Responding to changes in the unregulated drug supply: the need for a dynamic approach to drug checking technologies.
Drug checking services provide individuals who use drugs with the ability to test samples of their drugs for the presence of highly potent substances. However, there has been recent concern about whether the existing repertoire of point-of-care drug checking technologies, such as immunoassay strips and Fourier-transform infrared spectroscopy (FTIR), are adequate in identifying substances in the unregulated drug supply. Carfentanil and nitazene opioids, substances that are even more potent than fentanyl in vitro, have been found in the unregulated supply in North America and pose a challenge to our existing drug checking strategy. For example, etizolam has recently permeated the unregulated drug supply in North America, and has demonstrated the ability to evade point-of-care drug checking technologies. In response to the incessantly changing nature of the unregulated supply, we argue that drug checking technologies and service delivery models must continuously adapt alongside constantly changing drug markets. We provide two examples of emerging technologies, paper spray-mass spectrometry and surface-enhanced Raman spectroscopy, which address many of the shortcomings of existing technologies. For both technologies, we discuss their feasibility, where they can be offered, their advantages, and how they address gaps in our existing technologies. We contend that these technologies, and other emerging technologies, can be integrated into a future approach to drug checking that flexibly uses different technologies and service delivery methods to adapt to changes in the drug supply.


Bivalent ligands derived from Huperzine A as acetylcholinesterase inhibitors.
The naturally occurring alkaloid Huperzine A (HupA) is an acetylcholinesterase (AChE) inhibitor that has been used for centuries as a Chinese folk medicine in the context of its source plant Huperzia Serrata. The potency and relative safety of HupA rendered it a promising drug for the ameliorative treatment of Alzheimer's disease (AD) vis-à-vis the "cholinergic hypothesis" that attributes the cognitive decrements associated with AD to acetylcholine deficiency in the brain. However, recent evidence supports a neuroprotective role for HupA, suggesting that it could act as more than a mere palliative. Biochemical and crystallographic studies of AChE revealed two potential binding sites in the active-site gorge of AChE, one of which, the "peripheral anionic site" at the mouth of the gorge, was implicated in promoting aggregation of the beta amyloid (Abeta) peptide responsible for the neurodegenerative process in AD. This feature of AChE facilitated the development of dual-site binding HupA-based bivalent ligands, in hopes of concomitantly increasing AChE inhibition potency by utilizing the "chelate effect", and protecting neurons from Abeta toxicity. Crystal structures of AChE allowed detailed modeling and docking studies that were instrumental in enhancing the understanding of underlying principles of bivalent inhibitor-enzyme dynamics. This monograph reviews two categories of HupA-based bivalent ligands, in which HupA and HupA fragments serve as building blocks, with a focus on the recently solved crystallographic structures of Torpedo californica AChE in complex with such bifunctional agents. The advantages and drawbacks of such structured-based drug design, as well as species differences, are highlighted and discussed.


Flow cytometric analysis of ligand-receptor interactions and molecular assemblies.
Flow cytometers make homogeneous real-time measurements of ligand-receptor interactions and, simultaneously, the physiological responses of cells. Their multiparameter capabilities are also useful in resolving multicomponent assemblies or in developing multiplexed assays. Recent advances suggest that these approaches can be extended in several important ways. Sample delivery in the millisecond time domain is applicable to the analysis of complex binding kinetics and reaction mechanisms. The homogeneous discrimination of free components and particle-based assemblies can be extended into the micromolar concentration range. Measurements can be made of molecular assemblies among proteins, DNA, RNA, lipids, and carbohydrates on beads. The topography and assembly of components within cells can be evaluated with resonance energy transfer. Temperature dependence can be evaluated with Peltier temperature control. Many assembly endpoints can be assessed through new tools for high-throughput flow cytometry using plate-based assay formats and small volume samples.


Immunophenotyping and extracellular matrix remodeling in pulmonary and extrapulmonary sarcoidosis.
To investigate the significance of cellular immune markers, as well as that of collagen and elastic components of the extracellular matrix, within granulomatous structures in biopsies of patients with pulmonary or extrapulmonary sarcoidosis. We carried out qualitative and quantitative evaluations of inflammatory cells, collagen fibers, and elastic fibers in granulomatous structures in surgical biopsies of 40 patients with pulmonary and extrapulmonary sarcoidosis using histomorphometry, immunohistochemistry, picrosirius red staining, and Weigert's resorcin-fuchsin staining. The extrapulmonary tissue biopsies presented significantly higher densities of lymphocytes, macrophages, and neutrophils than did the lung tissue biopsies. Pulmonary granulomas showed a significantly higher number of collagen fibers and a lower density of elastic fibers than did extrapulmonary granulomas. The amount of macrophages in the lung samples correlated with FVC (p < 0.05), whereas the amount of CD3+, CD4+, and CD8+ lymphocytes correlated with the FEV1/FVC ratio and VC. There were inverse correlations between TLC and the CD1a+ cell count (p < 0.05), as well as between DLCO and collagen/elastic fiber density (r = -0.90; p = 0.04). Immunophenotyping and remodeling both showed differences between pulmonary and extrapulmonary sarcoidosis in terms of the characteristics of the biopsy samples. These differences correlated with the clinical and spirometric data obtained for the patients, suggesting that two different pathways are involved in the mechanism of antigen clearance, which was more effective in the lungs and lymph nodes.


Reliable signaling by chemical cues of male traits and health state in male lizards, Lacerta monticola.
In spite of the importance of chemoreception in social organization and sexual selection of lizards, there is a lack of general knowledge on how the characteristics of chemical signals mediate these behaviors. Moreover, it is unknown which are the mechanisms that might confer honesty to the information provided by chemical signals. We analyzed here whether characteristics of the lipophilic fraction of femoral gland secretions of Lacerta monticola male lizards can be related to the morphology, physical condition, and health state of the sender. Our results indicated that some male traits, such as body size, number of blue spots, and number of femoral pores and their level of fluctuating asymmetry, were related to variability in the relative proportions of some lipophilic chemical compounds found in secretions. Thus, conspecifics could obtain reliable information on the producer of a scent mark based on chemicals alone, and this might be the basis of female choice observed in this lizard. Moreover, only males with a greater T-cell immune response had higher proportions of two steroids (ergosterol and dehydrocholesterol) in their femoral secretions, which might suggest that the signal is honest and costly to produce. We suggest that only high-quality males could divert these compounds from metabolism to secretions in order to produce an exaggerated and honest "chemical ornament."


