Female genital mutilation and skilled birth attendance among women in sub-Saharan Africa.
There is evidence that women who have had their genitals cut suffer substantial difficulties during and/or after childbirth, including the need for a caesarean section, an episiotomy, an extended hospital stay, post-partum bleeding, and maternal fatalities. Whether or not women in sub-Saharan Africa who have undergone female genital mutilation utilize the services of skilled birth attendants during childbirth is unknown. Hence, we examined the association between female genital mutilation and skilled birth attendance in sub-Saharan Africa. The data for this study were compiled from 10 sub-Saharan African countries' most recent Demographic and Health Surveys. In the end, we looked at 57,994 women between the ages of 15 and 49. The association between female genital mutilation and skilled birth attendance was investigated using both fixed and random effects models. Female genital mutilation and skilled birth attendance were found to be prevalent in 68.8% and 58.5% of women in sub-Saharan Africa, respectively. Women with a history of female genital mutilation had reduced odds of using skilled birth attendance (aOR = 0.91, 95% CI = 0.86-0.96) than those who had not been circumcised. In Ethiopia, Guinea, Liberia, Kenya, Nigeria, Senegal, and Togo, women with female genital mutilation had reduced odds of having a trained delivery attendant compared to women in Burkina Faso. This study shed light on the link between female genital mutilation and skilled birth attendance among sub-Saharan African women. The study's findings provide relevant information to government agencies dealing with gender, children, and social protection, allowing them to design specific interventions to prevent female genital mutilation, which is linked to non-use of skilled birth attendance. Also, health education which focuses on childbearing women and their partners are necessary in enhancing awareness about the significance of skilled birth attendance and the health consequences of female genital mutilation.


Multicenter Evaluation of an ELISA for the Detection of Cryptosporidium spp. Antigen in Clinical Human Stool Samples.
Human cryptosporidiosis remains underdiagnosed, and rapid/accurate diagnosis is of clinical importance. Diagnosis of the Cryptosporidium oocyst in stool samples by conventional microscopy is labor-intensive, time-consuming, and requires skillful experience. Thus, we aimed to evaluate the usefulness of a coproantigen enzyme-linked immunosorbent assay (ELISA) test in detecting Cryptosporidium spp. from fecal specimens. For this aim, we evaluated the performances of a commercial ELISA (CoproELISA Cryptosporidium kit, Savyon Diagnostics, Israel) for the detection of Cryptosporidium spp. in random clinical stool samples through a multicenter study. The sensitivity and specificity for coproantigen ELISA were 98.86% and 94.32%, respectively. The coproantigen ELISA results indicate that the simple, rapid, reliable, and standardized immunoassay test is sensitive and specific for routine diagnosis, and may be useful for large-scale epidemiological studies of cryptosporidiosis.


Silver nanoparticles as an antimicrobial agent: A case study on Staphylococcus aureus and Escherichia coli as models for Gram-positive and Gram-negative bacteria.
The current research was focused on the characterization and antimicrobial activity of silver nanoparticles (AgNPs) produced by Bacillus licheniformis NM120-17. The synthesis was initially observed by a colour change from pale yellow to brown which was further confirmed by UV-Vis spectroscopy. The AgNPs were characterized using TEM, EDAX and FTIR. The synthesized nanoparticles were found to be spherical and uniformly distributed with a size in the range of 9-27.5 nm. The antibacterial activities and acting mechanism of AgNPs were studied with respect to Staphylococcus aureus and Escherichia coli by measuring the growth curves, protein and reducing sugar leakage, respiratory chain dehydrogenase activity, as well as the formation of bactericidal reactive oxygen species (ROS). The experimental results indicated that 50 mg/ml AgNPs could completely inhibit the growth of bacterial cells and destroy the permeability of bacterial membranes and depress the activity of some membranous enzymes, which cause bacteria to die eventually. These nontoxic nanomaterials, which can be prepared in a simple and cost-effective manner, may be suitable for the formulation of new types of bactericidal materials.


Rates of intra- and intermolecular electron transfers in hydrogenase deduced from steady-state activity measurements.
Electrons are transferred over long distances along chains of FeS clusters in hydrogenases, mitochondrial complexes, and many other respiratory enzymes. It is usually presumed that electron transfer is fast in these systems, despite the fact that there has been no direct measurement of rates of FeS-to-FeS electron transfer in any respiratory enzyme. In this context, we propose and apply to NiFe hydrogenase an original strategy that consists of quantitatively interpreting the variations of steady-state activity that result from changing the nature of the FeS clusters which connect the active site to the redox partner, and/or the nature of the redox partner. Rates of intra- and intermolecular electron transfer are deduced from such large data sets. The mutation-induced variations of electron transfer rates cannot be explained by changes in intercenter distances and reduction potentials. This establishes that FeS-to-FeS rate constants are extremely sensitive to the nature and coordination of the centers.


Improving the Recovery of Phenolic Compounds from Spent Coffee Grounds (SCG) by Environmentally Friendly Extraction Techniques.
The aim of this study was to investigate and compare the effects of different extraction techniques (high hydrostatic pressure-assisted extraction (HHPE), ultrasound-assisted extraction (UAE), and classical solvent extraction (CSE)) on phenolic compounds from spent coffee grounds (SCG). Different HHPE parameters (300, 400 and 500 MPa at 25 °C for 5, 10 and 15 min) and UAE parameters (40%, 50%, and 60% amplitude at 25 °C for 5, 10 and 15 min) were used. These techniques were compared with CSE (at 50 °C for 30 min) according to total phenolic content (TPC), antioxidant activity (AA), high-performance liquid chromatography (HPLC), scanning electron microscopy (SEM), and infrared (IR) spectroscopy. The results showed that eco-friendly techniques increased the TPC and AA compared to CSE and morphological changes were verified by SEM results. Furthermore, chlorogenic and caffeic acid were also quantified by using HPLC. Chlorogenic acid was found as the main phenolic compound in spent coffee grounds (SCG). The highest chlorogenic acid was detected as 85.0 ± 0.6 mg/kg FW with UAE at 60% amplitude for 15 min. In brief, for the extraction of phenolic compounds from waste SCG eco-friendly techniques such as HHPE and/or UAE were more convenient than CSE.


Quantitative examination of tissue concentration profiles associated with microdialysis.
Spatial solute concentration profiles resulting from in vivo microdialysis were measured in rat caudate-putamen by quantitative autoradiography. Radiolabeled sucrose was included in the dialysate, and the tissue concentration profile measured after infusions of 14 min and 61.5 min in an acute preparation. In addition, the changes in sucrose extraction fraction over time were followed in vivo and in a simple in vitro system consisting of 0.5% agarose. These experimental results were then compared with mathematical simulations of microdialysis in vitro and in vivo. Simulations of in vitro microdialysis agreed well with experimental results. In vivo, the autoradiograms of the tissue concentration profiles showed clear evidence of substantial differences between 14 and 61.5 min, even though the change in extraction fraction was relatively small over that period. Comparison with simulated results showed that the model substantially underpredicted the observed extraction fraction and overall amount of sucrose in the tissue. A sensitivity analysis of the various model parameters suggested a tissue extracellular volume fraction of approximately 40% following probe implantation. We conclude that the injury from probe insertion initially causes disruption of the blood-brain barrier in the vicinity of the probe, and this disruption leads to an influx of water and plasma constituents, causing a vasogenic edema.


[The relationship between coronary collateral circulation and blood high-sensitivity C-reactive protein levels].
We evaluated the relationship between coronary collateral circulation (CCC) and blood high-sensitivity C-reactive protein (hs-CRP) levels in patients with chronic stable coronary artery disease. The study included 104 patients who underwent coronary angiography at least one month after acute coronary event and were found to have total coronary occlusion in at least one major coronary artery. Patients with the diagnosis of acute coronary syndrome within the past month, severe valve disease, systemic disease, systemic inflammatory disease, or a history of coronary surgery or percutaneous coronary intervention were excluded. Collateral circulation was graded according to the Rentrop classification. Grades 0 and 1 were defined as poor, grades 2 and 3 were defined as good CCC. Blood hs-CRP levels were measured 1 to 7 days before coronary angiography. According to the Rentrop classification, CCC was graded as 0 in 10 patients, 1 in 26 patients, 2 in 29 patients, and 3 in 39 patients. Sixty-eight patients (65.4%) had a good CCC, and 36 patients (34.6%) had a poor CCC. The two groups were similar with respect to age, sex, risk factors, medications, localization of the occluded coronary artery, and the number of occluded arteries. However, hs-CRP levels were significantly higher in patients with a poor CCC (median 5.42 mg/dl; range 2.3-9.8 mg/dl) compared to those with a good CCC (median 3.36 mg/dl; range 2.2-9.7 mg/dl, p=0.003). Logistic regression analysis showed that hs-CRP level was a significant predictor exerting an adverse effect on collateral development (β=-320; odds ratio= 0.725; 95% confidence interval 0.587-0.894; p=0.003). Our findings suggest that high hs-CRP level is a significant predictor of poor collateral development in patients with chronic stable coronary artery disease.


Expression and release of adhesion molecules by human acute myelogenous leukemia blasts.
The expression and release of adhesion molecules by acute myelogenous leukemia (AML) blasts was investigated in vitro. For most patients AML blasts expressed relatively low levels of membrane-bound L-selectin and Intercellular adhesion molecule 1 (ICAM-1), but their soluble forms were detected in the supernatants for the majority of patients when AML blasts were cultured in vitro. These in vitro levels of SL-selectin and sICAM-1 were considerably lower than the normal serum levels. Divergent and relatively small alterations in SL-selectin and sICAM-1 levels were usually observed when exogenous growth factors were present during AML blast culture, whereas increased SL-selectin levels were observed after coculture of AML blasts and normal leucocytes. E- and P-selectin were neither expressed nor released by AML blasts. We conclude that AML blasts are a source of soluble adhesion molecules.


