjects performed a maximal repetition set at 50% 1RM to failure. Overall, the maximal repetition sets to failure at 50% and 70% 1RM resulted in higher peak EMG amplitude than during submaximal repetition sets with the same resistance. However, peak EMG amplitude was significantly (p ≤ 0.05) greater in the maximal 90% 1RM set than all other sets performed. When sets were performed to failure, ratings of perceived exertion (CR-10) did not differ over the intensity range of loads and suggests that perception is not capable of accurately detecting the actual amount of motor unit activation. The results of this investigation indicate that using higher external resistance is a more effective means of increasing motor unit activity than increasing the number of repetitions performed with lighter weights even when the end point is muscular failure. Accordingly, previous recommendations for the use of heavier loads during resistance training programs to stimulate the maximal development of strength and hypertrophy are further supported.


Characteristics of strain-sensitive photonic crystal cavities in a flexible substrate.
High-index semiconductor photonic crystal (PhC) cavities in a flexible substrate support strong and tunable optical resonances that can be used for highly sensitive and spatially localized detection of mechanical deformations in physical systems. Here, we report theoretical studies and fundamental understandings of resonant behavior of an optical mode excited in strain-sensitive rod-type PhC cavities consisting of high-index dielectric nanorods embedded in a low-index flexible polymer substrate. Using the three-dimensional finite-difference time-domain simulation method, we calculated two-dimensional transverse-electric-like photonic band diagrams and the three-dimensional dispersion surfaces near the first Γ-point band edge of unidirectionally strained PhCs. A broken rotational symmetry in the PhCs modifies the photonic band structures and results in the asymmetric distributions and different levels of changes in normalized frequencies near the first Γ-point band edge in the reciprocal space, which consequently reveals strain-dependent directional optical losses and selected emission patterns. The calculated electric fields, resonant wavelengths, and quality factors of the band-edge modes in the strained PhCs show an excellent agreement with the results of qualitative analysis of modified dispersion surfaces. Furthermore, polarization-resolved time-averaged Poynting vectors exhibit characteristic dipole-like emission patterns with preferentially selected linear polarizations, originating from the asymmetric band structures in the strained PhCs.


Effect of transcutaneous electrical acupuncture point stimulation on endometrial receptivity in women undergoing frozen-thawed embryo transfer: a single-blind prospective randomised controlled trial.
To evaluate the effect of transcutaneous electrical acupuncture point stimulation (TEAS) on endometrial HOXA10 protein expression and three-dimensional (3D) power Doppler ultrasound parameters as markers of endometrial receptivity in women undergoing frozen-thawed embryo transfer (FET). A total of 68 women undergoing FET were randomised to receive TEAS or mock TEAS at acupuncture points CV3, CV4 and SP6 and Zigong bilaterally. Both groups had six sessions per cycle for three menstrual cycles prior to the scheduled FET. Each session lasted 30 min and was repeated every other day. 3D power Doppler ultrasound parameters, HOXA10 protein expression and rates of embryo implantation, clinical pregnancy and live birth were compared. There were no significant differences between the two groups in endometrial thickness or endometrial volume. The ultrasonographic endometrial triple-line pattern was present more often in the TEAS group (p=0.002). The TEAS group had a greater endometrial and subendometrial vascularisation index (VI) than the mock TEAS group (p=0.001 and p<0.001, respectively) on 3D ultrasound and increased endometrial HOXA10 expression (p=0.001) immediately prior to FET. Subsequently, the rates of embryo implantation, clinical pregnancy and live birth rates were all higher in the TEAS group than in the mock TEAS group (p=0.024, p=0.038 and p=0.033, respectively). In patients undergoing FET, TEAS may have beneficial effects on endometrial HOXA10 expression and ultrasound markers of endometrial receptivity. These findings may explain the improvement in clinical outcome of FET associated with the use of TEAS. ChiCTR-TRC-14004448.


Declining incidence of candidemia and the shifting epidemiology of Candida resistance in two US metropolitan areas, 2008-2013: results from population-based surveillance.
Recent reports have demonstrated a decline in bacterial bloodstream infections (BSIs) following adherence to central line insertion practices; however, declines have been less evident for BSIs due to Candida species. We conducted active, population-based laboratory surveillance for candidemia in metropolitan Atlanta, GA and Baltimore, MD over a 5-year period. We calculated annual candidemia incidence and antifungal drug resistance rates. We identified 3,848 candidemia cases from 2008-2013. Compared with 2008, candidemia incidence per 100,000 person-years decreased significantly by 2013 in both locations (GA: 14.1 to 9.5, p<0.001; MD: 30.9 to 14.4, p<0.001). A total of 3,255 cases (85%) had a central venous catheter (CVC) in place within 2 days before the BSI culture date. In both locations, the number of CVC-associated cases declined (GA: 473 to 294; MD: 384 to 151). Candida albicans (CA, 36%) and Candida glabrata (CG, 27%) were the most common species recovered. In both locations, the proportion of cases with fluconazole resistance decreased (GA: 8.0% to 7.1%, -10%; MD: 6.6% to 4.9%, -25%), while the proportion of cases with an isolate resistant to an echinocandin increased (GA: 1.2% to 2.9%, +147%; MD: 2.0% to 3.5%, +77%). Most (74%) echinocandin-resistant isolates were CG; 17 (<1%) isolates were resistant to both drug categories (multidrug resistant [MDR], 16/17 were CG). The proportion of CG cases with MDR Candida increased from 1.8% to 2.6%. We observed a significant decline in the incidence of candidemia over a five-year period, and increases in echinocandin-resistant and MDR Candida. Efforts to strengthen infection control practices may be preventing candidemia among high-risk patients. Further surveillance for resistant Candida is warranted.


Regulation of LRRK2 expression points to a functional role in human monocyte maturation.
Genetic variants of Leucine-Rich Repeat Kinase 2 (LRRK2) are associated with a significantly enhanced risk for Parkinson disease, the second most common human neurodegenerative disorder. Despite major efforts, our understanding of LRRK2 biological function and regulation remains rudimentary. In the present study we analyze LRRK2 mRNA and protein expression in sub-populations of human peripheral blood mononuclear cells (PBMCs). LRRK2 mRNA and protein was found in circulating CD19(+) B cells and in CD14(+) monocytes, whereas CD4(+) and CD8(+) T cells were devoid of LRRK2 mRNA. Within CD14(+) cells the CD14(+)CD16(+) sub-population of monocytes exhibited high levels of LRRK2 protein, in contrast to CD14(+)CD16(-) cells. However both populations expressed LRRK2 mRNA. As CD14(+)CD16(+) cells represent a more mature subset of monocytes, we monitored LRRK2 expression after in vitro treatment with various stress factors known to induce monocyte activation. We found that IFN-γ in particular robustly increased LRRK2 mRNA and protein levels in monocytes concomitant with a shift of CD14(+)CD16(-) cells towards CD14(+)CD16(+) cells. Interestingly, the recently described LRRK2 inhibitor IN-1 attenuated this shift towards CD14(+)CD16(+) after IFN-γ stimulation. Based on these findings we speculate that LRRK2 might have a role in monocyte maturation. Our results provide further evidence for the emerging role of LRRK2 in immune cells and regulation at the transcriptional and translational level. Our data might also reflect an involvement of peripheral and brain immune cells in the disease course of PD, in line with increasing awareness of the role of the immune system in PD.


Use of quantitative ultrasound for identifying low bone density in older people.
This study examined criterion, convergent, and discriminant validities of quantitative ultrasound (QUS) for identifying low bone density among people aged 55 years and older in Taiwan. We recruited 453 community-dwelling volunteers and 30 patients with lower extremity fractures. Bone density was assessed using both calcaneal QUS and femoral neck dual-energy x-ray absorptiometry (DXA). Two QUS parameters, speed of sound (SOS) and broadband ultrasound attenuation (BUA), were also used to estimate heel bone mineral density (HBMD). Using DXA as the criterion for identifying low bone density (DXA T score of 1.0 or lower), likelihood ratios for BUA and SOS at the 50th percentile and HBMD for men were 1.50, 1.75, and 1.28, respectively; the counterparts for women were 1.54, 2.13, and 1.29. As for identifying osteoporosis (DXA T score of -2.5 or lower), higher likelihood ratios of the 3 QUS parameters were gained. For convergent validity, Pearson correlation coefficients for DXA with BUA, SOS, and HBMD ranged from 0.40 to 0.43 for men and from 0.48 to 0.53 for women. For the ability to discriminate men and women with lower extremity fractures from those without, no significant differences in the area under the receiver operating characteristic curve were detected between BUA, SOS, and HBMD and DXA after adjusting for age, body mass index, fall history, and current smoking. Although having very good convergent and discriminant validities and fair criterion validity, calcaneal QUS may be a screening tool for identifying low bone density.