Estimating locations of quantum-dot-encoded microparticles from ultra-high density 3-D microarrays.
We develop a maximum likelihood (ML)-based parametric image deconvolution technique to locate quantum-dot (q-dot) encoded microparticles from three-dimensional (3-D) images of an ultra-high density 3-D microarray. A potential application of the proposed microarray imaging is assay analysis of gene, protein, antigen, and antibody targets. This imaging is performed using a wide-field fluorescence microscope. We first describe our problem of interest and the pertinent measurement model by assuming additive Gaussian noise. We use a 3-D Gaussian point-spread-function (PSF) model to represent the blurring of the widefield microscope system. We employ parametric spheres to represent the light intensity profiles of the q-dot-encoded microparticles. We then develop the estimation algorithm for the single-sphere-object image assuming that the microscope PSF is totally unknown. The algorithm is tested numerically and compared with the analytical Cramér-Rao bounds (CRB). To apply our analysis to real data, we first segment a section of the blurred 3-D image of the multiple microparticles using a k-means clustering algorithm, obtaining 3-D images of single-sphere-objects. Then, we process each of these images using our proposed estimation technique. In the numerical examples, our method outperforms the blind deconvolution (BD) algorithms in high signal-to-noise ratio (SNR) images. For the case of real data, our method and the BD-based methods perform similarly for the well-separated microparticle images.


Elevated incidence of head and neck cancer in solid organ transplant recipients.
Solid organ transplant recipients are known to be at an increased risk of cancer development, but research on head and neck cancer in transplant recipients has been limited and prior risk assessments may not be accurate. A retrospective review using a national Veterans Administration database to query outpatient problem lists for ICD codes indicating solid organ transplant and subsequent diagnosis of head and neck cancer. In a study of 30 939 656 patients (37 969 solid organ transplants and 113 995 head and neck cancers), history of transplant significantly predicted head and neck cancer, with relative risks ranging from 1.85 (thyroid) to 2.91 (salivary gland). Worse overall survival (OS) was seen for head and neck cancer patients with prior transplants. In a large case-control study, prior transplant was a risk factor for head and neck cancer development and worse OS for head and neck cancer patients.


Colonisation of leaf litter by aquatic invertebrates in an Atlantic Forest stream.
Riparian vegetation along streams in the Atlantic Forest in Brazil contributes to the formation of a highly heterogeneous leaf litter in streambeds. To investigate the structure and composition of the aquatic invertebrate community during the process of leaf decomposition of two plant species present along the banks of the stream studied, 21 plastic mesh bags containing 2.5g (dry weight) of leaf matter from each species (Alchornea glandulosa (Vell) and Cabralea canjerana End. and Poeppig), for a total of 5.0g, were placed in the streambed. Three bags were removed after 3, 6, 9, 12, 24, 48 and 96 days. The taxonomic density was negatively correlated with the remaining weight. The high density of collector organisms, such as Chironomidae, Oligochaeta and Amphipoda, on the last day of incubation, probably occurred due to the increased amount of fine organic matter in the more advanced decomposition stages. The highest α diversity (Shannon-Wiener) values were observed for the 3rd and 96th days of the experiment, while the β diversity values showed that these days presented the highest variation in the taxonomic composition, thus presenting a different faunistic composition. This study showed that the trophic structure and composition of aquatic invertebrates changes during the decomposition of leaf litter. The faunistic abundance and diversity observed in this study indicate that the entrance of material from plants growing along streams provides favorable conditions for the colonisation and establishment of invertebrates in lower-order streams, and thus points to the need to preserve riparian vegetation.


Revisiting the placental clock: Early corticotrophin-releasing hormone rise in recurrent preterm birth.
To determine if maternal plasma CRH and preterm birth history were associated with recurrent preterm birth risk in a high-risk cohort. Secondary analysis of pregnant women with a prior preterm birth ≤35 weeks receiving 17-alpha hydroxyprogesterone caproate for the prevention of recurrent spontaneous preterm birth. All women with a 24-week blood sample were included. Maternal plasma CRH level at 24- and 32-weeks' gestation was measured using both enzyme-linked immunosorbent assay (ELISA) and extracted radioimmunoassay (RIA) technologies. The primary outcome was spontaneous preterm birth <37 weeks. The association of CRH, prior preterm birth history, and the two combined was assessed in relation to recurrent preterm birth risk. Recurrent preterm birth in this cohort of 169 women was 24.9%. Comparing women who subsequently delivered <37 versus ≥37 weeks, mean levels of CRH measured by RIA were significantly different at 24 weeks (111.1±87.5 vs. 66.1±45.4 pg/mL, P = .002) and 32 weeks (440.9±275.6 vs. 280.2±214.5 pg/mL, P = .003). The area under the receiver operating curve (AUC) at 24 and 32 weeks for (1) CRH level was 0.68 (95% CI 0.59-0.78) and 0.70 (95% CI 0.59-0.81), (2) prior preterm birth history was 0.75 (95% CI 0.67-0.83) and 0.78 (95% CI 0.69-0.87), and (3) combined was 0.81 (95% CI 0.73-0.88, P = .001) and 0.81 (95% CI 0.72-0.90, P = .01) respectively for delivery <37 weeks. CRH measured by ELISA failed to correlate with gestational age or other clinical parameters. In women with a prior preterm birth, CRH levels were higher and had an earlier rise in women who experienced recurrent preterm birth. Second trimester CRH may be useful in identifying a sub-group of women with preterm birth due to early activation of the placenta-fetal adrenal axis. Assay methodology is a variable that contributes to difficulties in reproducibility of CRH levels in the obstetric literature.


Understanding reactivity and stereoselectivity in palladium-catalyzed diastereoselective sp3 C-H bond activation: intermediate characterization and computational studies.
The origin of the high levels of reactivity and diastereoselectivity (>99:1 dr) observed in the oxazoline-directed, Pd(II)-catalyzed sp(3) C-H bond iodination and acetoxylation reactions as reported in previous publications has been studied and explained on the basis of experimental and computational investigations. The characterization of a trinuclear chiral C-H insertion intermediate by X-ray paved the way for further investigations into C-H insertion step through the lens of stereochemistry. Computational investigations on reactivities and diastereoselectivities of C-H activation of t-Bu- and i-Pr-substituted oxazolines provided good agreement with the experimental results. Theoretical predictions with DFT calculations revealed that C-H activation occurs at the monomeric Pd center and that the most preferred transition state for C-H activation contains two sterically bulky t-Bu substituents in anti-positions due to steric repulsion and that this transition state leads to the major diastereomer, which is consistent with the structure of the newly characterized C-H insertion intermediate. The structural information about the transition state also suggests that a minimum dihedral angle between C-H bonds and Pd-OAc bonds is crucial for C-H bond cleavage. We have also utilized density functional theory (DFT) to calculate the energies of various potential intermediates and transition states with t-Bu- and i-Pr-substituted oxazolines and suggested a possible explanation for the substantial difference in reactivity between the t-Bu- and i-Pr-substituted oxazolines.