Contribution of fruit, vegetables, whole cereals, and legumes to total fibre intake in adult Croatian Dalmatian population.
There is compelling evidence that fruit, vegetables, whole cereals, and legumes make about 80 % of the total food fibre intake and have a potential to help in the prevention of a number of diseases. The aim of our study was to estimate total fibre intake from consumption of this fibre-rich food, partly reported in our earlier study in Croatian adult population. Current data analysis involved a non-probabilistic sample of 1,034 adult participants from Dalmatia, Croatia who responded to a validated food frequency questionnaire between October 2014 and March 2015. We also analysed the sales data obtained from three shopping centres in the Zadar area (Croatian coast) to establish a list of most frequently bought fruit, vegetables, whole cereals, and legumes and to calculate dietary fibre (DF) intake for each of the top-selling items and conversion factors for each food group. We then used these conversion factors to calculate individual total fibre intake (TFI) in our population. It was 11.4 g per person per day, which is less than half the recommended dietary requirements. On average, respondents reported to consume one piece of fruit and one meal of vegetables a day, which is less than half the daily recommendation for either. 25.8 % of respondents reported no consumption of whole cereals at all, and only 0.2 % of the population consumed the recommended 3-5 servings of whole grains or legumes a day. We also observed significantly higher consumption of fruit and whole grains/legumes in women than men. Our findings alert to poor dietary fibre intake in Croatian adult population, which is similar to other western countries and points to issues deeply rooted in these economies. However, our findings may be either an over- or under-estimation and need to be verified through longitudinal research on a wider sample using more precise tools.


Stepped-wedge randomized controlled trial of a novel opioid court to improve identification of need and linkage to medications for opioid use disorder treatment for court-involved adults.
In response to the opioid crisis in New York State (NYS), the Unified Court System developed a new treatment court model-the opioid intervention court-designed around 10 Essential Elements of practice to address the flaws of existing drug courts in handling those with opioid addiction via broader inclusion criteria, rapid screening, and linkage to medications to treat opioid use disorder (MOUD). The new court model is now being rolled out statewide yet, given the innovation of the opioid court, the exact barriers to implementation in different counties with a range of resources are largely unknown. We describe a study protocol for the development and efficacy-test of a new implementation intervention (Opioid Court REACH; Research on Evidence-Based Approaches to Court Health) that will allow the opioid court, as framed by the 10 Essential Elements, to be scaled-up across 10 counties in NYS. Using a cluster-randomized stepped-wedge type-2 hybrid effectiveness-implementation design, we will test: (a) the implementation impact of Opioid Court REACH in improving implementation outcomes along the opioid cascade of care (screening, referral, treatment enrollment, MOUD initiation), and (b) the clinical and cost effectiveness of Opioid Court REACH in improving public health (treatment retention/court graduation) and public safety (recidivism) outcomes. Opioid Court REACH has the potential to improve management of individuals with opioid addiction in the court system via widespread scale-up of the opioid court model across the U.S., should this study find it to be effective.


Impact of health education on active trachoma in hyperendemic rural communities in Ethiopia.
Trachoma is one of the leading preventable causes of blindness worldwide. We evaluate the impact of a health education program on the prevalence of active trachoma in children 3 to 9 years old. Community randomized intervention study. Data were collected by means of cross-sectional surveys before and after intervention. Within 40 rural Ethiopian communities, households were selected at random, and all 3- to 9-year-old children within households were invited for examination. Health education messages broadcast by radio were received by all communities. Nongovernmental organization activities to prevent trachoma, based on the SAFE (surgery for trichiasis, antibiotic treatment, face washing, and environmental improvements) strategy, were received by 30 of the 40 communities. Ten of these communities received enhanced educational messages using videos. Cluster summary measures were compared across surveys and intervention arms. Active trachoma at follow-up was modeled using random-effects logistic regression, adjusting for baseline prevalence and study area variability, at the cluster and individual level. Active trachoma in 3- to 9-year-old children and adult knowledge and behavior related to the nature and transmission of trachoma infection. At baseline, 1410 of 1960 (72%) children examined and, at follow-up, 1289 of 2008 (64%) had active trachoma. The overall reduction in prevalence at cluster level was 8% (95% confidence interval [CI], 4%-12%; P<0.001). There was a statistically significant increase in the awareness of trachoma. After adjustment for area and cluster level baseline prevalence, the odds of active trachoma were reduced in both intervention arms, standard (odds ratio [OR], 0.78; 95% CI, 0.53-1.16) and enhanced (OR, 0.76; 95% CI, 0.48-1.21), compared with the control arm, but not significantly. Overall, there was a small but statistically significant reduction in the prevalence of active trachoma between surveys, but differences between the 3 intervention arms were not statistically significant. Awareness of trachoma control increased in all communities, but there was little change in behavior associated with the transmission of Chlamydia trachomatis. It is therefore unlikely that observed reductions in active trachoma were solely due to health education.


Insect models of central nervous system energy metabolism and its links to behavior.
Neuronal activity requires a vast amount of energy. Energy use in the brain is spatially and temporally dynamic, which reflects the changing activity of the neuronal circuits and might be important for modulating neuronal output. Much recent work has focused on understanding how brain glial cells take up nutrients from circulation and subsequently provide metabolic precursors to neurons. However, within the neurons, modulation of cellular metabolic pathway flux also regulates excitability and signaling. A coherent understanding of the links between energy availability and metabolism, neural signaling, and higher-level phenotypes like behavior requires a synthesis of the understanding of glial and neuronal metabolic dynamics. In the current review, we address this synthesis in the context of insect brain metabolism. Insects not only show evidence of a metabolic division of labor and plasticity in neural metabolism that closely resembles that observed in vertebrate species, there also seem to be direct links between brain metabolic dynamics and behavioral phenotypes. We summarize the current knowledge about the metabolic fuels available to the insect nervous system and how they are transported and distributed to the different neural cell types. We discuss the possibility of an ANLS-like metabolic division of labor between glial cells and neurons, and how it is regulated. We then discuss plasticity in flux through energy metabolic pathways in neurons, how flux is regulated, and how it influences neural signaling. We end by discussing how metabolic dynamics in the glia and neurons may interact to impact signaling.


Assessment of total body water using bioelectrical impedance analysis in neonates receiving intensive care.
To determine the most suitable anthropometric and impedance measures and current frequency for the application of bioelectrical impedance to neonates receiving intensive care; and to derive predictive models for the estimation of total body water. Twenty eight babies (median gestational age 30.5 weeks, range 24-38; median birthweight 1.388 kg, range 0.690-3.510) were each studied once during the first week after birth. Total body water was first measured by the method of dilution of isotopic water (H218O). Bioelectrical measurements were made using the tetrapolar surface electrode method from four main distal limb positions (right hand-right foot; right hand-left foot; left hand-left foot; left hand-right foot), the left upper arm-left thigh position and the left scapula-right buttock position, and using six frequencies ((500, 250, 100, 50, 10 and 5 kHz). Regression models, to predict total body water, which were both independent and dependent of body weight on the day of study, were derived. Resistance readings at 50 kHz obtained from the distal limb positions performed best. There was no difference between the distal limb positions. There was no difference in the goodness of fit of the models when using each of three indices of conductor length, foot, spine and sternum. The model total body water (litres) (TBW) = 0.016 + 0.674 body-weight(kg)-0.038 wt2 + 3.84 foot length (cm)2/resistance (50 kHz in OHMS) performed best, accounting for 99.5% of the variation in TBW, with a 95% prediction interval of 165 ml. The model TBW = 0.144 + 15.518 foot length (cm)2/resistance (50 kHz in ohms) accounted for 96.4% of the variation and had a 95% prediction interval of 420 ml. Bioelectrical impedance analysis is a simple, non-invasive method of estimating total body water in neonates receiving intensive care. It can be applied to both the assessment of changes in body water and body composition.


A novel, neural potential of non-hematopoietic human umbilical cord blood stem cells.
From the time of discovery that among the cord blood mononuclear cell population there are cells capable of changing their fate towards the neural lineage and producing functional neurons and macroglial cells, our attempts have been focused on the understanding of the underlying mechanism of this transition. We have deciphered the first steps of neural stem/progenitor gene induction in aggregating culture of cord blood mononuclear cells, their rapid phenotypic conversion under the influence of neuromorphogenic signals due to mitogen activation and their ability to expand and develop a prototypic, long-living line with neural stem cell properties. Evidence has accumulated that human umbilical cord-derived and neurally committed cells, due to their capacity for self-renewal, multilineage differentiation, plasticity and ability for long-lasting growth in vitro, provide unique material for the cell therapy of a wide spectrum of neurological diseases. The putative regenerating potential of these cord blood-derived neural stem/progenitor cells was evaluated after transplantation in experimental models of brain injury. In spite of initial promising data, the results indicate an urgent need to improve available animal model protocols in order to increase immuno-tolerance toward transplanted human cells.


A statement of the rights of scientists and engineers.
As the Editors of the Biomedical Imaging and Intervention Journal, we are pleased to introduce "The Bill of Rights" written by Dr William Hendee, Chair of the Publication Committee of the International Organization of Medical Physics (IOMP). This document covers the fundamental rights and responsibilities of a scientist - not just medical physicists but the entire biomedical imaging community, including the clinicians and researchers. The simultaneous publication of this document in worldwide leading medical physics and allied journals aims to disseminate these standards to the whole scientific world. We, as part of the wider biomedical imaging science community and as the editors of the biij, are fully committed to ensuring these rights are not infringed by anyone, anywhere.BJJ Abdullah and KH NgEditors, Biomedical Imaging and Intervention Journal.


Antibiotic guidelines lead to reductions in the use and cost of antibiotics in a university hospital.
The object of this study was to improve the use of antibiotics at Aker University Hospital, a 600-bed university hospital. We developed and implemented guidelines for antibiotic treatment and prophylaxis. We describe the impact of these guidelines on the use and cost of antibiotics and evaluate compliance with the guidelines. From 1994 to 1996 there was an 11% reduction in the use of antibacterial agents and a 42% reduction in the use of antifungal agents. The use of broad-spectrum antibiotics was reduced by 23%. The use of penicillin V and G increased by 5%, dikloxacillin/kloxacillin by 46% and erythromycin by 33%. Compared with 1994 values there was a 27% reduction in antibiotic costs in 1995, amounting to US$ 319,300, and a 32% reduction in antibiotic costs in 1996, amounting to US$ 380,000. A point-prevalence investigation conducted 18 months after the introduction of the guidelines indicated that compliance was > 95%. It proved possible to reduce the use of broad-spectrum antibacterial and antifungal agents, with significant cost savings. Point-prevalence studies may be a useful tool to detect deviations from guidelines and provide physicians with educational feedback.