Anisotropic growth of the thiophene-based layer on Si(111)-B.
The formation of large assemblies on the Si(111)-B surface is discussed with the help of STM simulations and DFT calculations. Although highly regular assemblies of DTB10B along the Si row direction are observed, the existence of two herringbone isomers introduces a lower periodicity within the 2D molecular network. The formation of herringbone units is explained by weak intermolecular interactions while the 1D assembling depends mainly on the interactions of the C10 side chains with the Si(111)-B surface.


Conserved structure and inferred evolutionary history of long terminal repeats (LTRs).
Long terminal repeats (LTRs, consisting of U3-R-U5 portions) are important elements of retroviruses and related retrotransposons. They are difficult to analyse due to their variability.The aim was to obtain a more comprehensive view of structure, diversity and phylogeny of LTRs than hitherto possible. Hidden Markov models (HMM) were created for 11 clades of LTRs belonging to Retroviridae (class III retroviruses), animal Metaviridae (Gypsy/Ty3) elements and plant Pseudoviridae (Copia/Ty1) elements, complementing our work with Orthoretrovirus HMMs. The great variation in LTR length of plant Metaviridae and the few divergent animal Pseudoviridae prevented building HMMs from both of these groups.Animal Metaviridae LTRs had the same conserved motifs as retroviral LTRs, confirming that the two groups are closely related. The conserved motifs were the short inverted repeats (SIRs), integrase recognition signals (5´TGTTRNR…YNYAACA 3´); the polyadenylation signal or AATAAA motif; a GT-rich stretch downstream of the polyadenylation signal; and a less conserved AT-rich stretch corresponding to the core promoter element, the TATA box. Plant Pseudoviridae LTRs differed slightly in having a conserved TATA-box, TATATA, but no conserved polyadenylation signal, plus a much shorter R region.The sensitivity of the HMMs for detection in genomic sequences was around 50% for most models, at a relatively high specificity, suitable for genome screening.The HMMs yielded consensus sequences, which were aligned by creating an HMM model (a 'Superviterbi' alignment). This yielded a phylogenetic tree that was compared with a Pol-based tree. Both LTR and Pol trees supported monophyly of retroviruses. In both, Pseudoviridae was ancestral to all other LTR retrotransposons. However, the LTR trees showed the chromovirus portion of Metaviridae clustering together with Pseudoviridae, dividing Metaviridae into two portions with distinct phylogeny. The HMMs clearly demonstrated a unitary conserved structure of LTRs, supporting that they arose once during evolution. We attempted to follow the evolution of LTRs by tracing their functional foundations, that is, acquisition of RNAse H, a combined promoter/ polyadenylation site, integrase, hairpin priming and the primer binding site (PBS). Available information did not support a simple evolutionary chain of events.


The effects of exercise on cardiovascular outcomes before, during, and after treatment for breast cancer.
Asymptomatic cardiotoxicity following breast cancer treatment is a significant issue for many patients, as these patients typically face an increased risk of cardiovascular disease (CVD). Exercise has well established benefits to improve and maintain cardiovascular function across patients with and without CVD. However, there is a dearth of information on the effects of exercise on cardiovascular outcomes in breast cancer patients. While pre-clinical studies support the use of exercise in mitigating cardiotoxicity, only one human study has specifically investigated cardiac function following an exercise intervention during chemotherapy treatment. No significant differences were observed between groups, which highlights the unidentified role of exercise in altering the risk of cardiotoxicity in breast cancer patients. Issues such as establishing the optimal timing, type, and intensity of an exercise program before, during, or after oncologic treatment for breast cancer are unclear. CVD risk and incidence increase in breast cancer survivors post therapy, and CVD is the number one killer of women in the United States. Thus, there is an increasing need to define the efficacy of exercise as a non-pharmacologic intervention in this growing population.


Effect of transmission reduction by insecticide-treated bednets (ITNs) on antimalarial drug resistance in western Kenya.
Despite the clear public health benefit of insecticide-treated bednets (ITNs), the impact of malaria transmission-reduction by vector control on the spread of drug resistance is not well understood. In the present study, the effect of sustained transmission reduction by ITNs on the prevalence of Plasmodium falciparum gene mutations associated with resistance to the antimalarial drugs sulfadoxine-pyrimethamine (SP) and chloroquine (CQ) in children under the age of five years was investigated during an ITN trial in Asembo area, western Kenya. During the ITN trial, the national first line antimalarial treatment changed from CQ to SP. Smear-positive samples collected from cross sectional surveys prior to ITN introduction (baseline, n = 250) and five years post-ITN intervention (year 5 survey, n = 242) were genotyped for single nucleotide polymorphisms (SNPs) at dhfr-51, 59, 108, 164 and dhps-437, 540 (SP resistance), and pfcrt-76 and pfmdr1-86 (CQ resistance). The association between the drug resistance mutations and epidemiological variables was evaluated. There were significant increases in the prevalence of SP dhps mutations and the dhfr/dhps quintuple mutant, and a significant reduction in the proportion of mixed infections detected at dhfr-51, 59 and dhps-437, 540 SNPs from baseline to the year 5 survey. There was no change in the high prevalence of pfcrt-76 and pfmdr1-86 mutations. Multivariable regression analysis further showed that current antifolate use and year of survey were significantly associated with more SP drug resistance mutations. These results suggest that increased antifolate drug use due to drug policy change likely led to the high prevalence of SP mutations 5 years post-ITN intervention and reduced transmission had no apparent effect on the existing high prevalence of CQ mutations. There is no evidence from the current study that sustained transmission reduction by ITNs reduces the prevalence of genes associated with malaria drug resistance.


Role of the hypervariable hinge region of phosphoprotein P of vesicular stomatitis virus in viral RNA synthesis and assembly of infectious virus particles.
The phosphoprotein (P protein) of vesicular stomatitis virus (VSV) is an essential subunit of the viral RNA-dependent RNA polymerase and has multiple functions residing in its different domains. In the present study, we examined the role of the hypervariable hinge region of P protein in viral RNA synthesis and recovery of infectious VSV by using transposon-mediated insertion mutagenesis and deletion mutagenesis. We observed that insertions of 19-amino-acid linker sequences at various positions within this region affected replication and transcription functions of the P protein to various degrees. Interestingly, one insertion mutant was completely defective in both transcription and replication. Using a series of deletion mutants spanning the hinge region of the protein, we observed that amino acid residues 201 through 220 are required for the activity of P protein in both replication and transcription. Neither insertion nor deletion had any effect on the interaction of P protein with N or L proteins. Infectious VSVs with a deletion in the hinge region possessed retarded growth characteristics and exhibited small-plaque morphology. Interestingly, VSV containing one P protein deletion mutant (PDelta7, with amino acids 141 through 200 deleted), which possessed significant levels of replication and transcription activity, could be amplified only by passage in cells expressing the wild-type P protein. We conclude that the hypervariable hinge region of the P protein plays an important role in viral RNA synthesis. Furthermore, our results provide a previously unidentified function for the P protein: it plays a critical role in the assembly of infectious VSV.


Laboratory evolution reveals regulatory and metabolic trade-offs of glycerol utilization in Saccharomyces cerevisiae.
Most microbial species, including model eukaryote Saccharomyces cerevisiae, possess genetic capability to utilize many alternative nutrient sources. Yet, it remains an open question whether these manifest into assimilatory phenotypes. Despite possessing all necessary pathways, S. cerevisiae grows poorly or not at all when glycerol is the sole carbon source. Here we discover, through multiple evolved lineages, genetic determinants underlying glycerol catabolism and the associated fitness trade-offs. Most evolved lineages adapted through mutations in the HOG pathway, but showed hampered osmotolerance. In the other lineages, we find that only three mutations cause the improved phenotype. One of these contributes counter-intuitively by decoupling the TCA cycle from oxidative phosphorylation, and thereby hampers ethanol utilization. Transcriptomics, proteomics and metabolomics analysis of the re-engineered strains affirmed the causality of the three mutations at molecular level. Introduction of these mutations resulted in improved glycerol utilization also in industrial strains. Our findings not only have a direct relevance for improving glycerol-based bioprocesses, but also illustrate how a metabolic pathway can remain unexploited due to fitness trade-offs in other, ecologically important, traits.