Graphene reinforced carbon fibers.
The superlative strength-to-weight ratio of carbon fibers (CFs) can substantially reduce vehicle weight and improve energy efficiency. However, most CFs are derived from costly polyacrylonitrile (PAN), which limits their widespread adoption in the automotive industry. Extensive efforts to produce CFs from low cost, alternative precursor materials have failed to yield a commercially viable product. Here, we revisit PAN to study its conversion chemistry and microstructure evolution, which might provide clues for the design of low-cost CFs. We demonstrate that a small amount of graphene can minimize porosity/defects and reinforce PAN-based CFs. Our experimental results show that 0.075 weight % graphene-reinforced PAN/graphene composite CFs exhibits 225% increase in strength and 184% enhancement in Young's modulus compared to PAN CFs. Atomistic ReaxFF and large-scale molecular dynamics simulations jointly elucidate the ability of graphene to modify the microstructure by promoting favorable edge chemistry and polymer chain alignment.


Congenital abnormalities of the feline vertebral column.
Radiographs of vertebral segments from 200 cats were retrospectively assessed to determine the incidence of congenital axial skeletal abnormalities. The axial skeleton was divided into cervical, thoracic, lumbar, sacral, and caudal segments and the presence and types of congenital abnormalities present were recorded for each segment. A total of 598 axial skeletal segments were examined. Congenital abnormalities were found in 46 cats and involved 54 spinal segments. Block vertebrae were identified in three cats. No hemivertebrae or spina bifida were noted. Transitional abnormalities were most common, and were identified in 51 spinal segments. Abnormalities at the sacrocaudal junction were the most common of these; 19 examples were found. The second most common transitional abnormality was thoracicization of L1, with 18 such cats identified. Extra ribs on L1 were often smaller and fragmented and it may be possible for an inexperienced clinician to confuse these with rib fractures. The last rib(s) are also often used for anatomic localization of surgical procedures; the presence of a transitional lumbar vertebra with one or two extra ribs introduces the possibility of error or confusion about choice of surgical site.


The long term effect of an iris-supported lens on the endothelium.
A retrospective study of 104 eyes that had iris-supported Sputnik intraocular lenses implanted and no surgery in the fellow eye and a separate series of 30 implanted eyes whose second eyes underwent surgery but did not receive implants disclosed that endothelial cell densities in the eyes with implants decreased immediately after surgery and then continued to decrease at the same rate as those of the control eyes. There was no sudden decrease in the endothelial cell counts during follow-up periods ranging from three to seven years. The main cause of large cell losses immediately after surgery, and possibly long-term corneal decompensation, was surgical manipulation rather than the presence of this style of intraocular lens.


Constitutively activating mutation in WASP causes X-linked severe congenital neutropenia.
The Wiskott-Aldrich syndrome protein (WASP; encoded by the gene WAS) and its homologs are important regulators of the actin cytoskeleton, mediating communication between Rho-family GTPases and the actin nucleation/crosslinking factor, the Arp2/3 complex. Many WAS mutations impair cytoskeletal control in hematopoietic tissues, resulting in functional and developmental defects that define the X-linked Wiskott-Aldrich syndrome (WAS) and the related X-linked thrombocytopenia (XLT). These diseases seem to result from reduced WASP signaling, often through decreased transcription or translation of the gene. Here we describe a new disease, X-linked severe congenital neutropenia (XLN), caused by a novel L270P mutation in the region of WAS encoding the conserved GTPase binding domain (GBD). In vitro, the mutant protein is constitutively activated through disruption of an autoinhibitory domain in the wild-type protein, indicating that loss of WASP autoinhibition is a key event in XLN. Our findings highlight the importance of precise regulation of WASP in hematopoietic development and function, as impairment versus enhancement of its activity give rise to distinct spectra of cellular defects and clinical phenotypes.


The long path to pregnancy: early experience with dual anonymous gamete donation in a European in vitro fertilisation referral centre.
This investigation describes features of patients undergoing in vitro fertilisation (IVF) and embryo transfer (ET) where both gametes were obtained from anonymous donors. Gamete unsuitability or loss was confirmed in both members of seven otherwise healthy couples presenting for reproductive endocrinology consultation over a 12-month interval in Ireland. IVF was undertaken with fresh oocytes provided by anonymous donors in Ukraine; frozen sperm (anonymous donor) was obtained from a licensed tissue establishment. For recipients, saline-enhanced sonography was used to assess intrauterine contour with endometrial preparation via transdermal estrogen. Among commissioning couples, mean+/-SD female and male age was 41.9 +/- 3.7 and 44.6 +/- 3.5 yrs, respectively. During this period, female age for non dual anonymous gamete donation IVF patients was 37.9 +/- 3 yrs (p < 0.001). Infertility duration was >/=3 yrs for couples enrolling in dual gamete donation, and each had >/=2 prior failed fertility treatments using native oocytes. All seven recipient couples proceeded to embryo transfer, although one patient had two transfers. Clinical pregnancy was achieved for 5/7 (71.4%) patients. Non-transferred cryopreserved embryos were available for all seven couples. Mean age of females undergoing dual anonymous donor gamete donation with IVF is significantly higher than the background IVF patient population. Even when neither partner is able to contribute any gametes for IVF, the clinical pregnancy rate per transfer can be satisfactory if both anonymous egg and sperm donation are used concurrently. Our report emphasises the role of pre-treatment counselling in dual anonymous gamete donation, and presents a coordinated screening and treatment approach in IVF where this option may be contemplated.


A complex RNA-cleaving DNAzyme that can efficiently cleave a pyrimidine-pyrimidine junction.
Several RNA-cleaving deoxyribozymes (DNAzymes) have been reported for efficient cleavage of purine-containing junctions, but none is able to efficiently cleave pyrimidine-pyrimidine (Pyr-Pyr) junctions. We hypothesize that a stronger Pyr-Pyr cleavage activity requires larger DNAzymes with complex structures that are difficult to isolate directly from a DNA library; one possible way to obtain such DNAzymes is to optimize DNA sequences with weak activities. To test this, we carried out an in vitro selection study to derive DNAzymes capable of cleaving an rC-T junction in a chimeric DNA/RNA substrate from DNA libraries constructed through chemical mutagenesis of five previous DNAzymes with a k(obs) of approximately 0.001 min-1 for the rC-T junction. After several rounds of selective amplification, DNAzyme descendants with a k(obs) of approximately 0.1 min-1 were obtained from a DNAzyme pool. The most efficient motif, denoted "CT10-3.29," was found to have a catalytic core of approximately 50 nt, larger than other known RNA-cleaving DNAzymes, and its secondary structure contains five short duplexes confined by a four-way junction. Several variants of CT10-3.29 exhibit a k(obs) of 0.3-1.4 min-1 against the rC-T junction. CT10-3.29 also shows strong activity (k(obs)>0.1 min-1) for rU-A and rU-T junctions, medium activity (>0.01 min-1) for rC-A and rA-T junctions, and weak activity (>0.001 min-1) for rA-A, rG-T, and rG-A junctions. Interestingly, a single-point mutation within the catalytic core of CT10-3.29 altered the pattern of junction specificity with a significantly decreased ability to cleave rC-T and rC-A junctions and a substantially increased ability to cleave rA-A, rA-T, rG-A, rG-T, rU-A, and rU-T junctions. This observation illustrates the intricacy and plasticity of this RNA-cleaving DNAzyme in dinucleotide junction selectivity. The current study shows that it is feasible to derive efficient DNAzymes for a difficult chemical task and reveals that DNAzymes require more complex structural solutions for such a task.