Virtually Transparent TiO2/Polyelectrolyte Thin Multilayer Films as High-Efficiency Nanoporous Photocatalytic Coatings for Breaking Down Formic Acid and for Escherichia coli Removal.
Virtually transparent photocatalytic multilayer films composed of TiO2 nanoparticles and polyelectrolytes were built on model surfaces using layer-by-layer assembly and investigated as photocatalytic nanoporous coatings. Formic acid (HCOOH) and Escherichia coli were used as models for the degradation of gaseous pollutants and for studying antibacterial properties. Positively charged TiO2 nanoparticles were coassembled with negatively charged poly(sodium 4-styrenesulfonate) (NaPSS) which leads to highly transparent nanoscale coatings in which the content of TiO2 particles is controlled mainly by the number of deposition cycles and the enhanced translucency with respect to titania powders is likely due to the presence of the polyelectrolytes in the interstitial space between the particles. Build-up and structural properties of the films were determined by ellipsometry, quartz crystal microbalance (QCM-D, with dissipation monitoring), and UV-vis spectrophotometry in transmission and scanning electron microscopy. Complementary photophysical and activity tests of (PSS/TiO2)n multilayer films were performed in the gas-phase under UV-A light and revealed a peculiar dependence on the number of layer pairs (LPs), corresponding to a clear deviation from the usual observations in photocatalysis with increasing TiO2 amounts. Most notably, a single LP film showed a strongly enhanced HCOOH mineralization and outperformed films with a higher number of LPs, with respect to the quantity of TiO2 catalyst present in the films. It is believed that the high quantum yield (8.1%) of a coating consisting of a single TiO2 layer which is 6-7 times higher than that of a 6-10 LP film could be due to the optimum accessibility of the TiO2 crystallites toward both HCOOH and water molecules. In thicker films, while no detrimental light screening was observed with increasing the number of LPs, diffusion phenomena could cap the efficiency of the access of the pollutant and water to the catalytic surface. Unlike for HCOOH mineralization, three PSS/TiO2 LPs were required for observing a maximum antibacterial activity of the nanocomposite coatings. This is likely due to the fact that micrometer-sized E. coli bacteria do not enter into the interstitial space between the TiO2 particles and require a different surface morphology with respect to the number of active contact points for optimum degradation.


[Mortality in Muggia in the upper Adriatic, from 1886 to 1918.].
Muggia is a town situated between Trieste and Koper in the upper Adriatic. It belonged to the Venetian Republic of San Marco and then, after the Napoleonic Wars, it came under the rule of the Austro-Hungarian Empire. Originally a small fishing village, it experienced industrial and demographic growth with the development of its shipyards, and in this it followed, albeit on a smaller scale, the fate of the nearby city of Trieste. Imperial regulations mandated that parish priests were to serve as civil registrars and that all death records (liber mortuorum) were to report the cause of each death, as communicated by the physician. This article examines the causes of death in the town of Muggia over a fairly homogenous period of time, up to the end of World War I. The main causes of death during this time include infectious diseases, both acute (see the town's contribution to the last cholera epidemic in 1886) and chronic (bronchopulmonary diseases and tuberculosis appear as a constant cause of death over the years). There was the usual high rate of child mortality, as well as workplace accidents or at any rate violent deaths, and a broad range of poorly delineated chronic conditions of diverse origin (neoplastic, malnutritional), which accounted for all those deaths whose definition was no longer of medical concern.


A hybrid attention network with convolutional neural network and transformer for underwater image restoration.
The analysis and communication of underwater images are often impeded by various elements such as blur, color cast, and noise. Existing restoration methods only address specific degradation factors and struggle with complex degraded images. Furthermore, traditional convolutional neural network (CNN) based approaches may only restore local color while ignoring global features. The proposed hybrid attention network combining CNN and Transformer focuses on addressing these issues. CNN captures local features and the Transformer uses multi-head self-attention to model global relationships. The network also incorporates degraded channel attention and supervised attention mechanisms to refine relevant features and correlations. The proposed method fared better than existing methods in a variety of qualitative criteria when evaluated against the public EUVP dataset of underwater images.


Long-term risk of hepatocellular carcinoma mortality in 23220 hospitalized patients treated with micafungin or other parenteral antifungals.
Liver tumours observed in rats exposed to micafungin led to a black box warning upon approval in Europe in 2008. Micafungin's risk for liver carcinogenicity in humans has not been investigated. We sought to describe the risk of fatal hepatocellular carcinoma (HCC) among persons who received micafungin and other parenteral antifungals (PAFs) with up to 12 years of follow-up. We assembled a US multicentre cohort of hospitalized patients who received micafungin or other PAFs between 2005 and 2012. We used propensity score (PS) matching on patient characteristics from electronic medical records to compare rates of HCC mortality identified through the National Death Index though to the end of December 2016. We computed HRs and 95% CIs. A total of 40110 patients who received a PAF were identified; 6903 micafungin recipients (87% of those identified) were successfully matched to 16317 comparator PAF users. Ten incident HCC deaths, one in the micafungin-exposed group and nine among comparator PAF users, occurred in 71285 person-years of follow-up. The HCC mortality rate was 0.05 per 1000 person-years in micafungin patients and 0.17 per 1000 person-years in comparator PAF patients. The PS-matched HR for micafungin versus comparator PAF was 0.29 (95% CI 0.04-2.24). Both micafungin and comparator PAFs were associated with HCC mortality rates of <0.2 per 1000 person-years. Given the very low event rates, any potential risk for HCC should not play a role in clinical decisions regarding treatment with micafungin or other PAFs investigated in this study.


A nutrient-tunable bistable switch controls motility in Salmonella enterica serovar Typhimurium.
Many bacteria are motile only when nutrients are scarce. In contrast, Salmonella enterica serovar Typhimurium is motile only when nutrients are plentiful, suggesting that this bacterium uses motility for purposes other than foraging, most likely for host colonization. In this study, we investigated how nutrients affect motility in S. enterica and found that they tune the fraction of motile cells. In particular, we observed coexisting populations of motile and nonmotile cells, with the distribution being determined by the concentration of nutrients in the growth medium. Interestingly, S. enterica responds not to a single nutrient but apparently to a complex mixture of them. Using a combination of experimentation and mathematical modeling, we investigated the mechanism governing this behavior and found that it results from two antagonizing regulatory proteins, FliZ and YdiV. We also found that a positive feedback loop involving the alternate sigma factor FliA is required, although its role appears solely to amplify FliZ expression. We further demonstrate that the response is bistable: that is, genetically identical cells can exhibit different phenotypes under identical growth conditions. Together, these results uncover a new facet of the regulation of the flagellar genes in S. enterica and further demonstrate how bacteria employ phenotypic diversity as a general mechanism for adapting to change in their environment. Many bacteria employ flagella for motility. These bacteria are often not constitutively motile but become so only in response to specific environmental cues. The most common is nutrient starvation. Interestingly, in Salmonella enterica serovar Typhimurium, nutrients enhance the expression of flagella, suggesting that motility is used for purposes other than foraging. In this work, we investigated how nutrients affect motility in S. enterica and found that nutrients tune the fraction of motile cells within a population. Using both experimental and mathematical analysis, we determined the mechanism governing this tunable response. We further demonstrated that the response is bistable: that is, genetically identical cells can exhibit different phenotypes under identical growth conditions. These results reveal a new facet of motility in S. enterica and demonstrate that nutrients determine not only where these bacteria swim but also the fraction of them that do so.


The role of telomeres and telomerase in the pathology of human cancer and aging.
Cellular senescence, the state of permanent growth arrest, is the inevitable fate of replicating normal somatic cells. Postulated to underlie this finite replicative span is the physiology of telomeres, which constitute the ends of chromosomes. The repetitive sequences of these DNA-protein complexes progressively shorten with each mitosis. When the critical length is bridged, telomeres trigger DNA repair and cell cycle checkpoint mechanisms that result in chromosomal fusions, cell cycle arrest, senescence and/or apoptosis. Should senescence be bypassed at such time, continued cell divisions in the face of dysfunctional telomeres and activated DNA repair machinery can result in the genomic instability favourable for oncogenesis. The longevity and malignant progression of the thus transformed cell requires coincident telomerase expression or other means to negate the constitutional telomeric loss. Practically then, telomeres and telomerase may represent plausible prognostic and screening cancer markers. Furthermore, if the argument is extended, with assumptions that telomeric attrition is indeed the basis of cellular senescence and that accumulation of the latter equates to aging at the organismal level, then telomeres may well explain the increased incidence of cancer with human aging.


Solvent-free, uncatalyzed asymmetric "ene" reactions of N-tert-butylsulfinyl-3,3,3-trifluoroacetaldimines: a general approach to enantiomerically pure α-(trifluoromethyl)tryptamines.
A novel approach to regioselectively substituted and stereoselectively α-trifluoromethylated tryptamines is reported based on the ene reaction of Boc-protected 3-methyleneindolines with optically pure (R)- or (S)-tert-butanesulfinyltrifluoroacetaldimine. Boc- and sulfinylamido-protected α-trifluoromethyltryptamines are obtained in 60-70% yield and 85/15 dr by just heating equimolar amounts of the two reaction partners at 80-90 °C for 2-3 h without a solvent. The absolute configuration of the amino α-carbon has been assigned based on the vibrational circular dichroism (VCD) spectral analysis. The two protecting group can be chemoselectively removed allowing further regio- and stereoselective elaboration of the ene products to various biologically interesting compounds.


Development and Pilot Testing of a Healthy Eating Video-Supported Program for Adults with Developmental Disabilities.
Video technology is a potentially effective means to teach individuals with developmental disabilities (DD) about healthy eating. Research in this area, however, is relatively unexplored. This study developed and tested a video intervention to teach healthy eating to adults with DD. A 5-segment educational video, an accompanying workbook, and a facilitator guide were developed to teach basic healthy eating concepts to adults with DD. Twelve adults with DD took part in a 5-week educational program led by trained facilitators using the materials created. Pre- and posttests were used to measure knowledge gained from participating in the intervention. Seventy-five percent (n = 9) of participants improved their knowledge scores, 8% (n = 1) maintained residue knowledge, and 17% (n = 2) had a decrease in their score. Video instructions can be an effective intervention modality to increase knowledge in adults with DD about healthy eating. Key enablers identified for participants' knowledge gain included video content developed based on the learning need and cognitive level of intended users; program delivered by facilitators trained in effective teaching strategies; and engaging the participants' staff, family, and caregivers to provide ongoing reinforcement about healthy eating.