Concurrent validity of the PROMIS® pediatric global health measure.
To evaluate the concurrent validity of the PROMIS Pediatric Global Health measure (PGH-7), child-report and parent-proxy versions. Surveys were administered via home computer on two separate occasions (December, 2011 and August/September, 2012) to a convenience sample of 4636 children 8-17 years old and 2609 parents who participated in a national Internet panel. Data analysis included: (1) evaluations of differences in PGH-7 scores between groups defined by sociodemographics, clinical characteristics, and access to health care; (2) associations with 15 PROMIS pediatric measures; and (3) correlations with two health-related quality-of-life instruments, the KIDSCREEN-10 and PedsQL-15. PGH-7 scores were lower for children with chronic conditions, Hispanic ethnicity, low socioeconomic status, and barriers to accessing health care. The PGH-7 showed excellent convergent and discriminant validity with PROMIS pediatric measures of physical, mental, and social health. The PGH-7 was strongly correlated with the KIDSCREEN-10, which assesses positive health, and moderately correlated with the PedsQL-15, which assesses problems with a child's health. The PGH-7 measures global health, summarizing a child's physical, mental, and social health into a single score. These properties make it a useful clinical, population health, and research tool for applications that require an efficient, precise, and valid summary measure of a children's self-reported health status. Future research should prospectively evaluate the PGH-7's capacity to detect change that results from alterations in clinical status, transformations of the healthcare delivery system, and children's health development.


Non-invasive physical treatments for chronic/recurrent headache.
Non-invasive physical treatments are often used to treat common types of chronic/recurrent headache. To quantify and compare the magnitude of short- and long-term effects of non-invasive physical treatments for chronic/recurrent headaches. We searched the following databases from their inception to November 2002: MEDLINE, EMBASE, BIOSIS, CINAHL, Science Citation Index, Dissertation Abstracts, CENTRAL, and the Specialised Register of the Cochrane Pain, Palliative Care and Supportive Care review group. Selected complementary medicine reference systems were searched as well. We also performed citation tracking and hand searching of potentially relevant journals. We included randomized and quasi-randomized controlled trials comparing non-invasive physical treatments for chronic/recurrent headaches to any type of control. Two independent reviewers abstracted trial information and scored trials for methodological quality. Outcomes data were standardized into percentage point and effect size scores wherever possible. The strength of the evidence of effectiveness was assessed using pre-specified rules. Twenty-two studies with a total of 2628 patients (age 12 to 78 years) met the inclusion criteria. Five types of headache were studied: migraine, tension-type, cervicogenic, a mix of migraine and tension-type, and post-traumatic headache. Ten studies had methodological quality scores of 50 or more (out of a possible 100 points), but many limitations were identified. We were unable to pool data because of study heterogeneity. For the prophylactic treatment of migraine headache, there is evidence that spinal manipulation may be an effective treatment option with a short-term effect similar to that of a commonly used, effective drug (amitriptyline). Other possible treatment options with weaker evidence of effectiveness are pulsating electromagnetic fields and a combination of transcutaneous electrical nerve stimulation [TENS] and electrical neurotransmitter modulation. For the prophylactic treatment of chronic tension-type headache, amitriptyline is more effective than spinal manipulation during treatment. However, spinal manipulation is superior in the short term after cessation of both treatments. Other possible treatment options with weaker evidence of effectiveness are therapeutic touch; cranial electrotherapy; a combination of TENS and electrical neurotransmitter modulation; and a regimen of auto-massage, TENS, and stretching. For episodic tension-type headache, there is evidence that adding spinal manipulation to massage is not effective. For the prophylactic treatment of cervicogenic headache, there is evidence that both neck exercise (low-intensity endurance training) and spinal manipulation are effective in the short and long term when compared to no treatment. There is also evidence that spinal manipulation is effective in the short term when compared to massage or placebo spinal manipulation, and weaker evidence when compared to spinal mobilization. There is weaker evidence that spinal mobilization is more effective in the short term than cold packs in the treatment of post-traumatic headache. A few non-invasive physical treatments may be effective as prophylactic treatments for chronic/recurrent headaches. Based on trial results, these treatments appear to be associated with little risk of serious adverse effects. The clinical effectiveness and cost-effectiveness of non-invasive physical treatments require further research using scientifically rigorous methods. The heterogeneity of the studies included in this review means that the results of a few additional high-quality trials in the future could easily change the conclusions of our review.


Why Are Water Droplets Highly Mobile on Nanostructured Oil-Impregnated Surfaces?
Porous lubricated surfaces (aka slippery liquid-infused porous surfaces, SLIPS) have been demonstrated to repel various liquids. The origin of this repellency, however, is not fully understood. By using surface-sensitive sum frequency generation vibrational spectroscopy, we characterized the water/oil interface of a water droplet residing on (a) an oil-impregnated nanostructured surface (SLIPS) and (b) the same oil layer without the underlying nanostructures. Different from water molecules in contact with bulk oil without nanostructures, droplets on SLIPS adopt a molecular orientation that is predominantly parallel to the water/oil interface, leading to weaker hydrogen bonding interactions between water droplets and the lubrication film, giving SLIPS their water repellency. Our results demonstrate that the molecular interactions between two contacting liquids can be manipulated by the implementation of nanostructured substrates. The results also offer the molecular principles for controlling nanostructure to reduce oil depletion-one of the limitations and major concerns of SLIPS.


Hydrocephalus in Uganda: the predominance of infectious origin and primary management with endoscopic third ventriculostomy.
The aim of this prospective study was to investigate the causes of hydrocephalus in Uganda, the efficacy of endoscopic third ventriculostomy (ETV) in this environment, and whether existing parameters could be used to guide patient selection. Three hundred consecutive children, 81.3% of whom were younger than 1 year of age, underwent ventriculoscopy preceding ETV as an initial treatment for hydrocephalus. In 179 patients (60%) the hydrocephalus was caused by a cerebrospinal fluid infection; in 76% of patients the infection had occurred in the 1st month of life. In 229 patients (76.3%) ETV was performed; 2% of patients were lost to follow up after less than 1 month and the surgical mortality rate was 1.8%. The first ETV was successful in 115 patients (52%); the mean follow-up period was 15.2 months. The mean time to repeated operation following a failed ETV was 1.5 months. Sixty-five patients underwent a second endoscopy; 37 underwent a second ETV, of which 14 procedures (38%) were successful (mean follow-up period 12.25 months). The overall success rate for ETV was 59%. Among patients older than 1 year of age, the procedure was successful in 22 (81%) of 27 with postinfectious hydrocephalus (PIHC) and 18 (90%) of 20 with nonpostinfectious hydrocephalus (NPIHC). The success rate of ETV among those patients younger than 1 year of age was 59% (60 of 101) for patients suffering from PIHC and 40% (21 of 52) for those suffering from NPIHC. Age correlated with success for NPIHC (p = 0.0002) and PIHC (p = 0.0421). The success rate of the surgery for patients with myelomeningocele and hydrocephalus who were younger than 1 year of age was 40% (eight of 20). The success rate of the surgery for PIHC in infants younger than 1 year of age was 70% (44 of 63) among patients with aqueductal obstruction but 45% (14 of 31) among patients with aqueductal patency (p = 0.0254). Fourth ventricular size as demonstrated on cranial ultrasonography or computerized tomography scanning predicted whether the aqueduct was patent (p = 0.0001). Infection is the most common cause of hydrocephalus in Uganda. In all children older than 1 year of age and in those younger than 1 year of age with PICH and aqueductal obstruction, which was reliably predicted by cranial ultrasonography, ETV was effective.


Split- versus single-dose preparation tolerability in a multiethnic population: decreased side effects but greater social barriers.
This study was performed to compare patient-reported tolerability and its barriers in single- vs. split-dose 4-L polyethylene glycol (PEG) bowel preparation for colonoscopy in a large multiethnic, safety-net patient population. A cross-sectional, dual-center study using a multi-language survey was used to collect patient-reported demographic, medical, socioeconomic, and tolerability data from patients undergoing outpatient colonoscopy. Univariate and multivariate analyses were used to identify demographic and clinical factors significantly associated with patient-reported bowel preparation tolerability. A total of 1023 complete surveys were included, of which 342 (33.4%) completed single-dose and 681 (66.6%) split-dose bowel preparation. Thirty-nine percent of the patients were Hispanic, 50% had Medicaid or no insurance, and 34% had limited English proficiency. Patients who underwent split-dose preparation were significantly more likely to report a tolerable preparation, with less severe symptoms, than were patients who underwent single-dose preparation. Multiple logistic regression revealed that male sex and instructions in the preferred language were associated with tolerability of the single-dose preparation, while male sex and concerns about medications were associated with tolerability of the split-dose preparation. In a large multiethnic safety-net population, split-dose bowel preparation was significantly more tolerable and associated with less severe gastrointestinal symptoms than single-dose preparation. The tolerability of split-dose bowel preparation was associated with social barriers, including concerns about interfering with other medications.