Anthropometric Characteristics and Vertical Jump Abilities by Player Position and Performance Level of Junior Female Volleyball Players.
Although absolute jump heights should be considered an important factor in judging the performance requirements of volleyball players, limited data is available on age-appropriate categories. The purpose of this study is to determine the differences in specific anthropometric characteristics and jumping performance variables in under-19 female volleyball players in relation to playing position and performance level. The sample of subjects consisted of 354 players who prepared for the U19 Women's Volleyball European Championship 2020 (17.4 ± 0.8 years, 1.81 ± 0.07 m, 67.5 ± 7.1 kg). Playing positions analyzed were setters (n = 55), opposites (n = 37), middle blockers (n = 82), outside hitters (n = 137), and liberos (n = 43). The results showed player position differences in every performance level group in variables of body height, spike, and block jump. Observed differences are a consequence of highly specific tasks of different positions in the composition of the team. Players of different performance levels are significantly different, with athletes of higher-ranked teams achieving better results. The acquired data could be useful for the selection and profiling of young volleyball players.


Establishment of a Pig Influenza Challenge Model for Evaluation of Monoclonal Antibody Delivery Platforms.
mAbs are a possible adjunct to vaccination and drugs in treatment of influenza virus infection. However, questions remain whether small animal models accurately predict efficacy in humans. We have established the pig, a large natural host animal for influenza, with many physiological similarities to humans, as a robust model for testing mAbs. We show that a strongly neutralizing mAb (2-12C) against the hemagglutinin head administered prophylactically at 15 mg/kg reduced viral load and lung pathology after pandemic H1N1 influenza challenge. A lower dose of 1 mg/kg of 2-12C or a DNA plasmid-encoded version of 2-12C reduced pathology and viral load in the lungs but not viral shedding in nasal swabs. We propose that the pig influenza model will be useful for testing candidate mAbs and emerging delivery platforms prior to human trials.


Serum cytokine levels in patients with hepatocellular carcinoma.
The role played by the microenvironment in cancer induction, promotion and progression is crucial. Emerging evidence suggests that cytokines, chemokines and growth factors are major players in carcinogenesis. Therefore, a detailed understanding of factors and mechanisms associated with the processes leading from inflammation to cancer could improve the therapeutic strategies against this disease. We have used hepatocarcinoma as our model in this study. We evaluated the serum levels of 50 different cytokines, chemokines and growth factors in patients affected by HCC with chronic HCV-related hepatitis and liver cirrhosis using multiplex biometric ELISA-based immunoassay. Our data showed that some pro-inflammatory molecules were significantly up-regulated in these patients, and highlighted the complexity of the cytokine network in this disease. This work suggests the need to monitor these proteins in order to define a profile that could characterize patients with HCC or to help identify useful markers. This could lead to better definition of the disease state, and to an increased understanding of the relationships between chronic inflammation and cancer.


Superioniclike Diffusion in an Elemental Crystal: bcc Titanium.
Recent theoretical investigations [A. B. Belonoshko et al. Nat. Geosci. 10, 312 (2017)1752-089410.1038/ngeo2892] revealed the occurrence of the concerted migration of several atoms in bcc Fe at inner-core temperatures and pressures. Here, we combine first-principles and semiempirical atomistic simulations to show that a diffusion mechanism analogous to the one predicted for bcc iron at extreme conditions is also operative and of relevance for the high-temperature bcc phase of pure Ti at ambient pressure. The mechanism entails a rapid collective movement of numerous (from two to dozens) neighbors along tangled closed-loop paths in defect-free crystal regions. We argue that this phenomenon closely resembles the diffusion behavior of superionics and liquid metals. Furthermore, we suggest that concerted migration is the atomistic manifestation of vanishingly small ω-mode phonon frequencies previously detected via neutron scattering and the mechanism underlying anomalously large and markedly non-Arrhenius self-diffusivities characteristic of bcc Ti.


In utero and postnatal imaging findings of parasitic conjoined twins (ischiopagus parasiticus tetrapus).
Conjoined twins are a rare developmental anomaly with a reported prevalence of 1.47 per 100,000 births. We present an uncommon case of a parasitic ischiopagus tetrapus with a parasitic ischiopagus partial twin joined to the complete fetus at the level of the ischium diagnosed in utero by fetal MRI. The correct prenatal diagnosis led to birth by caesarean section. Prenatal MRI findings are presented and corroborated by postnatal imaging delineating the full extent and associated anomalies of this rare malformation. Differential diagnosis of duplicated lower extremities is discussed.


Evaluation of 17 medicinal plants from Northern Côte d'Ivoire for their in vitro activity against Streptococcus pneumoniae.
Twenty crude extracts from 17 species out of 11 families were assessed for their antibacterial activity against Streptococcus pneumoniae (Pneumococcus). The selected plants are used in Northern Côte d'Ivoire to treat various infections including respiratory track diseases. From all the tested extracts, only 7 from 6 plants showed a promising in vitro bactericidal activity against Pneumococcus, including strains resistant to penicillin. The most active extracts were from Erythrina senegalensis (Fabaceae), Piliostigma thonningii (Caesalpiniaceae), Waltheria indica (Sterculiaceae), Andira inermis (Fabaceae), Uapaca togoensis (Euphorbiaceae), Keetia hispida (Rubiaceae) and Combretum molle (Combretaceae). This is the first time that the antipneumococcal activity of the tested plants is reported. The results of this preliminary investigation support the traditional use of these plants in the treatment of pneumococcal infections. The most active of them could be candidates for isolation of compounds which could serve as lead structures for the development of new drugs against Streptococcus pneumoniae.


[Anxious hostile behavior as a precursor of pregnancy-induced hypertension].
In 127 healthy pregnant women of the 27th and 28th gestational week, the influence of somatic and affective disorders was investigated with regard to pregnancy-induced hypertension (PIH) after the 30th gestational week prospectively. The women answered a five step self-rating scale including 28 somatic and affective symptoms. The incidence of PIH achieved 12.7%. The PIH-group rated disorders significantly higher than the group without PIH (p less than 0.001). The self rated anxious hostile behaviour disorders were significantly stronger in the PIH-group than in the controls. So, in our sample anxious hostile behaviour appeared to be precursor of PIH. Somatic and affective symptoms of anxiety and hostility are provocated by adrenaline and noradrenaline typically. Catecholamines stimulate synthesis of prostaglandins, favouring PGF and TX. The resulting imbalance of prostaglandins appears to cause PIH pathognomonically. There is discussed that persisting anxious hostile behaviour is able to induce PIH by catecholamine-prostaglandin-mechanism.