Intramolecular methionine alkylation constructs sulfonium tethered peptides for protein conjugation.
Continuous efforts have been invested in the selective modification of proteins. Herein, we first report the construction of sulfonium tethered cyclic peptides via an intramolecular cyclization by an aliphatic halide. This cyclization could enhance the stability and cellular uptake of peptides. Furthermore, the sulfonium center could be recognized by cysteine in the vicinity of the protein-peptide interacting interface and form a peptide-protein conjugate.


Vitamin D deficiency induces high blood pressure and accelerates atherosclerosis in mice.
Multiple epidemiological studies link vitamin D deficiency to increased cardiovascular disease (CVD), but causality and possible mechanisms underlying these associations are not established. To clarify the role of vitamin D-deficiency in CVD in vivo, we generated mouse models of diet-induced vitamin D deficiency in two backgrounds (LDL receptor- and ApoE-null mice) that resemble humans with diet-induced hypertension and atherosclerosis. Mice were fed vitamin D-deficient or -sufficient chow for 6 weeks and then switched to high fat (HF) vitamin D-deficient or -sufficient diet for 8-10 weeks. Mice with diet-induced vitamin D deficiency showed increased systolic and diastolic blood pressure, high plasma renin, and decreased urinary sodium excretion. Hypertension was reversed and renin was suppressed by returning chow-fed vitamin D-deficient mice to vitamin D-sufficient chow diet for 6 weeks. On a HF diet, vitamin D-deficient mice had ~2-fold greater atherosclerosis in the aortic arch and ~2-8-fold greater atherosclerosis in the thoracic and abdominal aorta compared to vitamin D-sufficient mice. In the aortic root, HF-fed vitamin D-deficient mice had increased macrophage infiltration with increased fat accumulation and endoplasmic reticulum (ER) stress activation, but a lower prevalence of the M1 macrophage phenotype within atherosclerotic plaques. Similarly, peritoneal macrophages from vitamin D-deficient mice displayed an M2-predominant phenotype with increased foam cell formation and ER stress. Treatment of vitamin D-deficient mice with the ER stress reliever PBA during HF feeding suppressed atherosclerosis, decreased peritoneal macrophage foam cell formation, and downregulated ER stress proteins without changing blood pressure. Thus, we suggest that vitamin D deficiency activates both the renin angiotensin system and macrophage ER stress to contribute to the development of hypertension and accelerated atherosclerosis, highlighting vitamin D replacement as a potential therapy to reduce blood pressure and atherosclerosis.


The Effects of Non-Pharmaceutical Interventions on COVID-19 Epidemic Growth Rate during Pre- and Post-Vaccination Period in Asian Countries.
There is little knowledge about how the influence of non-pharmaceutical interventions (NPIs) reduces the COVID-19 infection rate during the period of vaccine rollout. This study aimed to examine the effectiveness of NPIs on decreasing the epidemic growth of COVID-19 between before and after the vaccine rollout period among Asian countries. Our ecological study included observations from 30 Asian countries over the 20 weeks of the pre- and post-vaccination period. Data were extracted from the Oxford COVID-19 Government Response Tracker and other open databases. Longitudinal analysis was utilized to evaluate the impacts of public health responses and vaccines. The facial covering policy was the most effective intervention in the pre-vaccination period, followed by border control and testing policies. In the post-vaccination period, restrictions on gatherings and public transport closure both play a key role in reducing the epidemic growth rate. Vaccine coverage of 1-5%, 5-10%, 10-30%, and over 30% of the population was linked with an average reduction of 0.12%, 0.32%, 0.31%, and 0.59%, respectively. Our findings support the evidence that besides the vaccine increasingly contributing to pandemic control, the implementation of NPIs also plays a key role.


Variations in the functional electrical coupling between the subendocardial Purkinje and ventricular layers of the canine left ventricle.
Action potential propagation from the subendocardial Purkinje network into the ventricular muscle is an essential link in cardiac activation. Studies of papillary muscles have indicated that ventricular muscle activation by the Purkinje network occurs only at discrete, localized regions near the papillary muscle base. Over the rest of the endocardial surface, however, the spatial distribution of these subendocardial Purkinje to ventricular muscle connections has been less well defined. We therefore studied in vitro 12 canine left ventricular preparations (eight from the septum, four from the lateral wall), using a high-density (1-mm spacings), high-resolution extracellular mapping technique to determine the subendocardial Purkinje and ventricular muscle activation sequences. These studies show that the distribution of subendocardial Purkinje to ventricular muscle electrical coupling is spatially inhomogeneous, and that the junctional regions themselves have variable degrees of electrical coupling. We also attempted to determine whether ventricular muscle coupling to the Purkinje network might influence Purkinje network conduction velocity. We found that on the papillary muscle apex, a region without direct Purkinje to ventricular muscle propagation, Purkinje network conduction velocity was slowed, suggesting that the Purkinje network might be electrically loaded by the underlying ventricular muscle. Finally, we performed numerical simulations using a model consisting of two layers of excitable cells to evaluate the effects that different electrical coupling patterns and/or different coupling resistivities between the two layers might have on activation of each layer. These simulation studies suggest that a coupling pattern having discrete junctional sites between the two layers (similar to our findings for subendocardial Purkinje to ventricular muscle coupling) is beneficial, as this arrangement allows more rapid activation of both layers by minimizing electrical loading of the thin Purkinje layer by the thicker ventricular muscle layer.


Associations between antibiotic exposure and abnormal cardiac enzyme profiles in older Chinese adults.
Biomonitoring methods can be used to measure exposure to antibiotics in the general population; however, epidemiological data on the associations between urinary antibiotic levels and the cardiac profiles of enzymes lactate dehydrogenase, creatine kinase, and creatine kinase isoenzyme in older adults remain sparse. We investigated these associations in 990 individuals from the Cohort of Elderly Health and Environment Controllable Factors. Antibiotic residues in urine samples were analyzed using high-performance liquid chromatography-tandem mass spectrometry. Urinary levels of 34 antibiotics were measured. The participants' cardiac enzyme profiles were influenced by sex, age, marital status, education level, cohabitation status, physical activity, dietary structure, body mass index, depression presence and salt, sugar, and oil consumption (P < 0.05). Oxytetracycline, tetracycline, doxycycline, sulfaclozine, and, florfenicol concentrations were negatively associated with the risk of having an abnormal cardiac enzyme profile. Older adults exposed to higher concentrations of norfloxacin had a higher risk of LDH anomalies. After antibiotics were classified, we identified associations between exposure to chloramphenicols, sulfonamides, or veterinary antibiotics and a lower risk of having an abnormal cardiac enzyme profile. Obtaining an accurate epidemiological profile of antibiotic exposure is indispensable for the prevention and detection of cardiac enzyme profile abnormalities in older adults.


Patient-reported Outcomes in Practice: Clinicians' Perspectives From an Inpatient Psychiatric Setting.
The use of patient-reported outcomes (PROs) has become increasingly common. They have been used to assess quality of care and to support policy decisions, but the evidence concerning their utility to improve patient outcomes is inconsistent. A better understanding of clinicians' experience with PROs has the potential to improve their effectiveness. This exploratory, quantitative, and qualitative study investigated the perspectives of clinicians (N=70) from multiple disciplines (psychiatrists, psychologists, social workers, and psychiatric nurses) on the utility of PROs in an inpatient psychiatric setting. During scheduled, monthly, discipline-specific administrative meetings, clinicians in attendance completed a 1-time, 5-item survey. The highest rated item related to the frequency of reviewing outcomes reports; this item was rated higher than all other items (mean±SD, 4.5±1.5), which 37.5% of the participants in the overall sample stated they "always" did. The lowest rated item related to the frequency of conveying the results of the outcomes reports to patients (3.3±1.9), which 20% of participants reported "always" doing; this item was rated lower than all other items (P<0.03). Qualitative analyses were based on 30 comments from 22 clinicians, which resulted in the emergence of 6 themes. The 2 themes that received the highest number of comments related to: (1) the sensitivity and specificity of measures across the PROs platform and (2) the value of the reports in directly influencing treatment decisions. Clinicians' relatively favorable perspective of PROs in practice in this study may be related to the assessment-oriented culture at the study institution. Nonetheless, many barriers to the routine use of PROs exist. Addressing clinician concerns has the potential to improve utilization of this facet of good clinical care.


Furthering development of the Eating Disorder Examination-Pregnancy Version (EDE-PV): Exploratory factor analysis and psychometric performance among a community sample of pregnant individuals with body mass index ≥ 25.
Psychometrically sound measures of disordered eating during pregnancy are needed, particularly for pregnant individuals with body mass index (BMI) ≥ 25, who are at high risk for disordered eating attitudes/behaviors. We previously adapted the Eating Disorder Examination (EDE) for use among pregnant individuals with BMI ≥ 25. This study examined the factor structure of the EDE-Pregnancy Version (EDE-PV) in a community sample of pregnant individuals with BMI ≥ 25. The EDE-PV was administered to 257 pregnant individuals with pre-pregnancy BMI ≥ 25 between 12 and 20 weeks gestation. The EDE-PV factor structure was determined using an exploratory factor analysis with oblique geomin rotation, internal consistency coefficients were calculated, and convergent and discriminant validity of the EDE-PV factors were assessed. An 11-item, two-factor solution produced an acceptable model fit. The subscales did not replicate those of the EDE and were interpreted as Pregnancy Eating and Weight Change Concerns and Pregnancy Shape and Weight Concerns (αs=.67 and .85; ωs=.70 and .85, respectively). These subscales showed small-to-moderate, positive correlations with weight and psychosocial distress measures and differentiated between participants with and without lifetime histories of any eating disorder diagnosis, demonstrating adequate convergent and discriminant validity. The results indicate that the EDE-PV can more reliably identify factors associated with disordered eating attitudes/behaviors among pregnant individuals with BMI ≥ 25 compared to the EDE and support our call for the development and use of new and/or adapted measures to appropriately assess disordered eating during pregnancy.