Systolic ventricular filling.
The evidence of the ventricular myocardial band (VMB) has revealed unavoidable coherence and mutual coupling of form and function in the ventricular myocardium, making it possible to understand the principles governing electrical, mechanical and energetical events within the human heart. From the earliest Erasistratus' observations, principal mechanisms responsible for the ventricular filling have still remained obscured. Contemporary experimental and clinical investigations unequivocally support the attitude that only powerful suction force, developed by the normal ventricles, would be able to produce an efficient filling of the ventricular cavities. The true origin and the precise time frame for generating such force are still controversial. Elastic recoil and muscular contraction were the most commonly mentioned, but yet, still not clearly explained mechanisms involved in the ventricular suction. Classical concepts about timing of successive mechanical events during the cardiac cycle, also do not offer understandable insight into the mechanism of the ventricular filling. The net result is the current state of insufficient knowledge of systolic and particularly diastolic function of normal and diseased heart. Here we summarize experimental evidence and theoretical backgrounds, which could be useful in understanding the phenomenon of the ventricular filling. Anatomy of the VMB, and recent proofs for its segmental electrical and mechanical activation, undoubtedly indicates that ventricular filling is the consequence of an active muscular contraction. Contraction of the ascendent segment of the VMB, with simultaneous shortening and rectifying of its fibers, produces the paradoxical increase of the ventricular volume and lengthening of its long axis. Specific spatial arrangement of the ascendent segment fibers, their interaction with adjacent descendent segment fibers, elastic elements and intra-cavitary blood volume (hemoskeleton), explain the physical principles involved in this action. This contraction occurs during the last part of classical systole and the first part of diastole. Therefore, the most important part of ventricular diastole (i.e. the rapid filling phase), in which it receives >70% of the stroke volume, belongs to the active muscular contraction of the ascendent segment. We hope that these facts will give rise to new understanding of the principal mechanisms involved in normal and abnormal diastolic heart function.


Future prospects of radiotherapy in gynecologic oncology.
Major areas of progress in radiotherapy over the past decade have included important refinements in equipment and treatment techniques, as well as improved and expanded training programs for radiation oncologists. In 1975, approximately 14% of all new cancers were gynecologic, representing almost 68,000 new cases. Although end results in treatment of early cervix and corpus uteri lesions are quite good, results in treatment of early cervix and corpus uteri lesions are quite good, results in treatment of the later stage lesions, as well as ovarian and vulvo-vaginal tumors, are discouraging. Progress in the future will center around five primary areas: 1) greater understanding and utilization of radiation sensitizing agents such as hyperbaric oxygen, metronidazol, and other electroaffinic agents, purine and pyrimadine analogs, and antibiotics such as Actinomycin D and Adriamycin; 2) introduction into clinical use of high LET particle beams, such as fast neutrons, pi mesons, low atomic number nuclei, and heavy accelerated nuclei; 3) combined modality therapy utilizing radiation and chemotherapy or radiation and immunotherapy for management of subclinical disease; 4) radiobiologic and clinical advances in the utilization of radiation and hyperthermia; and 5) improved understanding of the pathophysiology and natural history of the gynecologic malignancies with increasing use of staging laparotomies, lymphangiography and peritoneoscopy.


Faunal breaks and species composition of Indo-Pacific corals: the role of plate tectonics, environment and habitat distribution.
Species richness gradients are ubiquitous in nature, but the mechanisms that generate and maintain these patterns at macroecological scales remain unresolved. We use a new approach that focuses on overlapping geographical ranges of species to reveal that Indo-Pacific corals are assembled within 11 distinct faunal provinces. Province limits are characterized by co-occurrence of multiple species range boundaries. Unexpectedly, these faunal breaks are poorly predicted by contemporary environmental conditions and the present-day distribution of habitat. Instead, faunal breaks show striking concordance with geological features (tectonic plates and mantle plume tracks). The depth range over which a species occurs, its larval development rate and genus age are important determinants of the likelihood that species will straddle faunal breaks. Our findings indicate that historical processes, habitat heterogeneity and species colonization ability account for more of the present-day biogeographical patterns of corals than explanations based on the contemporary distribution of reefs or environmental conditions.


Transglutaminase 2 inhibits Rb binding of human papillomavirus E7 by incorporating polyamine.
Transglutaminase 2 (TGase 2) is one of a family of enzymes that catalyze protein modification through the incorporation of polyamines into substrates or the formation of protein crosslinks. However, the physiological roles of TGase 2 are largely unknown. To elucidate the functions of TGase 2, we have searched for its interacting proteins. Here we show that TGase 2 interacts with E7 oncoprotein of human papillomavirus type 18 (HPV18) in vitro and in vivo. TGase 2 incorporates polyamines into a conserved glutamine residue in the zinc-binding domain of HPV18 E7 protein. This modification mediates the inhibition of E7's Rb binding ability. In contrast, TGase 2 does not affect HPV16 E7, due to absence of a glutamine residue at this polyamination site. Using E7 mutants, we demonstrate that TGase 2-dependent inhibition of HPV E7 function correlates with the presence of the polyamination site. Our results indicate that TGase 2 is an important cellular interfering factor and define a novel host-virus interaction, suggesting that the inability of TGase 2 to inactivate HPV16 E7 could explain the high prevalence of HPV16 in cervical cancer.


Nrf2 Inhibits Periodontal Ligament Stem Cell Apoptosis under Excessive Oxidative Stress.
The present study aimed to analyze novel mechanisms underlying Nrf2-mediated anti-apoptosis in periodontal ligament stem cells (PDLSCs) in the periodontitis oxidative microenvironment. We created an oxidative stress model with H₂O₂-treated PDLSCs. We used real-time PCR, Western blotting, TUNEL staining, fluorogenic assay and transfer genetics to confirm the degree of oxidative stress and apoptosis as well as the function of nuclear factor-erythroid 2-related factor 2 (Nrf2). We demonstrated that with upregulated levels of reactive oxygen species (ROS) and malondialdehyde (MDA), the effect of oxidative stress was obvious under H₂O₂ treatment. Oxidative molecules were altered after the H₂O₂ exposure, whereby the signaling of Nrf2 was activated with an increase in its downstream effectors, heme oxygenase-1 (HO-1), NAD(P)H:quinone oxidoreductase 1 (NQO1) and γ-glutamyl cysteine synthetase (γ-GCS). Additionally, the apoptosis levels gradually increased with oxidative stress by the upregulation of caspase-9, caspase-3, Bax and c-Fos levels in addition to the downregulation of Bcl-2. However, there was no alterations in levels of caspase-8. The enhanced antioxidant effect could not mitigate the occurrence of apoptosis. Furthermore, Nrf2 overexpression effectively improved the anti-oxidative levels and increased cell proliferation. At the same time, overexpression effectively restrained TUNEL staining and decreased the molecular levels of caspase-9, caspase-3, Bax and c-Fos, but not that of caspase-8. In contrast, silencing the expression of Nrf2 levels had the opposite effect. Collectively, Nrf2 alleviates PDLSCs via its effects on regulating oxidative stress and anti-intrinsic apoptosis by the activation of oxidative enzymes.


Job terminations among persons with severe mental illness participating in supported employment.
For persons with psychiatric disabilities, maintaining a job is often more difficult than acquiring a job. A large proportion of jobs end unsatisfactorily. This study explored job terminations among 63 persons with severe mental illness who participated in competitive jobs through supported employment programs. More than half of the job terminations were unsatisfactory, defined as the client quitting without having other job plans or being fired. Baseline ratings of demographic and clinical characteristics, preemployment skills training, and early ratings of job satisfaction and work environment did not predict unsatisfactory terminations. Clients with better work histories were less likely to experience unsatisfactory terminations. In addition, unsatisfactory terminations were associated retrospectively with multiple problems on the job that were related to interpersonal functioning, mental illness, dissatisfaction with jobs, quality of work, medical illnesses, dependability, and substance abuse. These results suggest that supported employment programs need to address job maintenance with interventions that identify and address different types of difficulties as they arise on the job.