Structure and dynamics of nucleosomal DNA.
The last five years have seen exciting advances in our understanding of the structure of the nucleosome core particle, the basic repeating unit in all eukaryotic chromatin. A picture emerges in which nucleosomal DNA, while distorted and compacted fivefold by tight interactions with the histone octamer core, is at the same time highly dynamic and adaptable. Here, we summarize the salient features from recent structural studies of nucleosome core particles (both published and unpublished) that concern the structure and dynamics of nucleosomal DNA, and the nature of protein-DNA interactions. Current mechanisms for chromatin remodeling and nucleosome sliding are discussed in light of new structural evidence. Finally, techniques to study nucleosome stability and ultimately dynamics are introduced.


Comparison of 3D Printed Spherical Implants versus Femoral Head Allografts for Tibiotalocalcaneal Arthrodesis.
Successful tibiotalocalcaneal (TTC) arthrodesis can be difficult to achieve in patients with bulk bone defects even with the use of femoral head allograft. Retrograde intramedullary nail placement through custom 3-dimensional (3D) spherical implants is an innovative option for these patients. The purpose of this study was to compare fusion rates, graft resorption, and complication rates between patients undergoing TTC fusion with 3D sphere implants versus femoral head allografts. Patients who underwent TTC arthrodesis with an intramedullary nail along with a 3D spherical implant (n = 8) or femoral head allograft (n = 7) were included in this study. The rate of successful fusion of the tibia, calcaneus, and talar neck to the 3D sphere or femoral head allograft was compared between the groups. The rate of total fused articulations was significantly higher in the 3D sphere group (92%) than the femoral head allograft group (62%; p = .018). The number of patients achieving successful fusion of all 3 articulations was higher in the 3D sphere group (75%) than the femoral head allograft group (42.9%, p = .22). The rate of graft resorption was significantly higher in the femoral head allograft group (57.1%) than the 3D sphere group (0%, p = .016). There were no significant differences between the groups in terms of complications. These data demonstrate that the use of a custom 3D printed sphere implant is safe in patients with severe bone loss undergoing TTC arthrodesis with a retrograde intramedullary nail and may result in improved rates of successful arthrodesis.


Racial/Ethnic Variations in Colorectal Cancer Screening Self-Efficacy, Fatalism and Risk Perception in a Safety-Net Clinic Population: Implications for Tailored Interventions.
Ethnic and racial minority groups in the U.S. receive fewer colorectal cancer (CRC) screening tests and are less likely to be up-to-date with CRC screening than the population as a whole. Access, limited awareness of CRC and barriers may, in part, be responsible for inhibiting widespread adoption of CRC screening among racial and ethnic minority groups. The purpose of this study was to examine the role of self-efficacy, fatalism and CRC risk perception across racial and ethnic groups in a diverse sample. This study was a cross-sectional analysis from baseline measures gathered on a group of patients recruited into a trial to track colorectal cancer screening in underserved adults over 50. Out of 470 Participants, 42% were non-Hispanic; 27% Hispanic and 28% non-Hispanic White. Hispanic and non-Hispanic Blacks were more likely to have fatalistic beliefs about CRC than non-Hispanic Whites. Non-Hispanic Blacks perceived higher risk of getting colon cancer. Self-efficacy for completing CRC screening was higher among Non-Hispanic Blacks than among Hispanics. Racial and ethnic differences in risk perceptions, fatalism and self-efficacy should be taken into consideration in future CRC interventions with marginalized and uninsured populations.


[Acute Leriche's syndrome in a patient undergoing coronary artery bypass grafting with extracorporeal circulation].
We are reporting a case of an acute thromboembolic obstruction of the aortic bifurcation in a 66-year-old patient undergoing coronary artery bypass grafting with extracorporeal circulation. After declamping of the aorta, the arterial pressure measured in the femoral artery suddenly dropped, whereas the pressure measured in the aortic cannula and in both radial arteries stayed normal. Transoesophageal echocardiography was performed to exclude an acute aortic dissection. While the patient always had a constant sinus rhythm, an angiography following the end of surgery, showed a complete obstruction of the abdominal aorta. Subsequent embolectomy through bifemoral arteriotomies was performed and a histologically fresh embolus (6,5 g in weight) was extracted. Neither the pre- and intraoperative echocardiography, nor the preoperative ventriculography showed signs of an intracardiac thrombus. Insufficient anticoagulation and a lack of inhibitor potential were almost excluded. Considering the histological findings, we assumed that the embolus was formed intraoperatively. Without further complications the patient left our department on the 8th postoperative day.


Effect of In Situ short-term temperature increase on carbon metabolism and dissolved organic carbon (DOC) fluxes in a community dominated by the seagrass Cymodocea nodosa.
Seagrasses form one of the most productive and threatened ecosystems worldwide because of global change and anthropogenic pressures. The frequency of extreme climatic events, such as heat waves, are expected to increase and may drive even more adverse effects than gradual warming. This study explores for the first time the effects of a sudden and temporary increase of temperature in situ on carbon metabolism and dissolved organic carbon (DOC) fluxes in a community dominated by a seagrass (Cymodocea nodosa) during two contrasting seasons (winter and summer). Results showed a positive correlation between temperature and seagrass production between seasons, while the experimental sudden and temporary increase in water temperature did not produce significant differences in carbon community metabolism and DOC fluxes in winter. In contrast, high temperature conditions in summer enhanced significantly the net community production and affected positively to DOC fluxes. Hence, this study indicates that a sudden and temporary increase in water temperature, which characterize marine heat waves, in temperate areas may enhance the autotrophic metabolism of seagrass communities and can yield an increase in the DOC released, in contrast to previous researches suggesting solely negative effects on seagrasses.


Freezing transitions in a system of two-dimensional octupolar multipoles.
We have investigated the fluid-solid freezing transitions in a system of axially symmetric particles confined to a two-dimensional plane and interacting via purely repulsive octupolar interaction potential varying as the seventh power of the inverse interparticle separation. Both the one-component and two-component cases have been considered. The classical density functional theory of freezing has been employed to study the relative stability of the triangular solid phase of the system with respect to the fluid phase of the system using the structural inputs calculated by solving the Rogers-Young integral equation theory. Considering the freezing of the fluid into substitutionally disordered solid, in the case of binary mixtures, we observe that the temperature-composition phase diagram is a spindle for moderate particle asymmetries in the range 0.90-0.75. Further increasing the asymmetry to 0.70 results in the coexistence of the fluid phases of two different compositions.