Antibiotic resistance in the ECOR collection: integrons and identification of a novel aad gene.
The 72 Escherichia coli strains of the ECOR collection were examined for resistance to 10 different antimicrobial agents including ampicillin, tetracycline, mercury, trimethoprim, and sulfonamides. Eighteen strains were resistant to at least one of the antibiotics tested, and nearly 20% (14 of 72) were resistant to two or more. Several of the resistance determinants were shown to be carried on conjugative elements. The collection was screened for the presence of the three classes of integrons and for the sul1 gene, which is generally associated with class 1 integrons. The four strains found to carry a class 1 integron also had Tn21-encoded mercury resistance. One of the integrons encoded a novel streptomycin resistance gene, aadA7, with an attC site (or 59-base element) nearly identical to the attC site associated with the qacF gene cassette found in In40 (M.-C. Ploy, P. Courvalin, and T. Lambert, Antimicrob. Agents Chemother. 42:2557-2563, 1998). The conservation of associated attC sites among unrelated resistance cassettes is similar to arrangements found in the Vibrio cholerae superintegrons (D. Mazel, B. Dychinco, V. A. Webb, and J. Davies, Science 280:605-608, 1998) and supports the hypothesis that resistance cassettes are picked up from superintegron pools and independently assembled from unrelated genes and related attC sites.


Novel guanidine-containing molecular transporters based on lactose scaffolds: lipophilicity effect on the intracellular organellar selectivity.
We have synthesized two lactose-based molecular transporters, each containing seven guanidine residues attached to the lactose scaffold through omega-aminocarboxylate linker chains of two different lengths, and have examined their cellular uptakes and intracellular and organellar localizations in HeLa cells, as well as their tissue distributions in mice. Both molecular transporters showed higher cellular uptake efficiencies than Arg8, and wide tissue distributions including the brain. Mitochondrial localization is of special interest because of its potential relevance to "mitochondrial diseases". Interestingly, it has been found that the intracellular localization sites of the G7 molecular transporters-namely either mitochondria or lysosomes and endocytic vesicles-are largely determined by the linker chain lengths, or their associated lipophilicities.


Comparison of two calcium antagonists, verapamil and gallopamil (D-600), in exercise-induced asthma.
The effect of inhaled verapamil and gallopamil (estimated dose 3 mg) was studied in 10 patients with exercise-induced asthma. Saline was used as a control. Verapamil and gallopamil modified exercise-induced asthma in 8 of the 10 patients and the degree of inhibition with both the drugs was comparable. Gallopamil, which is a more potent vascular smooth muscle calcium antagonist when compared to verapamil, failed to show a greater protective effect in exercise-induced asthma in the patients studied.


Dietary Characteristics of Elders with Frailty and with Mild Cognitive Impairment: Cross-Sectional Findings and Implications from the Nutrition and Health Survey in Taiwan 2014-2017.
It is unclear whether low dietary intake accompanied with multiple nutrient deficiencies or specific nutrient inadequacy is associated with geriatric syndrome. This study aimed to examine the nutrition inadequacy profiles associated with frailty and cognitive impairment (CI). With information from the Nutrition and Health Survey in Taiwan, 2014-2017, sex-specific nutrient intakes and intake per kg of body weight (BW) were estimated from 24-hour recall data for two age groups (65-74 years; ≥75 years) regarding the three frailty and three CI subgroups. Total energy intakes were significantly lower with the severity of both frailty and CI in analysis combining both gender and age groups, and in both the 65-to-74-year-old women or the over-75-year-old women. These trends were observed but not significant in either of the two age groups in men. Significantly lower levels of energy intake have been observed when age, sex, and sampling strata were adjusted. Intake levels of multiple nutrients also decreased with the severity of frailty and CI. A greater number of nutrient inadequacies for the frail and the CI was found in the 65-to-74-year-old group than the over-75-year-old age group. However, most of the associations between micronutrients and the two geriatric syndromes disappeared after energy adjustment. The remaining few did not show consistency across age-sex subgroups. In conclusion, frailty or CI was associated with low amounts of food consumption accompanied by multiple nutrient insufficiencies. Dietary intervention to ensure adequate total energy and multiple nutrient intakes should be trialed in the geriatric population to address both the causal and efficacy issues.


Murine hematopoietic progenitor cells with colony-forming or radioprotective capacity lack expression of the beta 2-integrin LFA-1.
Recently, we have demonstrated that antibodies that block the function of the beta2-integrin leukocyte function-associated antigen-1 (LFA-1) completely abrogate the rapid mobilization of hematopoietic progenitor cells (HPC) with colony-forming and radioprotective capacity induced by interleukin-8 (IL-8) in mice. These findings suggested a direct inhibitory effect of these antibodies on LFA-1-mediated transmigration of stem cells through the bone marrow endothelium. Therefore, we studied the expression and functional role of LFA-1 on murine HPC in vitro and in vivo. In steady state bone marrow +/- 50% of the mononuclear cells (MNC) were LFA-1(neg). Cultures of sorted cells, supplemented with granulocyte colony-stimulating factor (G-CSF)/granulocyte-macrophage colony-stimulating factor (GM-CSF)/IL-1/IL-3/IL-6/stem cell factor (SCF) and erythropoietin (EPO) indicated that the LFA-1(neg) fraction contained the majority of the colony-forming cells (CFCs) (LFA-1(neg) 183 +/- 62/7,500 cells v LFA-1(pos) 29 +/- 17/7,500 cells, P <.001). We found that the radioprotective capacity resided almost exclusively in the LFA-1(neg) cell fraction, the radioprotection rate after transplantation of 10(3), 3 x 10(3), 10(4), and 3 x 10(4) cells being 63%, 90%, 100%, and 100% respectively. Hardly any radioprotection was obtained from LFA-1(pos) cells. Similarly, in cytokine (IL-8 and G-CSF)-mobilized blood, the LFA-1(neg) fraction, which comprised 5% to 10% of the MNC, contained the majority of the colony-forming cells, as well as almost all cells with radioprotective capacity. Subsequently, primitive bone marrow-derived HPC, represented by Wheat-germ-agglutinin (WGA)+/Lineage (Lin)-/Rhodamine (Rho)- sorted cells, were examined. More than 95% of the Rho- cells were LFA-1(neg). Cultures of sorted cells showed that the LFA-1(neg) fraction contained all CFU. Transplantation of 150 Rho- LFA-1(neg) or up to 600 Rho-LFA-1(pos) cells protected 100% and 0% of lethally irradiated recipient mice, respectively. These results show that primitive murine HPC in steady-state bone marrow and of cytokine-mobilized blood do not express LFA-1.


T-type calcium channels: functional regulation and implication in pain signaling.
Low-voltage-activated T-type Ca(2+) channels (T-channels), especially Cav3.2 among the three isoforms (Cav3.1, Cav3.2, and Cav3.3), are now considered to play pivotal roles in processing of pain signals. Cav3.2 T-channels are functionally modulated by extracellular substances such as hydrogen sulfide and ascorbic acid, by intracellular signaling molecules including protein kinases, and by glycosylation. Cav3.2 T-channels are abundantly expressed in both peripheral and central endings of the primary afferent neurons, regulating neuronal excitability and release of excitatory neurotransmitters such as substance P and glutamate, respectively. Functional upregulation of Cav3.2 T-channels is involved in the pathophysiology of inflammatory, neuropathic, and visceral pain. Thus, Cav3.2 T-channels are considered to serve as novel targets for development of drugs for treatment of intractable pain resistant to currently available analgesics.


Clinical presentation of two β-thalassemic Indian patients with 1p36 deletion syndrome: Case report.
Here, we present two thalassemic patients (one male and one female), having unusual clinical phenotypes. Both had mental retardation in which one was associated with microcephaly and other had congenital cataract. They were referred to our institute for clinical evaluation and cytogenetic testing. Both patients were tested for presence of abnormal hemoglobin by high performance liquid chromatography and found to be thalassemic. Their β-globin mutation was also determined by amplification refractory mutation system-polymerase chain reaction. The male patient was found to have intervening sequence 1-5 (G-C)/+, indicating β-thalassemia trait and the female was found to have Cod 26 (G-A)/IVS 1-5 (G-C), indicating hemoglobin E-β thalassemia. Their cytogenetic analysis of blood lymphocytes were studied with high-resolution GTG-banding analysis by using chromosome profiling (Cyto-vision software 3.6) on their chromosomes. Results revealed 46,XY,del(1)(p36.21) in the male and 46,XX,del(1)(p36.3) in the female. Their genotype variation showed (based on genome browser) significant gene loss which probably leads to marked phenotype variation. We believe, thalassemia with mental retardation associated with microcephaly and congenital cataract, both having loss in chromosome 1, p36 position, is reported probably first time from India. This report will definitely enlighten all concerns and add to the information in growing literature.


Timing of automatic contralateral groin exploration in male infants with unilateral hernias.
The effect of using 6 months as the cutoff age for automatic exploration of the asymptomatic contralateral side in male infants undergoing inguinal herniorrhaphy was studied by evaluating the operative findings and follow-up of 300 consecutive male infants admitted for symptomatic unilateral groin hernias. Males under the age of 6 months were automatically explored on the contralateral asymptomatic side. Those between 6 and 24 months underwent repair of only the symptomatic presenting side. The negative exploration rate in the 121 infants less than 6 months was 38 per cent. The return rate for contralateral exploration in children between 6 months and 2 years was 1 per cent. Follow-up ranged from 1 to 5 years. This data suggests that lowering the age for automatic exploration of the male contralateral groin to 6 months does not increase the rate of positive findings on the asymptomatic side. Nor does it appreciably increase the rate of later required contralateral operations.