Antibiotic consumption for sore throat and the potential effect of a vaccine against group A Streptococcus: a systematic review and modelling study.
Antibiotic consumption can lead to antimicrobial resistance and microbiome imbalance. We sought to estimate global antibiotic consumption for sore throat, and the potential reduction in consumption due to effective vaccination against group A Streptococcus (Strep A). We reviewed and analysed articles published between January 2000 and February 2022, identified though Clarivate Analytics' Web of Science search platform, with reference to antibiotic prescribing or consumption, sore throat, pharyngitis, or tonsillitis. We then used those analyses, combined with assumptions for the effectiveness, duration of protection, and coverage of a vaccine, to calculate the estimated reduction in antibiotic prescribing due to the introduction of Strep A vaccines. We identified 101 studies covering 38 countries. The mean prescribing rate for sore throat was approximately 5 courses per 100 population per year, accounting for approximately 5% of all antibiotic consumption. Based on 2020 population estimates for countries with empiric prescribing rates, antibiotic consumption for sore throat was estimated to exceed 37 million courses annually, of which half could be attributable to treatment for Strep A. A vaccine that reduces rates of Strep A infection by 80%, with 80% coverage and 10 year's duration of protection, could avert 2.8 million courses of antibiotics prescribed for sore throat treatment among 5-14 year-olds in countries with observed prescribing rates, increasing to an estimated 7.5 million averted if an effective vaccination program also reduced precautionary prescribing. A vaccine that prevents Strep A throat infections in children may reduce antibiotic prescribing for sore throat by 32-87% depending on changes to prescribing and consumption behaviours. The Wellcome Trust, grant agreement number 215490/Z/19/Z.


Percutaneous cryoablation for the treatment of osteoid osteoma in the adult population.
To evaluate the technical feasibility and efficacy of percutaneous cryoablation for the treatment of osteoid osteoma (OO) in adults. 21 patients (12 male and nine female; mean age, 29.9 years) who underwent CT-guided percutaneous cryoablation for the treatment of OO were retrospectively evaluated. Procedures were carried out under local anaesthesia and conscious sedation in 13 patients, and under general anaesthesia in eight patients. Then, the ablation zone was evaluated with post-procedure magnetic resonance imaging at 6 weeks. Clinical outcome was assessed using a visual analogue scale (VAS) to evaluate severity of pain before procedure, as well as at primary (6 weeks) and secondary follow-up (6-40 months). All procedures were technically successful. Median VAS scores were: 8 (range, 5-10) before procedure and after procedure, respectively, 0 (range, 0-2; p < .0001) and 0 (range, 0-7; p < .0001) at primary and secondary follow-up. There were three minor complications (14.3%) and no major complication. A single patient reported symptom recurrence (4.8%) at secondary follow-up and successfully underwent a second cryoablation procedure. CT-guided percutaneous cryoablation is safe and effective in the treatment of OO in adults, and can be accomplished without general anaesthesia in selected cases. • CT-guided percutaneous cryoablation of osteoid osteoma is safe and effective • Cryoablation allows precise visual control of the aggregated iceball during procedure • Percutaneous cryoablation can be accomplished without general anaesthesia in selected cases • Another advantage of cryoablation is reduction of immediate postprocedural pain • Post-procedure MRI is helpful in the evaluation of technical success.


Different lepidopteran elicitors account for cross-talk in herbivory-induced phytohormone signaling.
Salicylic acid (SA), jasmonic acid (JA), ethylene (ET), and their interactions mediate plant responses to pathogen and herbivore attack. JA-SA and JA-ET cross-signaling are well studied, but little is known about SA-ET cross-signaling in plant-herbivore interactions. When the specialist herbivore tobacco hornworm (Manduca sexta) attacks Nicotiana attenuata, rapid and transient JA and ET bursts are elicited without significantly altering wound-induced SA levels. In contrast, attack from the generalist beet armyworm (Spodoptera exigua) results in comparatively lower JA and ET bursts, but amplified SA bursts. These phytohormone responses are mimicked when the species' larval oral secretions (OS(Se) and OS(Ms)) are added to puncture wounds. Fatty acid-amino acid conjugates elicit the JA and ET bursts, but not the SA burst. OS(Se) had enhanced glucose oxidase activity (but not beta-glucosidase activity), which was sufficient to elicit the SA burst and attenuate the JA and ET levels. It is known that SA antagonizes JA; glucose oxidase activity and associated hydrogen peroxide also antagonizes the ET burst. We examined the OS(Ms)-elicited SA burst in plants impaired in their ability to elicit JA (antisense [as]-lox3) and ET (inverted repeat [ir]-aco) bursts and perceive ET (35s-etr1b) after fatty acid-amino acid conjugate elicitation, which revealed that both ET and JA bursts antagonize the SA burst. Treating wild-type plants with ethephone and 1-methylcyclopropane confirmed these results and demonstrated the central role of the ET burst in suppressing the OS(Ms)-elicited SA burst. By suppressing the SA burst, the ET burst likely facilitates unfettered JA-mediated defense activation in response to herbivores that otherwise would elicit SA.


Randomized double-blind, double-dummy crossover clinical trial of oral tramadol versus rectal tramadol administration in opioid-naive cancer patients with pain.
Tramadol is commonly used as second step drug of the analgesic ladder. In circumstances where the oral route is unavailable, rectal administration of opioids might be a simple alternative. The aim of this study was to compare the analgesic activity and tolerability of tramadol by oral and rectal administration in a double-blind, double-dummy crossover trial. The study included 60 cancer patients with cancer pain no longer responsive to non-opioid drugs. Each patient initially received oral tramadol 50 mg (drops), followed by tramadol sustained release 100 mg orally, and placebo rectally, or tramadol 100 mg rectally and placebo orally, twice a day, in a randomized sequence, on each of 3 days. Patients were allowed to take 50 mg of oral tramadol by drops as needed (four doses per day, to a maximum of 400 mg/day, including the basal dose given by the oral or rectal route). Pain intensity and relief and symptom scores were recorded every day and at the end of each phase of the crossover. The mean age of the patients was 66.1 years (SD 13.5 years); 36 were female, and 44 completed both periods. Patients dropped out due to adverse effects (15 patients) and refusal (1 patient). No differences in the use of rescue dose of oral tramadol were observed between the groups. No differences in pain intensity and relief scores, or in other symptoms between the two treatments were observed. No differences in treatment efficacy as judged by the clinician (P=0.73), in patient compliance (P=0.35), or in patient satisfaction regarding treatment (P<0.35) were found. No differences in adverse effects were found between the two treatments (25.5%, 13 patients, and 20.4%, 11 patients, with oral and rectal treatment, respectively). The proportion of preferences favored oral administration for both physicians (P=0.0002) and patients (P=0.002). Rectal administration of tramadol appears a reliable, noninvasive alternative method of pain control for patients no longer responsive to non-opioid analgesics, unable to take oral tramadol.


Myotonic dystrophies 1 and 2: complex diseases with complex mechanisms.
Two multi-system disorders, Myotonic Dystrophies type 1 and type 2 (DM1 and DM2), are complex neuromuscular diseases caused by an accumulation of expanded, non-coding RNAs, containing repetitive CUG and CCUG elements. Similarities of these mutations suggest similar mechanisms for both diseases. The expanded CUGn and CCUGn RNAs mainly target two RNA binding proteins, MBNL1 and CUGBP1, elevating levels of CUGBP1 and reducing levels of MBNL1. These alterations change processing of RNAs that are regulated by these proteins. Whereas overall toxicity of CUGn/CCUGn RNAs on RNA homeostasis in DM cells has been proven, the mechanisms which make these RNAs toxic remain illusive. A current view is that the toxicity of RNA CUGn and CCUGn is associated exclusively with global mis-splicing in DM patients. However, a growing number of new findings show that the expansion of CUGn and CCUGn RNAs mis-regulates several additional pathways in nuclei and cytoplasm of cells from patients with DM1 and DM2. The purpose of this review is to discuss the similarities and differences in the clinical presentation and molecular genetics of both diseases. We will also discuss the complexity of the molecular abnormalities in DM1 and DM2 caused by CUG and CCUG repeats and will summarize the outcomes of the toxicity of CUG and CCUG repeats.