H2S Scavenging Capacity and Rheological Properties of Water-Based Drilling Muds.
Drilling hydrocarbon formations where hydrogen sulfide (H2S) is present could lead to the carryover of H2S with the drilling mud (i.e., drilling fluid) to the surface, exposing working personnel to this lethal gas. Additionally, H2S is very corrosive, causing severe corrosion of metal parts of the drilling equipment, which in turn results in serious operational problems. The addition of an effective H2S scavenger(s) in the drilling mud formulations will overcome these health, safety, and operational issues. In this work, zinc oxide (ZnO), which is a common H2S scavenger, has been incorporated into water-based drilling mud. The H2S scavenging performance of this ZnO-containing drilling mud has been assessed. Additionally, drilling mud formulations containing either copper nitrate (Cu(NO3)2·3H2O) or potassium permanganate (KMnO4) have been prepared, and their H2S scavenging performances have been studied and compared to that of the ZnO-containing drilling mud. It has been observed that the scavenging performance (in terms of the H2S amounts scavenged up to the breakthrough time and at the saturation condition) of the ZnO-containing drilling mud is very poor compared to those of the copper nitrate-containing and KMnO4-containing drilling muds. For instance, the amounts of H2S scavenged up to the breakthrough time by ZnO-containing, copper nitrate-containing, and KMnO4-containing drilling muds were 5.5, 15.8, and 125.3 mg/g, respectively. Furthermore, the amounts of H2S scavenged at the saturation condition by these drilling muds were, respectively, 35.1, 146.8, and 307.5 mg/g, demonstrating the superiority of the KMnO4-containing drilling mud. Besides its attractive H2S scavenging performance, the KMnO4-containing drilling mud possessed more favorable rheological properties [i.e., plastic viscosity (PV), yield point (YP), carrying capacity of the drill cuttings, and gelling characteristics] relative to the base and the ZnO-containing and copper nitrate-containing drilling muds. The addition of KMnO4 to the base drilling mud increased its apparent viscosity, PV, and YP by 20, 33, and 10%, respectively. Additionally, all tested drilling muds possessed acceptable fluid loss characteristics. To the best of our knowledge, there are so far no published studies concurrently tackling the H2S scavenging (i.e., breakthrough time, breakthrough capacity, saturation time, saturation capacity, and scavenger utilization) and the rheological properties of water-based drilling muds, as demonstrated in the current study, highlighting the novelty of this work.


Regulation of energy partitioning and alternative electron transport pathways during cold acclimation of lodgepole pine is oxygen dependent.
Second year needles of Lodgepole pine (Pinus contorta L.) were exposed for 6 weeks to either simulated control summer ['summer'; 25 °C/250 photon flux denisty (PFD)], autumn ('autumn'; 15°C/250 PFD) or winter conditions ('winter'; 5 °C/250 PFD). We report that the proportion of linear electron transport utilized in carbon assimilation (ETR(CO2)) was 40% lower in both 'autumn' and 'winter' pine when compared with the 'summer' pine. In contrast, the proportion of excess photosynthetic linear electron transport (ETR(excess)) not used for carbon assimilation within the total ETR(Jf) increased by 30% in both 'autumn' and 'winter' pine. In 'autumn' pine acclimated to 15°C, the increased amounts of 'excess' electrons were directed equally to 21 kPa O2-dependent and 2 kPa O2-dependent alternative electron transport pathways and the fractions of excitation light energy utilized by PSII photochemistry (Φ(PSII)), thermally dissipated through Φ(NPQ) and dissipated by additional quenching mechanism(s) (Φ(f,D)) were similar to those in 'summer' pine. In contrast, in 'winter' needles acclimated to 5 °C, 60% of photosynthetically generated 'excess' electrons were utilized through the 2 kPa O2-dependent electron sink and only 15% by the photorespiratory (21 kPa O2) electron pathway. Needles exposed to 'winter' conditions led to a 3-fold lower Φ(PSII), only a marginal increase in Φ(NPQ) and a 2-fold higher Φ(f,D), which was O2 dependent compared with the 'summer' and 'autumn' pine. Our results demonstrate that the employment of a variety of alternative pathways for utilization of photosynthetically generated electrons by Lodgepole pine depends on the acclimation temperature. Furthermore, dissipation of excess light energy through constitutive non-photochemical quenching mechanisms is O2 dependent.


Single-nucleotide polymorphism analysis by pyrosequencing.
There is a growing demand for high-throughput methods for analysis of single-nucleotide polymorphic (SNP) positions. Here, we have evaluated a novel sequencing approach, pyrosequencing, for such purposes. Pyrosequencing is a sequencing-by-synthesis method in which a cascade of enzymatic reactions yields detectable light, which is proportional to incorporated nucleotides. One feature of typing SNPs with pyrosequencing is that each allelic variant will give a unique sequence compared to the two other variants. These variants can easily be distinguished by a pattern recognition software. The software displays the allelic alternatives and allows for direct comparison with the pyrosequencing raw data. For optimal determination of SNPs, various protocols of nucleotide dispensing order were investigated. Here, we demonstrate that typing of SNPs can efficiently be performed by pyrosequencing using an automated system for parallel analysis of 96 samples in approximately 5 min, suitable for large-scale screening and typing of SNPs.


EEG Signature of Object Categorization from Event-related Potentials.
Human visual system recognizes objects in a fast manner and the neural activity of the human brain generates signals which provide information about objects categories seen by the subjects. The brain signals can be recorded using different systems like the electroencephalogram (EEG). The EEG signals carry significant information about the stimuli that stimulate the brain. In order to translate information derived from the EEG for the object recognition mechanism, in this study, twelve various categories were selected as visual stimuli and were presented to the subjects in a controlled task and the signals were recorded through 19-channel EEG recording system. Analysis of signals was performed using two different event-related potential (ERP) computations namely the "target/rest" and "target/non-target" tasks. Comparing ERP of target with rest time indicated that the most involved electrodes in our task were F3, F4, C3, C4, Fz, Cz, among others. ERP of "target/non-target" resulted that in target stimuli two positive peaks occurred about 400 ms and 520 ms after stimulus onset; however, in non-target stimuli only one positive peak appeared about 400 ms after stimulus onset. Moreover, reaction times of subjects were computed and the results showed that the category of flower had the lowest reaction time; however, the stationery category had the maximum reaction time among others. The results provide useful information about the channels and the part of the signals that are affected by different object categories in terms of ERP brain signals. This study can be considered as the first step in the context of human-computer interface applications.


p35 deficiency accelerates HMGB-1-mediated neuronal death in the early stages of an Alzheimer's disease mouse model.
The activities of CDK5 and p35 are thought to be important in the pathogenesis of neurodegenerative diseases, including Alzheimer's disease (AD). We studied the effect of p35 deletion in Tg2576 mice, which is an AD animal model. To obtain the desired mice, we crossed p35(-/-) with Tg2576 mice. The resulting p35(-/-)/Tg2576 (KO/Tg) mice displayed higher mortality rates and exhibited impaired spatial learning and memory at 6 months of age. Using immunohistochemical and biochemical approaches, we observed a reduction in the expression of pre- and post-synaptic markers such as NMDAR1, synaptophysin and GluR1. In addition, the intensity of MAP-2-positive dendrites extending from neuronal cell bodies was significantly decreased in KO/Tg mice compared with KO/WT and WT/Tg mice. We also detected increased neuronal cell death in the hippocampus, along with thinned and collapsed morphological changes in the alveus region and a dramatic increase in the number of microglial cells. Microglial infiltration in the hippocampus could result in the increased secretion of the soluble high mobility group box-1 protein (HMGB-1). The secretion of HMGB-1 is increased by Aβ, and secretion of HMGB-1 promotes neuronal cell death. Moreover, we found that HMGB-1 secretion induced by Aβ in KO/Tg mice gave rise to ER-mediated cell death. In summary, during the stages of KO/Tg mice model, the microglial infiltration and secretion of soluble HMGB-1 were significantly increased in the hippocampus. These conditions promote neuronal death, synaptic destruction and behavioral deficits.