Relative Validity and Reproducibility of an Interviewer Administered 14-Item FFQ to Estimate Flavonoid Intake Among Older Adults with Mild-Moderate Dementia.
There is a large burden on researchers and participants when attempting to accurately measure dietary flavonoid intake using dietary assessment. Minimizing participant and researcher burden when collecting dietary data may improve the validity of the results, especially in older adults with cognitive impairment. A short 14-item food frequency questionnaire (FFQ) to measure flavonoid intake, and flavonoid subclasses (anthocyanins, flavan-3-ols, flavones, flavonols, and flavanones) was developed and assessed for validity and reproducibility against a 24-hour recall. Older adults with mild-moderate dementia (n = 49) attended two interviews 12 weeks apart. With the assistance of a family carer, a 24-h recall was collected at the first interview, and the flavonoid FFQ was interviewer-administered at both time-points. Validity and reproducibility was assessed using the Wilcoxon signed-rank sum test, Spearman's correlation coefficient, Bland-Altman Plots, and Cohen's kappa. Mean flavonoid intake was determined (FFQ1 = 795 ± 492.7 mg/day, 24-h recall = 515.6 ± 384.3 mg/day). Tests of validity indicated the FFQ was better at estimating total flavonoid intake than individual flavonoid subclasses compared with the 24-h recall. There was a significant difference in total flavonoid intake estimates between the FFQ and the 24-h recall (Wilcoxon signed-rank sum p < 0.001; Bland-Altman plots indicated large bias and wide limits of agreement), but they were well correlated (Spearman's correlation coefficient r = 0.74, p < 0.001; Cohen's kappa κ = 0.292, p < 0.001). The FFQ showed good reproducibility, with a small mean percentage difference (12.6%). The Wilcoxon signed-rank sum test showed no significant difference, Spearman's correlation coefficient indicated excellent reliability (r = 0.75, p < 0.001), Bland-Altman plots visually showed small, nonsignificant bias and wide limits of agreement, and Cohen's kappa indicated fair agreement (κ = 0.429, p < 0.001). A 14-item FFQ developed to easily measure flavonoid intake in older adults with dementia demonstrates fair validity against a 24-h recall and good reproducibility.


Cutting edge issues in the Churg-Strauss syndrome.
Churg-Strauss syndrome (CSS) is a rare systemic small-vessel vasculitis that develops in the background of bronchial asthma, which is characterized by eosinophilia and eosinophilic infiltration of various tissues. It belongs to the group of antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitides. The triggering factors and pathogenesis of CSS are still unknown. The possible role of eotaxin-3 and CCR4-related chemokines in selective recruitment of eosinophils to the target tissues in CSS has been recently suggested, but the role of eosinophilic inflammation in the development of vasculitic lesions is not completely understood. From the clinical view, two distinct phenotypes of the disease are slowly emerging depending on the ANCA-positivity status. Glucocorticoids are still the mainstay of treatment; however, data are accumulating regarding the beneficial role of novel immunosuppressants and biologic compounds, especially in patients with poorer prognosis.


[Blood-brain barrier evaluation in bone marrow transplantation].
The blood-brain barrier (BBB) contributes to the central nervous system (CNS) immunological isolation. BBB has never been studied in patients who developed chronic graft-versus-host disease (GVHD) after allogeneic bone marrow transplants (BMT), from HLA identical related donors. BBB disruption was investigated through the cerebrospinal fluid (CSF) proteins, quantitative and graphically, in order to detect the incidence and possible pathophysiology of the CNS involvement in chronic GVHD. Thirty three CSF and matched serum samples from chronic myeloid leukemia patients were collected pre BMT pos BMT and during chronic GVHD. There was no evidence of BBB disruption in any patient studied.


Polarization-insensitive subwavelength sharp bends in asymmetric metal/multi-insulator configuration.
A new silicon-based sharp waveguide bend in asymmetric metal/multi-insulator configuration is described. TE and TM modes are calculated rigorously electromagnetically from which the general design rules are derived. Numerical simulations show that the respective insertion losses of < 0.085 dB and < 0.229 dB for TE and TM modes can be achieved by introducing a low-index layer between the metal and high-index core. The bending length is determined by the TE mode and has much smaller impacts on the TM that exhibits no resonance-like behavior as does the TE. The combined TE modal and radiation power in the air region is shown to couple back to the Si core through an asymmetric output taper, yielding a high transmission efficiency. Structure-enabled successive photonic-plamsonic mode conversions are shown to increase the TM mode confinement in the high-index core while the plasmonic mode carries up to 42.6% of the input power along the bending section.


[Coronary angioplasty in elderly patients].
The value of coronary angioplasty in elderly patients with angina pectoris is disputed. We studied the effects of coronary angioplasty in patients more than 70 years of age during a four-year follow-up. Successful coronary angioplasty was done in 136 patients with the age 70-83 years. All patients had high-grade angina, and 58% had multivessel disease. One procedure-related death occurred. The symptomatic effect of coronary angioplasty was good and persisting during the follow-up period. Additional revascularizations were done in 23% of the patients, most of these in the first year due to restenosis. Complete revascularization was done in 54%. After four years, 88% of the patients were alive. In selected elderly patients coronary angioplasty can be performed safely and provides good symptomatic relief and favourable long-term outcome. There is need for additional revascularizations especially during the first year, mainly because of restenosis.


Lipid domains in bacterial membranes and the action of antimicrobial agents.
There has been increasing interest in recent years in describing the lateral organization of membranes and the formation of membrane domains. Much of the focus in this area has been on the formation of cholesterol-rich domains in mammalian membranes. However, it is likely that there are domains in all biological membranes. One of the challenges has been to define the chemical composition, lifetime and size of these domains. There is evidence that bacteria have domains that are enriched in cardiolipin. In addition, the formation of lipid domains can be induced in bacteria by clustering negatively charged lipids with polycationic substances. Many antimicrobial compounds have multiple positive charges. Such polycationic compounds can sequester anionic lipids to induce lipid phase separation. The molecular interactions among lipids and their lateral packing density will be different in a domain from its environment. This will lead to phase boundary defects that will lower the permeability barrier between the cell and its surroundings. The formation of these clusters of anionic lipids may also alter the stability or composition of existing membrane domains that may affect bacterial function. Interestingly many antimicrobial agents are polycationic and therefore likely have some effect in promoting lipid phase segregation between anionic and zwitterionic lipids. However, this mechanism is expected to be most important for substances with sequential positive charges contained within a flexible molecule that can adapt to the arrangement of charged groups on the surface of the bacterial cell. When this mechanism is dominant it can allow the prediction of the bacterial species that will be most affected by the agent as a consequence of the nature of the lipid composition of the bacterial membrane.


Antidepressant medication use among working age first-generation migrants resident in Finland: an administrative data linkage study.
A higher risk of common mental health disorders has been found for first-generation migrants in high income countries, but few studies have examined the use of mental health care. This study aimed to identify the level of antidepressant use amongst the largest first generation migrant groups resident in Finland. This cohort study used record-based data linkage methodology to examine the hazard of antidepressant use between migrant groups in Finland using Cox proportional hazard models. Data was derived using socio-demographic and prescription data from Statistics Finland and the Finnish Population Registry. The cohort included a random sample of 33% of the working age population in 2007 (N = 1,059,426, 49.8% women, 2.5% migrants) and dispensed antidepressant prescriptions from 2008 to 2014. After adjustment for socio-demographic characteristics, results show higher antidepressant use for female migrants from North Africa and the Middle East compared to the Finland-born majority, a similar level of use for migrants from Western countries, and lower use for migrants from other non-Western countries. The gender and country of origin dependent use of antidepressant medication is discussed in terms of socio-political and cultural between-group differences. Recommendations are made to address inequalities in accessing services, particularly for migrants from non-Western countries.


Effect of various mixing ratios on antibacterial properties and hardness of endodontic sealers.
Most chemically cured two-component dental materials, including endodontic sealers, are marketed with mixing instructions but with no strict mixing ratios. The present study evaluated the antibacterial properties and hardness of three endodontic sealers: Roth's cement (RC), CRCS, and AH26, mixed to four controlled consistencies within the range of the manufacturer recommendations. Using Enterococcus faecalis as the test microorganism, antibacterial activity was evaluated by agar diffusion and direct contact test. Surface hardness of sealers with the same consistency was evaluated on week-old specimens by the Knoop Hardness Number tester. In the agar diffusion test, light consistency of RC showed larger zones of inhibition than heavier consistency, whereas no significant differences were found with AH26 or CRCS. In the direct contact test, RC and CRCS exhibited complete inhibition of bacterial growth at all consistencies, whereas AH26 with the heavier consistencies did not inhibit bacterial growth at 24 h samples. The hardness of AH26 and CRCS was significantly lower with lighter consistencies. It is concluded that endodontic sealers possess different antibacterial and physical properties according to their mixing consistencies.


Association between tumor architecture derived from generalized Q-space MRI and survival in glioblastoma.
While it is recognized that the overall resistance of glioblastoma to treatment may be related to intra-tumor patterns of structural heterogeneity, imaging methods to assess such patterns remain rudimentary. We utilized a generalized Q-space imaging (GQI) algorithm to analyze magnetic resonance imaging (MRI) derived from a rodent model of glioblastoma and 2 clinical datasets to correlate GQI, histology, and survival. In a rodent glioblastoma model, GQI demonstrated a poorly coherent core region, consisting of diffusion tracts <5 mm, surrounded by a shell of highly coherent diffusion tracts, 6-25 mm. Histologically, the core region possessed a high degree of necrosis, whereas the shell consisted of organized sheets of anaplastic cells with elevated mitotic index. These attributes define tumor architecture as the macroscopic organization of variably aligned tumor cells. Applied to MRI data from The Cancer Imaging Atlas (TCGA), the core-shell diffusion tract-length ratio (c/s ratio) correlated linearly with necrosis, which, in turn, was inversely associated with survival (p = 0.00002). We confirmed in an independent cohort of patients (n = 62) that the c/s ratio correlated inversely with survival (p = 0.0004). The analysis of MR images by GQI affords insight into tumor architectural patterns in glioblastoma that correlate with biological heterogeneity and clinical outcome.


[The transosseous approach to the hip joint in reconstructive operations].
The authors noted a number of peculiarities and positive moments in case of application of hip joint transosseous access after Kulish with 87 patients, aged 14-64 years, with deforming coxarthrosis, femoral head aseptic necrosis, coxa vara, congenital hip dislocation and femoral head epiphyseolysis. The access is simple, effective, comparatively low traumatic and can be successfully applied in hip joint reconstructive orthopedics.