Rates and predictors of anti-depressant prescribing in Northern Ireland 2011-2015: a data linkage study using the Administrative Data Research Centre (NI).
Research indicates that anti-depressant prescribing is higher in Northern Ireland (NI) than in the rest of the UK, and that socio-economic and area-level factors may contribute to this. The current study provides comprehensive population-based estimates of the prevalence of anti-depressant prescription prescribing in NI from 2011 to 2015, and examined the associations between socio-demographic, socio-economic, self-reported health and area-level factors and anti-depressant prescription. Data were derived from the 2011 NI Census (N = 1 588 355) and the Enhanced Prescribing Database. Data linkage techniques were utilised through the Administrative Data Research Centre in NI. Prevalence rates were calculated and binary logistic analysis assessed the associations between contextual factors and anti-depressant prescription. From 2011 to 2015, the percentages of the population in NI aged 16 or more receiving anti-depressant prescriptions were 12.3%, 12.9%, 13.4%, 13.9% and 14.3%, respectively, and over the 5-year period was 24.3%. The strongest predictors of anti-depressant prescription in the multivariate model specified were 'very bad' (OR = 4.02) or 'Bad' general health (OR = 3.98), and self-reported mental health problems (OR = 3.57). Other significant predictors included social renting (OR = 1.67) and unemployment (OR = 1.25). Protective factors included Catholic religious beliefs, other faith/philosophic beliefs and no faith/philosophic beliefs in comparison to reporting Protestant/other Christian religious beliefs (ORs = 0.78-0.91). The prevalence of anti-depressant prescription in NI appears to be higher than the prevalence of depressive disorders, although this may not necessarily be attributable to over-prescribing as anti-depressants are also prescribed for conditions other than depression. Anti-depressant prescription was linked to several factors that represent socio-economic disadvantage.


Patient Attitudes Toward Local Anesthesia With or Without Sedation for Minor Hand Procedures.
The purpose of this study was to assess patient preferences in this population with respect to anesthesia for minor hand procedures. This prospective cohort study assessed 183 patients undergoing minor hand surgery to determine their preferences for local-only anesthesia with or without sedation and the reasons for their choices. Fifty-six percent of patients preferred local anesthesia with sedation, 43% preferred local-only anesthesia, and 2% had no preference. Caucasian patients were 2.7 times more likely to choose local-only anesthesia. Other than race, no other demographics showed statistical significance with respect to anesthesia preference. Patients with a prior history of local-only anesthesia were half as likely to choose it again for future surgeries. Use of an IV and awareness of procedure were the most consistent factors affecting patient decisions. Nearly half of the patients preferred local-only anesthesia. Further prospective studies evaluating outcomes and patient satisfaction with these two types of anesthesia are necessary. (Journal of Surgical Orthopaedic Advances 27(4):317-320, 2018).


Overall cancer incidence not increased after prosthetic knee replacement: 14,551 patients followed for 66,622 person-years.
It is unknown whether patients as a consequence of prosthetic joint replacement are at a higher risk of developing cancer. We therefore analyzed cancer incidence following prosthetic knee replacement (TKR). The observed cancer incidence in 14,551 patients from the population-based Swedish Knee Arthroplasty Register who have undergone TKR because of osteoarthrosis (OA, n = 10,120) or rheumatoid arthritis (RA, n = 4431) were compared with the expected cancer incidence for a Swedish reference population. The cohort was followed for a total of 66,622 person-years. We followed 33% of the patients with OA and 59% of those with RA for more than 5 years. All patients who underwent TKR, whether for OA or for RA, had lower than expected total cancer incidence. We found a markedly low incidence of colorectal carcinoma, especially in patients with RA. Our results do not indicate an increased incidence of cancer following TKR.


The effect of Euryale ferox (Makhana), an herb of aquatic origin, on myocardial ischemic reperfusion injury.
Fox nut or gorgon nut (Euryale ferox--Family Nymphaeaceae), popularly known as Makhana, has been widely used in traditional oriental medicine to cure a variety of diseases including kidney problems, chronic diarrhea, excessive leucorrhea and hypofunction of the spleen. Based on the recent studies revealing antioxidant activities of Euryale ferox and its glucosides composition, we sought to determine if Euryale ferox seeds (Makhana) could reduce myocardial ischemic reperfusion injury. Two different models were used: acute model, where isolated rat hearts were preperfused for 15 min with Krebs Henseleit bicarbonate (KHB) buffer containing three different doses of makhana (25, 125 or 250 microg/ml) followed by 30 min of ischemia and 2 h of reperfusion; and chronic model, where rats were given two different doses of makhana (250 and 500 mg/kg/day) for 21 days, after which isolated hearts were subjected to 30 min of ischemia followed by 2 h of reperfusion. In both cases, the hearts of the Makhana treated rats were resistant to ischemic reperfusion injury as evidenced by their improved post-ischemic ventricular function and reduced myocardial infarct size. Antibody array technique was used to identify the cardioprotective proteins. The Makhana-treated hearts had increased amounts of thioredoxin-1 (Trx-1) and thioredoxin-related protein-32 (TRP32) compared to the control hearts. Western blot analysis confirmed increased expression of TRP32 and thioredoxin proteins. In vitro studies revealed that Makhana extracts had potent reactive oxygen species scavenging activities. Taken together, the results of this study demonstrate cardioprotective properties of Makhana and suggest that such cardioprotective properties may be linked with the ability of makhana to induce TRP32 and Trx-1 proteins and to scavenge ROS.


Detection of cardiovascular disease associated miR-29a using paper-based microfluidics and surface enhanced Raman scattering.
The development of viable point-of-care diagnostic formats is integral to achieving better patient care and improved outcomes. The need for robust and low-cost tests is especially important in under-resourced and rural settings. Perhaps the greatest challenge is ensuring that an untrained individual is capable of operating and interpreting the test, out with a care facility. Here we present a paper-based diagnostic device capable of sensing miR-29a using both colorimetric and surface enhanced Raman scattering (SERS) analysis. Rather, than carry out the two types of analyses in tandem, we envisage that the colorimetric output is easy enough to be interpreted by the untrained-individual administering the test to provide them with qualitative feedback. If deemed positive, the test can be further validated at a centralized care facility using a handheld-Raman spectrometer to provide a semi-quantitative result. Detection of miR-29a, a microRNA associated with myocardial infarction, was achieved at a level of pg μL-1 through the combination of three-dimensional paper-based microfluidics, colorimetric detection, and surface enhanced Raman scattering (SERS) analysis. RGB analysis of the colorimetric output generated from samples containing miR-29a at different concentrations (18-360 pg μL-1) showed differentiation from the control sample, however significant repeat variability indicated that it could not be used for quantifying miR-29a levels. However, the SERS analysis exhibited greater reproducibility at varying concentrations, achieving an LoD of 47 pg μL-1. The union of the paper-based device and the two analysis methods resulted in the production of a sensitive, reproducible and facile, point of care test (POCT), which paves the way for future implementation in the diagnosis of a range of diseases.


Msx3 protein recruits histone deacetylase to down-regulate the Msx1 promoter.
Msx1 promoter is known to be repressed by Msx1 protein [Shetty, Takahashi, Matsui, Iyengar and Raghow (1999) Biochem. J. 339, 751-758]. We show that in the transiently transfected C(2)C(12) myoblasts, co-expression of Msx3 also causes potent repression of Msx1 promoter that can be relieved by exogenous expression of cAMP-response-element-binding protein-binding protein (CBP) and p300 in a dose-dependent manner. Co-immunoprecipitation and Western blot analyses revealed that Msx3 interacts with CBP and p300 and this interaction significantly decreases the histone acetyltransferase (HAT) activity of both proteins. We also discovered that Msx3-mediated repression of Msx1 promoter is synergized by the exogenous co-expression of histone deacetylase 1 (HDAC1). Furthermore, the repression of Msx1 promoter by Msx3 could be relieved by treating transfected cells with trichostatin A, an inhibitor of HDAC(s). Finally, we show that Msx3 and HDAC1 can be co-immunoprecipitated in a complex that does not contain CBP and that Msx3 and HDAC1 proteins are co-localized in the nucleus. Taken together, our results strongly suggest that two distinct multiprotein complexes are present within the nuclei of C(2)C(12) cells: one containing Msx3 and HDAC(s) and another containing Msx3 and CBP and/or p300. On the basis of these results, we propose a dual mechanism of repression by Msx3 protein that involves the squelching of the HAT activity of co-activators, CBP and p300, and recruitment of HDAC(s).