Correlation of dominance as determined by agonistic interactions with feeding order in cats.
To determine whether the direction of dominance as determined by agonistic interactions away from food was different from the direction of dominance as determined by access to a resource in cats. 28 cats. Dyadic relationships and hierarchy formed from observation of agonistic interactions away from food were compared with those formed from interactions at the food bowl. A cat was scored as subordinate to another cat if it lost 3 of 3 interactions or lost > or = 75% of the interactions when > 3 interactions occurred. Cats were observed for 449.4 hours. Hierarchy rank determined by agonistic interactions away from food was significantly correlated with rank determined by interactions at the food bowl. In 27 of 31 dyads, the direction of dominance was the same for food bowl and agonistic relationships, which was significant. In post hoc analyses, when considering the relationship between 2 cats, the heavier cat most likely ranked higher in each hierarchy; however, age was not significantly correlated with either hierarchy. On the basis of dyadic information, the older cat in a dyad was more often dominant in agonistic interactions. Males had a higher mean dominance rank than females; however, sex had no effect on rank determined by interactions at the food bowl. Factors influencing dominant-subordinate relationships are of interest for understanding and treating behavior problems such as aggression and resource control. The outcome of agonistic interactions away from food was related to, but not perfectly correlated with, the outcome of interactions at the food bowl, although winners of those agonistic interactions tended to have control of food.


[Mycobacteria tuberculosis bacteremia].
Mycobacterial bacteremia is common in patients with acquired immunodeficiency syndrome, and mycobacterium avium-intracellulare is isolated most frequently. Although bacteremia due to mycobacterium tuberculosis was described as early as 1917, there are few recent reports regarding this phenomenon. However, mycobacterium tuberculosis infection is relative rare in those developed countries as compared to ours. It is estimated about 12,000 newly diagnosed tuberculous patients in Taiwan area every year. This study was designed to see the incidence of TB bacteremia and the possible relationship between TB bacteremia and disease pattern. From January 1989 to June 1990, we used lysis-centrifugation blood culture system to detect the incidence of mycobacterium tuberculosis bacteremia. 27 cases of newly diagnosed tuberculous patients were included, all proved by chest X ray, bacteriology and/or pathology. These 27 cases included 3 miliary T.B, 13 far-advanced pulmonary T.B., 7 moderate advanced pulmonary T.B., 1 minimal pulmonary T.B., 1 T.B. pericarditis and 3 T.B. pleuritis. Only one miliary T.B. yield bacteremia.


Efficacy of dulaglutide on vascular health indexes in subjects with type 2 diabetes: a randomized trial.
Recent cardiovascular outcome trials have shown significant reductions in major cardiovascular (CV) events with glucagon-like peptide (GLP)-1 receptor agonists. Additionally, adjunctive surrogates for cardiovascular risk validated by some studies include arterial stiffness and endothelial function indexes. To date, no randomized trial has addressed the possible effects of antidiabetic interventional drugs such as GLP1 agonists on endothelial and arterial stiffness indexes as surrogate markers of vascular damage. We aimed to evaluate metabolic efficacy and surrogate vascular efficacy endpoints of once-weekly dulaglutide (1.5 mg) plus traditional antidiabetic treatment compared with traditional antidiabetic treatment alone in subjects with type 2 diabetes. Men and women (aged ≥ 50 years) with established or newly detected type 2 diabetes whose HbA1c level was 9.5% or less on stable doses of up to two oral glucose- lowering drugs with or without basal insulin therapy were eligible for randomization. Subcutaneous dulaglutide was initiated at the full dose (1.5 mg/day weekly). Arterial stiffness (PWV: pulse wave velocity and augmentation index) and endothelial function (RHI: reactive hyperaemia index) were evaluated at baseline and at three-month and nine-month examination visits. At each visit (at 3 and 9 months), the subjects were also evaluated for glycaemic variables such as fasting plasma glucose (FPG) and HbA1c and lipid variables such as total cholesterol, LDL cholesterol, HDL cholesterol and triglyceride levels. At the three-month follow-up, the subjects treated with dulaglutide showed significantly lower serum levels of FPG and HbA1c than control subjects treated with conventional therapy. At the 9-month follow-up, subjects treated with dulaglutide showed significant lower values of the mean diastolic blood pressure, BMI, total serum cholesterol, LDL cholesterol, FPG, HbA1c and PWV and higher mean RHI values than control subjects treated with conventional therapy. Our randomized trial showed that subjects with type 2 diabetes treated with conventional therapy plus 1.5 mg/day of subcutaneous dulaglutide compared with subjects treated with conventional therapy alone showed favourable metabolic effects associated with positive effects on vascular health markers such as arterial stiffness and endothelial function markers. These findings are consistent with previous study findings indicating the strict relationship between cardiovascular risk factors such as systolic blood pressure, total serum cholesterol and LDL levels and cardiovascular events and vascular health surrogate markers.


Steroid hormones and psychological responses to soccer matches: Insights from a systematic review and meta-analysis.
The present systematic review and meta-analysis aimed to assess the perturbations in hormonal and psychological homeostasis in response to soccer match-play. These perturbations were explored according to match outcome (i.e., win versus loss), gender, type of contest (i.e., competitive versus non-competitive fixtures) and competitive level (i.e., novice versus high-level). The review was conducted according to the Population/Intervention or Exposure/Comparison/Outcome(s) (PICO) criteria and the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. Match outcome, type of contest and competitive levels were moderator variables in the examined steroid hormones responses to a soccer match-play. Different testosterone responses were seen between match winners (increase) and losers (decrease) when compared to pre-game or baseline values (p <0.05), whilst no changes could be detected for cortisol relative to match outcome in female soccer players. Males (Δ% = 6.26; ES = 0.28) demonstrated a marginally lower increase in testosterone levels when compared to females (Δ% = 49.16; ES = 1.00), though not statistically significant. Females (Δ% = 162.7; ES = 0.98) did not demonstrate elevated cortisol match response compared to males (Δ% = 34.60; ES = 1.20). Male novice soccer match-play increased cortisol levels compared to high-level soccer match-play (Q = 18.08, p<0.001). Competitive soccer matches increased cortisol levels compared to non-competitive fixtures (i.e., collegiate tournament). Additionally, competitive levels moderate the relationship between a soccer match and testosterone levels (p <0.001), regardless of gender differences. From the presented systematic review and meta-analysis it appears (1) cortisol changes are associated with cognitive anxiety in starter female soccer players, while (2) testosterone changes are associated with changes in mood state in females and social connectedness in male soccer players. This apparent psycho-physiological relationship may proffer the opportunity for targeted intervention(s) by practitioners to favorably influence performance and/or recovery agendas. Further mechanistic and/or applied evidence is required in this regard in addition to further data sets from females.