Shaping the Water-Harvesting Behavior of Metal-Organic Frameworks Aided by Fine-Tuned GPT Models.
We construct a data set of metal-organic framework (MOF) linkers and employ a fine-tuned GPT assistant to propose MOF linker designs by mutating and modifying the existing linker structures. This strategy allows the GPT model to learn the intricate language of chemistry in molecular representations, thereby achieving an enhanced accuracy in generating linker structures compared with its base models. Aiming to highlight the significance of linker design strategies in advancing the discovery of water-harvesting MOFs, we conducted a systematic MOF variant expansion upon state-of-the-art MOF-303 utilizing a multidimensional approach that integrates linker extension with multivariate tuning strategies. We synthesized a series of isoreticular aluminum MOFs, termed Long-Arm MOFs (LAMOF-1 to LAMOF-10), featuring linkers that bear various combinations of heteroatoms in their five-membered ring moiety, replacing pyrazole with either thiophene, furan, or thiazole rings or a combination of two. Beyond their consistent and robust architecture, as demonstrated by permanent porosity and thermal stability, the LAMOF series offers a generalizable synthesis strategy. Importantly, these 10 LAMOFs establish new benchmarks for water uptake (up to 0.64 g g-1) and operational humidity ranges (between 13 and 53%), thereby expanding the diversity of water-harvesting MOFs.


Transformation and Articulation of Clinical Data to Understand Students' and Health Professionals' Clinical Reasoning: Protocol for a Scoping Review.
There are still unanswered questions regarding effective educational strategies to promote the transformation and articulation of clinical data while teaching and learning clinical reasoning. Additionally, understanding how this process can be analyzed and assessed is crucial, particularly considering the rapid growth of natural language processing in artificial intelligence. The aim of this study is to map educational strategies to promote the transformation and articulation of clinical data among students and health care professionals and to explore the methods used to assess these individuals' transformation and articulation of clinical data. This scoping review follows the Joanna Briggs Institute framework for scoping reviews and the PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews) checklist for the analysis. A literature search was performed in November 2022 using 5 databases: CINAHL (EBSCOhost), MEDLINE (Ovid), Embase (Ovid), PsycINFO (Ovid), and Web of Science (Clarivate). The protocol was registered on the Open Science Framework in November 2023. The scoping review will follow the 9-step framework proposed by Peters and colleagues of the Joanna Briggs Institute. A data extraction form has been developed using key themes from the research questions. After removing duplicates, the initial search yielded 6656 results, and study selection is underway. The extracted data will be qualitatively analyzed and presented in a diagrammatic or tabular form alongside a narrative summary. The review will be completed by February 2024. By synthesizing the evidence on semantic transformation and articulation of clinical data during clinical reasoning education, this review aims to contribute to the refinement of educational strategies and assessment methods used in academic and continuing education programs. The insights gained from this review will help educators develop more effective semantic approaches for teaching or learning clinical reasoning, as opposed to fragmented, purely symptom-based or probabilistic approaches. Besides, the results may suggest some ways to address challenges related to the assessment of clinical reasoning and ensure that the assessment tasks accurately reflect learners' developing competencies and educational progress. DERR1-10.2196/50797.


[The molecular biological mechanisms of the functioning of microbial glycopolymers and carbohydrases].
Special attention has been paid to glycopolymers which perform various functions in the microbial cell, determine its interaction with the environment, possess a broad range of biological activity (antigenicity, cytotoxicity, immunomodulating properties, participation in the bean-rhizobial symbiosis). Composition and structure of the following polysaccharides, lipopolysaccharides and their components: O-polysaccharide, core oligosaccharide and lipid A from bacteria of genera Clavibacter, Ralstonia, Pseudomonas and Rhizobium, have been studied. Phenotypization of the studied strains has been carried out and chemotaxonomic criteria for creation of serological classification schemes have been proposed. Serogrouping of strains is determined by the availability and chemical nature of lateral substituents of the basic chain of O-specific polysaccharide. Interrelation between physico-chemical characteristics of the polysaccharide complex of rhizobia and formation of bean-rhizobial symbiotic structures has been shown. It is established that polysaccharides, lipo- and exopolysaccharides are efficient immunomodulators, manifest high antileucosis and antimetastasis activities. Physico-chemical properties, specificity, kinetics and action mechanism, structure of active and substrate-binding centres of bacterial and fungal enzymes: alpha-amylase, alpha-galactosidase, galactose oxidase. Data obtained permitted developing recommendations on enzymes application to some fields of the national economy.


Comparison of surgical trends in zone 2 flexor tendon repair between Turkish and international surgeons.
The aim of this study was to evaluate Turkish trends in zone 2 flexor repair with regards to surgical technique, suture materials, anesthesia and post-operative rehabilitation and compare this with international surgeons by modifying Gibson's survey. A printed and online survey consisting of 19 questions modified from Gibson's survey was sent to 590 Turkish and international surgeons. The surgeon's years in practice, province of practice, residency type, number of zone 2 flexor tendon repairs done in a year, preferred surgical technique, suture material, complications and postoperative protocols were asked to the respondents. A total of 194 surgeons completed the survey (a 25% response rate). Of those who completed the survey, 91 were international (mostly from far eastern countries) and 103 were Turkish surgeons. Years in practice and educational background had influence on the decision-making. There were differences between the Turkish and international surgeons in the core and epitendinous suture thickness preference and flexor tendon sheath repair. There was a statistically significant relationship between the province of practice and the use of WALANT (Wide awake local anesthesia no tourniquet) (p < 0.05). While the majority of respondents who preferred postoperative early passive motion protocol were from Turkey (61.5%), the majority of respondents who preferred early active motion protocol were practicing abroad (73.9%). Despite some variations the surgeons involved in this study follow to a large extent the current literature.


The influence of expressed emotion, family dynamics, and symptom type on the social adjustment of schizophrenic young adults.
The goal of this study was to test a path analytic model that reflects the hypothesis that family cohesion and family adaptability underlie family members' expressed emotion (critical comments and emotional overinvolvement), that these family variables underlie the preponderance of positive symptoms in a patient with schizophrenia 9 months after relatives are interviewed, and that all of these variables influence the patient's social adjustment at follow-up. The subjects were 69 patients who met the DSM-III-R criteria for schizophrenia and 108 of their relatives. Relatives were assessed with the Camberwell Family Interview and the Family Adaptability and Cohesion Evaluation Scales III. Patients were interviewed 9 months later with the Brief Psychiatric Rating Scale and the Social Adjustment Scale II. Significant amounts of variance were explained by the model for three of the five social adjustment components. Neither family cohesion nor adaptability was associated with either critical comments or emotional overinvolvement. Family cohesion was negatively associated and emotional overinvolvement was positively associated with a preponderance of positive symptoms. Greater family adaptability was associated with lower social adjustment scores, and greater emotional overinvolvement was associated with higher social adjustment. Cohesion had a significant positive indirect effect on social adjustment through its association with symptom type. Critics of expressed emotion will be pleased to see that one component of high expressed emotion (emotional overinvolvement) is actually associated with a better social outcome in patients. Proponents of the expressed emotion concept will be pleased to see the applicability of expressed emotion to other facets of schizophrenic outcome. The results highlight the importance of using the expressed emotion scales in their continuous rather than dichotomized state and of analyzing critical comments and emotional overinvolvement separately.


Alcohol consumption and overall accident mortality in 14 European countries.
To evaluate the effects of changes in aggregate alcohol consumption on overall accident mortality in 14 western European countries after 1950, and to compare traditional beer, wine, and spirits countries with respect to the impact of alcohol. The countries were sorted into three groups--traditional spirits countries of northern Europe, traditional beer countries of central Europe and wine countries of southern Europe. Gender- and age-specific annual mortality rates were analysed in relation to per capita alcohol consumption, utilizing the Box-Jenkins technique for time series analysis. All series were different to remove long-term trends. The results of the analyses in individual countries were pooled within each group of countries to increase the statistical power. Overall accident mortality data for 5-year age groups were converted to gender and age specific mortality rates in the age groups 15-29, 30-49 and 50-69 years. Rates were age adjusted within groups. Data on per capita alcohol consumption were converted to consumption per inhabitant 15 years and older. The analyses demonstrated a statistically significant and positive relationship between changes in aggregate alcohol consumption in all three groups of countries. The estimated effect parameter was larger in northern Europe than in central Europe, and smallest in southern Europe. The results are compatible with the hypothesis that accident mortality rates are influenced by per capita alcohol consumption in southern, central and northern Europe. However, alcohol appears to play a larger role in northern Europe than in southern Europe.


Positron emission tomography with ([11C]methyl)-L-methionine, [11C]D-glucose, and [68Ga]EDTA in supratentorial tumors.
Sixteen patients with supratentorial tumors were examined with positron emission tomography (PET) using [( 11C]methyl)-L-methionine, [11C]D-glucose, and [68Ga]EDTA as well as CT. There were nine astrocytomas (grade II), three oligoastrocytomas (grade II), two anaplastic astrocytomas (grade III), and two meningiomas. Six patients with low-grade astrocytomas and all three patients with oligoastrocytomas had an accumulation of [11C]methionine varying from slightly to intensely increased as compared with normal brain tissue. There was a markedly increased uptake of methionine in the anaplastic astrocytomas. Three of the low-grade astrocytomas had a decreased uptake of [11C]methionine in at least part of the tumor as compared with normal brain tissue. Contrast enhancement on CT or uptake of [68Ga]EDTA was not a prerequisite for increased accumulation of methionine. Uptake of [11C]glucose was lower than or equal to that of normal brain tissue in the low-grade tumors and also in one of the two anaplastic astrocytomas and in the bulk of the other. In each individual case the methionine uptake tended to be higher--or less decreased--than the glucose uptake. In the low-grade tumors the uptake of methionine and that of glucose were often different, occasionally markedly different, as far as the tumoral-peritumoral areas involved. These differences were even more remarkable in the two anaplastic astrocytomas. An increased uptake of methionine was often seen in areas appearing normal on CT. It appears that PET with [11C]glucose has limitations with regard to delineation of the low-grade astrocytomas, whereas PET with [11C]methionine usually better reflects the extent of these tumors and, to a lesser degree, the extent of the high-grade neoplasms. The results of PET with [68Ga]EDTA were similar to those with postcontrast CT in most patients. The two meningiomas exhibited a high uptake of all tracers used for PET as well as a marked contrast enhancement on CT. The extent of the meningiomas judged by PET with the various tracers correlated well with the extent assessed by postcontrast CT.