The impact of chemical structure and molecular packing on the electronic polarisation of fullerene arrays.
Electronic polarisation contributes to the electronic landscape as seen by separating charges in organic materials. The nature of electronic polarisation depends on the polarisability, density, and arrangement of polarisable molecules. In this paper, we introduce a microscopic, coarse-grained model in which we treat each molecule as a polarisable site, and use an array of such polarisable dipoles to calculate the electric field and associated energy of any arrangement of charges in the medium. The model incorporates chemical structure via the molecular polarisability and molecular packing patterns via the structure of the array. We use this model to calculate energies of charge pairs undergoing separation in finite fullerene lattices of different chemical and crystal structures. The effective dielectric constants that we estimate from this approach are in good quantitative agreement with those measured experimentally in C60 and phenyl-C61-butyric acid methyl ester (PCBM) films, but we find significant differences in dielectric constant depending on packing and on direction of separation, which we rationalise in terms of density of polarisable fullerene cages in regions of high field. In general, we find lattices containing molecules of more isotropic polarisability tensors exhibit higher dielectric constants. By exploring several model systems we conclude that differences in molecular polarisability (and therefore, chemical structure) appear to be less important than differences in molecular packing and separation direction in determining the energetic landscape for charge separation. We note that the results are relevant for finite lattices, but not necessarily for infinite systems. We propose that the model could be used to design molecular systems for effective electronic screening.


Long driving time is associated with haematological markers of increased cardiovascular risk in taxi drivers.
To examine the association between driving time and changes in haematological markers of increased risks for cardiovascular diseases (CVD). The authors conducted a cross sectional analysis of baseline data from the Taxi Drivers' Health Study cohort in Taipei, Taiwan. They retrieved information on comorbidity, laboratory tests, age, and anthropometric measures from medical records of 1157 subjects (mean age 44.6 (SD 8.6) years). Whole blood cell (WBC) count was used as the primary haematological marker for increased CVD risk, and platelet count and haematocrit as the secondary markers. Standardised questionnaires were implemented to collect information on demographics, lifestyle, work related physical and psychosocial factors, and driving time profiles. Multiple regression was used to estimate the adjusted effects of driving time on three haematological markers. The mean measured hematological marker was 6656 (SD 1656) cells x10(6)/l for WBC, 47.2 (SD 3.5) % for hematocrit, and 243 (SD 52) cells x10(9)/l for platelets. The driving time was 264 (SD 76) hours/month. Compared with drivers who drove < or =208 hours/month (1st quartile cut off), drivers who drove >208 hours/month had a higher WBC count (by 317 x10(6)/l; 95% CI 99 to 535), haematocrit (by 0.8%; 95% CI 0.3 to 1.2), and platelets (7.9 x10(9)/l; 95% CI 1.0 to 14.8). After adjusting for conventional CVD risk factors (age, sex, smoking, hypertension, diabetes, and hypercholesterolaemia), obesity, alcohol drinking, regular exercise, and sociodemographics (education, marital status, income, and so on), long driving time was still associated with significant increases in WBC and platelets, whereas the effect on haematocrit was diminished and became statistically non-significant. Additional controls for physical workload, self-perceived job stress, and job dissatisfaction did not alter the associations with increased WBC and platelets. Longitudinal studies are needed to confirm the observed cross sectional association and to further examine the specific occupational exposures accountable for the association between driving time and haematological markers of systemic inflammation and haemostatic alteration.


Similarities and differences between selective and nonselective BAFF blockade in murine SLE.
B cells have multiple roles in immune activation and inflammation separate from their capacity to produce antibodies. B cell depletion is currently under intense investigation as a therapeutic strategy for autoimmune diseases. The TNF family members B cell-activating factor of the TNF family (BAFF) and its homolog A proliferation-inducing ligand (APRIL) are B cell survival and differentiation factors and are therefore rational therapeutic targets. We compared the effects of BAFF receptor-Ig, which blocks only BAFF, with those of transmembrane activator and calcium modulator ligand interactor-Ig, which blocks both BAFF and APRIL, in a murine SLE model. Both reagents prolonged the life of NZB/W F1 mice when given either before or after disease onset. Many immunologic effects of the 2 reagents were similar, including B cell and B cell subset depletion and prevention of the progressive T cell activation and dendritic cell accumulation that occurs with age in NZB/W mice without substantial effects on the emergence of the IgG anti-double-stranded DNA response. Furthermore, both reagents inhibited the T cell-independent marginal zone B cell response to particulate antigen delivered i.v., but not the B1 B cell response to the same antigen delivered i.p. In contrast, blockade of both BAFF and APRIL, but not blockade of BAFF alone, reduced the serum levels of IgM antibodies, decreased the frequency of plasma cells in the spleen, and inhibited the IgM response to a T cell-dependent antigen. The differences between selective and nonselective BAFF blockade are relevant to the choice of a BAFF blocking agent for the treatment of autoimmune and malignant diseases.


The Cumulative Effects of Predictability on Synaptic Gain in the Auditory Processing Stream.
Stimulus predictability can lead to substantial modulations of brain activity, such as shifts in sustained magnetic field amplitude, measured with magnetoencephalography (MEG). Here, we provide a mechanistic explanation of these effects using MEG data acquired from healthy human volunteers (N = 13, 7 female). In a source-level analysis of induced responses, we established the effects of orthogonal predictability manipulations of rapid tone-pip sequences (namely, sequence regularity and alphabet size) along the auditory processing stream. In auditory cortex, regular sequences with smaller alphabets induced greater gamma activity. Furthermore, sequence regularity shifted induced activity in frontal regions toward higher frequencies. To model these effects in terms of the underlying neurophysiology, we used dynamic causal modeling for cross-spectral density and estimated slow fluctuations in neural (postsynaptic) gain. Using the model-based parameters, we accurately explain the sensor-level sustained field amplitude, demonstrating that slow changes in synaptic efficacy, combined with sustained sensory input, can result in profound and sustained effects on neural responses to predictable sensory streams.SIGNIFICANCE STATEMENT Brain activity can be strongly modulated by the predictability of stimuli it is currently processing. An example of such a modulation is a shift in sustained magnetic field amplitude, measured with magnetoencephalography. Here, we provide a mechanistic explanation of these effects. First, we establish the oscillatory neural correlates of independent predictability manipulations in hierarchically distinct areas of the auditory processing stream. Next, we use a biophysically realistic computational model to explain these effects in terms of the underlying neurophysiology. Finally, using the model-based parameters describing neural gain modulation, we can explain the previously unexplained effects observed at the sensor level. This demonstrates that slow modulations of synaptic gain can result in profound and sustained effects on neural activity.


Lung cancer and mesothelioma in the pleura and peritoneum among Swedish insulation workers.
To estimate the risk of cancer and death in Swedish insulation workers some years after their exposure to asbestos had stopped. One hypothesis was that the risk of lung cancer would tend to decrease some years after the exposure had ended. In a cohort study the cancer morbidity and cause of death was investigated in 248 insulation workers and compared with the corresponding morbidity and mortality in the general population. Due to stringent regulations, exposure to asbestos of all types had almost ended in Sweden in the mid-1970s. Through a questionnaire, surviving insulation workers were asked about their exposure to asbestos and their smoking habits. Between 1970 and 1994 there were 86 deaths compared with the 46.0 expected (standardised incidence ratio (SIR) 1.9; 95% confidence interval (95% CI) 1.5 to 2.3), the increase was mainly due to an increased cancer mortality. The morbidity was increased for lung cancer (11 cases v 2.5 expected (SIR 4.4; 95% CI 2.2 to 7.9)), peritoneal mesothelioma (seven cases; no expected incidence could be calculated as the occurrence is too rare in the general population), cancer in pancreas (five cases v 0.7 expected (SIR 7.1; 95% CI 2.3 to 16.7)). No cases of pleural mesothelioma were found. The risk of lung cancer did not tend to approach that of the general population after the exposure to asbestos decreased. In the 1980s and the early 1990s, Swedish insulation workers still have a highly increased risk of diseases related to asbestos. The attributable risk for death and cancer was about 50%. The study also confirms the previous finding that mesothelioma in insulation workers seems to be situated in the peritoneum more often than in the pleura.


Development of Novel Alkoxyisoxazoles as Sigma-1 Receptor Antagonists with Antinociceptive Efficacy.
A novel series of sigma (σ) receptor ligands based on an alkoxyisoxazole scaffold has been designed and synthesized. Preliminary receptor binding assays identified highly potent (Ki < 1 nM) and selective σ1 ligands devoid of binding interactions with the monoamine transporters DAT, NET, and SERT. In particular, compound 53 was shown to possess significant antinociceptive activity in the mouse formalin-induced inflammation pain model when administered intraperitoneally at 40 and 80 mg/kg. Initial pharmacokinetics evaluation indicated an excellent brain exposure following oral dosing in mice, suggesting that further investigation into the use of alkoxyisoxazoles as σ1 ligands for antinociception is warranted. This study supports the notion that selective σ1 antagonism could be a useful strategy in the development of novel antipain therapy.