Compensatory mechanisms in Parkinson's disease: Circuits adaptations and role in disease modification.
The motor features of Parkinson's disease (PD) are well known to manifest only when striatal dopaminergic deficit reaches 60-70%. Thus, PD has a long pre-symptomatic and pre-motor evolution during which compensatory mechanisms take place to delay the clinical onset of disabling manifestations. Classic compensatory mechanisms have been attributed to changes and adjustments in the nigro-striatal system, such as increased neuronal activity in the substantia nigra pars compacta and enhanced dopamine synthesis and release in the striatum. However, it is not so clear currently that such changes occur early enough to account for the pre-symptomatic period. Other possible mechanisms relate to changes in basal ganglia and motor cortical circuits including the cerebellum. However, data from early PD patients are difficult to obtain as most studies have been carried out once the diagnosis and treatments have been established. Likewise, putative compensatory mechanisms taking place throughout disease evolution are nearly impossible to distinguish by themselves. Here, we review the evidence for the role of the best known and other possible compensatory mechanisms in PD. We also discuss the possibility that, although beneficial in practical terms, compensation could also play a deleterious role in disease progression.


PCB concentrations in riparian spiders (Tetragnathidae) consistently reflect concentrations in water and aquatic macroinvertebrates, but not sediment: Analysis of a seven-year field study.
Tetragnathid spiders have been used as sentinels to study the biotransport of contaminants between aquatic and terrestrial environments because a significant proportion of their diet consists of adult aquatic insects. A key knowledge gap in assessing tetragnathid spiders as sentinels is understanding the consistency of the year-to-year relationship between contaminant concentrations in spiders and sediment, water, and macroinvertebrates. We collected five years of data over a seven-year investigation at a PCB contaminated-sediment site to investigate if concentrations in spiders were consistently correlated with concentrations in sediment, water, and aquatic macroinvertebrates. Despite significant year-to-year variability in spider PCB concentrations, they were not correlated with sediment concentrations (p = 0.186). However, spider PCB concentrations were significantly, positively correlated with PCB concentrations in water (p < 0.0001, annual r2 = 0.35-0.84) and macroinvertebrates (p < 0.0001; annual r2 = 0.59-0.71). Analysis of covariance (ANCOVA) showed that spider PCB concentrations varied consistently with water (β = 0.63) and macroinvertebrate PCB concentrations (β = 1.023) among years. Overall, this study filled a critical knowledge gap in the utilization of tetragnathid spiders as sentinels of aquatic pollution by showing that despite year-to-year changes in PCB concentrations across environmental compartments, consistent relationships existed between spiders and water and aquatic macroinvertebrates.


[The effect of the dioxin-containing herbicide 2,4-D on the hormonal status of experimental animals].
The article presents studies of hormonal state in rats under daily or 20-day peroral administration of variable doses of 2,4-D herbicide containing dioxine. Changed levels of thyroid hormones, insulin, cortisol, testosterone and estradiol appeared to be divergent and dose-dependent, proving direct toxic effects of the herbicide in endocrine organs, altered hormonal effects in target organs and disorders of peripheral hormonal metabolism.


EPHA3 as a novel therapeutic target in the hematological malignancies.
The Eph receptors are the largest family of tyrosine kinases and are of increasing interest in developmental therapeutics. Their unique method of interaction with their ligands, the ephrins, via bidirectional signaling, and their variable expression in different tissues are well documented. Ephs are upregulated in, and critical to, embryological processes, most notably development of the neurological system. They are central in many processes involving cell motility and adhesion. Recent findings on elevated expression of Eph receptors in human malignancies as well as in stem cell environments are of particular interest. With increasing focus on molecularly targeted anticancer therapies, exploration of the potential of Eph receptors as therapeutic targets in both solid and hematologic malignancies has begun. The most promising of the Eph receptors in this regard is EPHA3, which is overexpressed in many hematologic malignancies. Preclinical data support the value of pursuing this target for further development, and lead compounds are now entering the clinic.


Long-term risks of bisphosphonate therapy.
The objective this study was to summarize long-term risks associated with bisphosphonate therapy. Search of relevant medical publications for data from clinical trials, trial extensions, observational studies and post-marketing reports. Trial extensions and modifications did not reveal significant long-term safety issues. Observational data suggest at least as many benefits as risks. Post-marketing reports of musculoskeletal pain, osteonecrosis of the jaw and atypical femur fractures have been widely circulated in the lay press. Most focus on long-terms risks has been on osteonecrosis of the jaw and atypical femur fractures which occur in patients who have not received bisphosphonate therapy but may be more frequent (though still uncommon) in patients who have been on treatment for 5 years or longer. Lower-risk patients may be able to stop treatment after 3-5 years for a "drug holiday," which mitigates these long-term risks; for higher risk patients, therapy through 6-10 years appears to be advisable and offers more benefits than risks.


Signal detection of adverse events with imperfect confirmation rates in vaccine safety studies using self-controlled case series design.
The Vaccine Safety Datalink project captures electronic health record data including vaccinations and medically attended adverse events on 8.8 million enrollees annually from participating managed care organizations in the United States. While the automated vaccination data are generally of high quality, a presumptive adverse event based on diagnosis codes in automated health care data may not be true (misclassification). Consequently, analyses using automated health care data can generate false positive results, where an association between the vaccine and outcome is incorrectly identified, as well as false negative findings, where a true association or signal is missed. We developed novel conditional Poisson regression models and fixed effects models that accommodate misclassification of adverse event outcome for self-controlled case series design. We conducted simulation studies to evaluate their performance in signal detection in vaccine safety hypotheses generating (screening) studies. We also reanalyzed four previously identified signals in a recent vaccine safety study using the newly proposed models. Our simulation studies demonstrated that (i) outcome misclassification resulted in both false positive and false negative signals in screening studies; (ii) the newly proposed models reduced both the rates of false positive and false negative signals. In reanalyses of four previously identified signals using the novel statistical models, the incidence rate ratio estimates and statistical significances were similar to those using conventional models and including only medical record review confirmed cases.


Boron content of plasma and urine as indicators of boron intake in cattle.
Yearling beef heifers were offered drinking water (0.8 mg of B/L of water) to which 0, 15, 30, 60, or 120 mg of B/L of water was added for 10-day periods. Feed and water consumption were unaffected by treatments. There were no overt signs of toxicosis. Increased B ingestion increased plasma and urine B concentrations. The percentage of renally filtered B that was excreted was increased with the 30, 60, and 120 mg of B/L of water treatments, and B clearance exceeded endogenous creatinine clearance with these treatments. Ingesting increased amounts of B was associated with decreased plasma PO4(-3) concentration and increased renal clearance and urinary excretion of PO4(-3). The B status of cattle can be predicted from plasma or urine B concentrations. Results indicated that prediction can be made from the B/creatinine ratio of urine. With an induced urine sample, the equation for predicting B ingestion is Y = -67.79 + 976.74X - 141.91X2 (r = 0.96; Syx = 121.57) where Y is B in milligrams per 100 kg of body weight per day, and X is the ratio of urine B (mg/L of urine) to creatinine (mg/L of urine).


Supramolecular Polysaccharide Nanotheranostics that Inhibit Cancer Cells Growth and Monitor Targeted Therapy Response.
Targeted anticancer therapies directed against specific molecular drivers of tumors are emerging as effective treatment strategies, however, monitoring their response is still challenging. Current clinical imaging techniques that measure either morphological or metabolic changes in the tumor are not always indicative of clinical outcome due to delayed or variable responses. Here, dual-stage polysaccharide-based supramolecular nanotheranostics (SPN) were designed that enable co-delivery of kinase inhibitor and an activatable imaging probe. Methods: The SPNs were prepared by supramolecular assembly of two components, polysaccharide construct conjugated with kinase inhibitor-function activatable probe and kinase inhibitor- β-cyclodextrin conjugate. Physiochemical characterization of SPNs including size, stability, zeta potential and pH-responsiveness of the assembly was performed. The efficacy of SPNs in inducing cancer cell death by inhibition of kinase signaling and imaging the response was evaluated in murine BRAFV600E melanoma (D4M) and triple-negative breast cancer (4T1) cell lines. Finally, the in vivo efficacy was investigated in D4M melanoma tumor model. Results: The polysaccharide-constructs along with kinase inhibitor- β-cyclodextrin conjugates self-assemble to produce SPNs of around 200 nm in diameter and were stable for over a week under physiologically relevant conditions. The SPNs exhibited enhanced cytotoxic effect and significant inhibition of kinase signaling as compared to the free inhibitor. In vitro imaging studies confirmed their enzyme-activatable therapy response tracking abilities both in cancer cells and tumor spheroids. Furthermore, SPN treated mice exhibited better tumor growth inhibition as compared to the control groups and therapy response could be imaged at both early (24-48h) and later time points. Conclusion: These findings demonstrate that the supramolecular polysaccharide nanotheranostics can not only inhibit kinase signaling pathway in aggressive tumor, but also monitor targeted therapy response early.


Trajectories of picky eating during childhood: A general population study.
This cohort study describes the prevalence of picky eating and examines prognostic factors for picky eating trajectories during childhood. 4,018 participants of a population-based cohort with measurements from pregnancy onwards were included. Picky eating was assessed by maternal report when children were 1.5, 3, and 6 years old. The associations of child and family characteristics with trajectories of picky eating were examined using logistic regression. Never picky eaters were used as the reference group. Prevalence of picky eating was 26.5% at 1.5 years of age, 27.6% at the age of 3 and declined to 13.2% at 6 years. Four main picky eating trajectories were defined: (1) never picky eating at all three assessments (55% of children), (2) remitting (0-4 years, 32%), (3) late-onset (6 years only, 4%), and (4) persistent (all ages, 4%). This implies that almost two thirds of the early picky eaters remitted within 3 years. Male sex, lower birth weight, non-Western maternal ethnicity, and low parental income predicted persistent picky eating. More often late-onset picky eaters were children of parents with low income and non-Western ethnicity. We found that nearly half (46%) of children were picky eaters at some point during early childhood. Remittance was very high. This suggests that picky eating is usually a transient behavior and part of normal development in preschool children. However, a substantial group of persistent picky eaters, often from a socially disadvantaged background, continues to have problems beyond the preschool age.