Endoscopic ultrasound (EUS) guided fine needle biopsy (FNB) with the Procore™ needle provides inadequate material for the histological diagnosis of early chronic pancreatitis.
diagnosis of early chronic pancreatitis (CP) is hampered due to the low accuracy of current imaging techniques and the absence of methods for histological confirmation. We aimed to evaluate the efficacy of endoscopic ultrasound-guided fine needle biopsy (EUS-FNB) for the histological diagnosis of early CP. a prospective, cross-sectional, single-center study was designed. Consecutive patients referred for EUS with a clinical suspicion of CP were evaluated for inclusion into the study. Inclusion criteria were age > 18 years and indeterminate EUS findings for the diagnosis of CP according to the Rosemont classification. EUS-FNB of the body of the pancreas was performed with Procore™ needles. Tissue samples were immersed into a methanol-based buffered preservative solution for cytohistological evaluation. The quality of the samples obtained and the histological findings were evaluated. Procedure-related complications were recorded. the study was stopped after eleven patients were included due to safety concerns and poor diagnostic yield. The mean age of the patients was 50.3 years (range 33-70 years) and six were male. Samples were of poor quality in five cases, but were sufficient for cell-block evaluation. An inflammatory infiltration with mild fibrosis was identified in two cases and neither inflammatory infiltration nor fibrosis was identified in three cases. With regard to the other six cases, isolated inflammatory cells were observed in one case, although the cellularity was poor and unsuitable for cytological evaluation in five cases. There was one major complication (9.1%) of acute pancreatitis that required hospitalization for 48 hours. EUS-FNB is technically feasible in patients with EUS findings categorized as indeterminate for a CP diagnosis. However, the diagnostic yield is poor and there is a non-negligible risk of complications.


Increased expression of toll-like receptor-2 and -4 on leukocytes from patients with sepsis.
The reduced responsiveness of monocytes or granulocytes toward endotoxin (endotoxin tolerance) during sepsis may depend on Toll-like receptors (TLR). The expression of TLR-2 and TLR-4 was measured on neutrophils (PMN) and monocytes from patients with sepsis (n = 21) or healthy controls (n = 12). Leukocytes (1 x 10/mL) were incubated at 37 degrees C with or without a TLR-4 (LPS 1 microg/mL) or a TLR-2 ligand (MALP-2 2 nM). Surface expression of TLR-2 and TLR-4 at 0, 4, and 16 h was determined in FACS after staining with specific antibodies. The release of IL-8 and TNF-alpha was measured by ELISA. Freshly isolated PMN from patients with sepsis exhibited significantly (P < 0.05) higher mean fluorescence for TLR-2 (78.0 +/- 18.6) and TLR-4 (11.4 +/- 2.3) than controls (12.8 +/- 2.2 and 2.3 +/- 0.4). Similarly, monocytes from patients exhibited higher TLR-2 and TLR-4 expression (300.8 +/- 40.6 and 92.7 +/- 12.1) than cells from controls (149.5 +/- 27.1 and 52.2 +/- 7.6). In patients with sepsis, expression of TLR-2 and TLR-4 on PMN increased during 16 h of incubation (106.2 +/- 22.1 and 34.5 +/- 5.3), whereas it remained unchanged in controls (19.3 +/- 6.1 and 5.4 +/- 1.9). Incubation with LPS or MALP-2 had no effect on TLR-4 or TLR-2 expression in cells from either controls or patients. Despite increased TLR expression in cells from patients with sepsis, the endotoxin-induced release of TNF-alpha and IL-8 was indistinguishable from that in controls. Therefore, the endotoxin tolerance seen in patients with sepsis does not depend solely on TLR-2 or TLR-4 expression, and other mechanisms must be involved.


Sporadic Creutzfeldt-Jakob Disease MM1+2C and MM1 are Identical in Transmission Properties.
The genotype (methionine, M or valine, V) at polymorphic codon 129 of the PRNP gene and the type (1 or 2) of abnormal prion protein in the brain are the major determinants of the clinicopathological features of sporadic Creutzfeldt-Jakob disease (CJD), thus providing molecular basis for classification of sporadic CJD, that is, MM1, MM2, MV1, MV2, VV1 or VV2. In addition to these "pure" cases, "mixed" cases presenting mixed neuropathological and biochemical features have also been recognized. The most frequently observed mixed form is the co-occurrence of MM1 and MM2, namely MM1+2. However, it has remained elusive whether MM1+2 could be a causative origin of dura mater graft-associated CJD (dCJD), one of the largest subgroups of iatrogenic CJD. To test this possibility, we performed transmission experiments of MM1+2 prions and a systematic neuropathological examination of dCJD patients in the present study. The transmission properties of the MM1+2 prions were identical to those of MM1 prions because MM2 prions lacked transmissibility. In addition, the neuropathological characteristics of MM2 were totally absent in dCJD patients examined. These results suggest that MM1+2 can be a causative origin of dCJD and causes neuropathological phenotype similar to that of MM1.


Female peers in small work groups enhance women's motivation, verbal participation, and career aspirations in engineering.
For years, public discourse in science education, technology, and policy-making has focused on the "leaky pipeline" problem: the observation that fewer women than men enter science, technology, engineering, and mathematics fields and more women than men leave. Less attention has focused on experimentally testing solutions to this problem. We report an experiment investigating one solution: we created "microenvironments" (small groups) in engineering with varying proportions of women to identify which environment increases motivation and participation, and whether outcomes depend on students' academic stage. Female engineering students were randomly assigned to one of three engineering groups of varying sex composition: 75% women, 50% women, or 25% women. For first-years, group composition had a large effect: women in female-majority and sex-parity groups felt less anxious than women in female-minority groups. However, among advanced students, sex composition had no effect on anxiety. Importantly, group composition significantly affected verbal participation, regardless of women's academic seniority: women participated more in female-majority groups than sex-parity or female-minority groups. Additionally, when assigned to female-minority groups, women who harbored implicit masculine stereotypes about engineering reported less confidence and engineering career aspirations. However, in sex-parity and female-majority groups, confidence and career aspirations remained high regardless of implicit stereotypes. These data suggest that creating small groups with high proportions of women in otherwise male-dominated fields is one way to keep women engaged and aspiring toward engineering careers. Although sex parity works sometimes, it is insufficient to boost women's verbal participation in group work, which often affects learning and mastery.


A silver-alginate-coated dressing to reduce peripherally inserted central catheter (PICC) infections in NICU patients: a pilot randomized controlled trial.
Our aim was to evaluate the safety of a silver-alginate-containing dressing to reduce peripherally inserted central catheter (PICC) infections in neonatal intensive care unit (NICU) patients. Patients were randomized 3:1 to receive a patch containing silver, alginate and maltodextrin or standard of care. Patches were placed under the regular transparent retention dressing at the PICC exit site at insertion and were replaced with every dressing change at least every 2 weeks until PICC discontinuation. All study infants were monitored for adverse skin reactions. A total of 100 infants were followed up for 1922 person-days, including 75 subjects with 89 PICCs who received the patch. The median birth weight (1330 g) and median gestational age (30 weeks) was lower in the patch group when compared with the controls (P=0.001 and 0.005, respectively). Study patients received the patch with their PICC at a median age of 5 days; the patch stayed in place for a median of 13 days. We noted no adverse skin reactions and found no evidence that the patch alters the microbiology of PICC-associated infections. This pilot trial suggests that silver-alginate-coated dressings are skin safe and their inclusion in future trials aimed at reduction of PICC-associated bloodstream infections in the NICU should be considered.


Effects of Inula racemosa root and Gymnema sylvestre leaf extracts in the regulation of corticosteroid induced diabetes mellitus: involvement of thyroid hormones.
The efficacy of Inula racemosa (root) and Gymnema sylvestre (leaf) extracts either alone or in combination was evaluated in the amelioration of corticosteroid-induced hyperglycaemia in mice. Simultaneously thyroid hormone levels were estimated by radio-immunoassay (RIA) in order to ascertain whether the effects are mediated through thyroid hormones or not. While the corticosteroid (dexamethasone) administration increased the serum glucose concentration, it decreased serum concentrations of the thyroid hormones, thyroxine (T4) and triiodothyronine (T3). Administration of the two plant extracts either alone or in combination decreased the serum glucose concentration in dexamethasone induced hyperglycaemic animals. However, the administration of Inula racemosa and Gymnema sylvestre extracts in combination proved to be more effective than the individual extracts. These effects were comparable to a standard corticosteroid-inhibiting drug, ketoconazole. As no marked changes in thyroid hormone concentrations were observed by the administration of any of the plant extracts in dexamethasone treated animals, it is further suggested that these plant extracts may not prove to be effective in thyroid hormone mediated type II diabetes, but for steroid induced diabetes.