Molecular cloning and characterization of a geranyl diphosphate-specific aromatic prenyltransferase from lemon.
Prenyl residues confer divergent biological activities such as antipathogenic and antiherbivorous activities on phenolic compounds, including flavonoids, coumarins, and xanthones. To date, about 1,000 prenylated phenolics have been isolated, with these compounds containing various prenyl residues. However, all currently described plant prenyltransferases (PTs) have been shown specific for dimethylallyl diphosphate as the prenyl donor, while most of the complementary DNAs encoding these genes have been isolated from the Leguminosae. In this study, we describe the identification of a novel PT gene from lemon (Citrus limon), ClPT1, belonging to the homogentisate PT family. This gene encodes a PT that differs from other known PTs, including flavonoid-specific PTs, in polypeptide sequence. This membrane-bound enzyme was specific for geranyl diphosphate as the prenyl donor and coumarin as the prenyl acceptor. Moreover, the gene product was targeted to plastid in plant cells. To our knowledge, this is the novel aromatic PT specific to geranyl diphosphate from citrus species.


[Covid-19 - radiologic and histologic features].
We here describe the current knowledge about the radiologic and histologic pulmonary features of covid-19, caused by SARS-CoV-2, and present lung histology from a case with fatal disease. Initial findings on computed tomography (CT) typically include peripheral multifocal bilateral ground-glass opacities, and correspondingly microscopic alveolar edema. This is followed by peripheral consolidations with air bronchogram and perilobular pattern on CT, signs of organizing pneumonia, corresponding to loose (potentially reversible) fibrosis. The posterior parts of the lungs and the lower lobes are typically more markedly affected. In severe disease with acute respiratory distress syndrome, thickened interlobular septa and crazy paving pattern appear on CT, which corresponds to histologic diffuse alveolar damage with, depending on the stage of the disease, features such as edema, hyaline membranes, reactive epithelium, inflammation, and fibrosis.


Comparison of four different categories of prosthetic feet during ramp ambulation in unilateral transtibial amputees.
Comparative effectiveness of prosthetic feet during ramp ambulation in unilateral transtibial amputees, who function at different Medicare Functional Classification Levels, has not been published. To determine differences in symmetry in external work between four categories of prosthetic feet in K-Level-2 and K-Level-3 unilateral transtibial amputees during ramp ascent and descent. Randomized repeated-measures trial. Ten subjects completed six testing sessions during which symmetry in external work was calculated using F-scan in-sole sensors. Between testing sessions 1 and 2, subjects received standardized functional prosthetic training. In Sessions 3-6, subjects tested four feet--solid ankle cushion heel, stationary attachment flexible endoskeleton, Talux (categories K1, K2, and K3, respectively), and Proprio-Foot (microprocessor ankle)--using a study socket and had a 10- to 14-day accommodation period with each foot. During ramp descent, K-Level-2 subjects demonstrated higher symmetry in external work values with Talux and Proprio-Foot compared to the solid ankle cushion heel foot. K-Level-3 subjects also had higher symmetry in external work values with the Talux foot than the solid ankle cushion heel foot. Ramp ascent symmetry in external work values were not significantly different between feet. Prosthetic foot category appears to influence symmetry in external work more during decline walking than incline walking. K-Level-2 unilateral transtibial amputees achieve greater symmetry from K3 dynamic response prosthetic feet with J-shaped ankle and microprocessor ankles while descending ramps. The findings suggest that K-Level-2 unilateral transtibial amputees benefit from K3 dynamic response prosthetic feet with J-shaped ankle. These results support the prescription of K3 feet for K-Level-2 amputees who frequently negotiate ramps.


Effects of glove powder on radiographic quality.
The use of powered rubber gloves in the provision of dental care has produced a new variable in radiographic quality assurance procedures. Wearing powder-coated gloves while processing X-ray films can reduce the quality of the images obtained on processed radiographic film. To ensure that the optimum quality of processed film images is achieved, the operator must be careful to prevent the contamination of the film and processing solutions with powder.


Analysis of 177Lu-DOTA-octreotate therapy-induced DNA damage in peripheral blood lymphocytes of patients with neuroendocrine tumors.
Ionizing radiation-induced DNA double-strand breaks (DSBs) can lead to cell death, genome instability, and carcinogenesis. Immunofluorescence detection of phosphorylated histone variant H2AX (γ-H2AX) is a reliable and sensitive technique to monitor external-beam ionizing radiation-induced DSBs in peripheral blood lymphocytes (PBLs). Here, we investigated whether γ-H2AX could be used as an in vivo marker to assess normal-tissue toxicity after extended internal irradiation with (177)Lu-DOTA-octreotate (LuTate) peptide receptor radionuclide therapy (PRRT) of neuroendocrine tumors. We analyzed the kinetics of γ-H2AX foci in PBLs of 11 patients undergoing PRRT. The number of γ-H2AX foci was determined before and up to 72 h after treatment. These values were compared with the estimated absorbed dose to blood, spleen, bone marrow, and tumor and with subsequent PBL reduction. The decrease in (177)Lu activity in blood with time followed a biexponential kinetic pattern, with approximately 90% of circulating activity in blood cleared within 2 h. Absorbed dose to blood, but not to spleen or bone marrow, correlated with the administered (177)Lu activity. PRRT increased γ-H2AX foci in lymphocytes in all patients, relative to pretherapy values. The response varied significantly between patients, but the average number of foci indicated a general trend toward an increase at 0.5-4 h with a subsequent decrease by 24-72 h after treatment. The peak number of foci correlated with the absorbed dose to tumor and bone marrow and the extent of PBL reduction. γ-H2AX can be exploited in the LuTate PRRT as a biomarker of PBL cytotoxicity. Long-term follow-up studies investigating whether elevated residual γ-H2AX values are associated with acute myelotoxicity and secondary blood malignancy may be worthwhile.


Changes to the cervicovaginal microbiota and cervical cytokine profile following surgery for cervical intraepithelial neoplasia.
Persistent HPV infection associated with immune modulation may result in high-grade squamous intraepithelial lesions (CIN)2/3. Currently, there is little information on the cervicovaginal microbiome, local cytokine levels and HPV infection related to CIN. Follow-up of patients after local surgery provides an opportunity to monitor changes in the cervicovaginal environment. Accordingly, we undertook this longitudinal retrospective study to determine associations between HPV genotypes, cervicovaginal microbiome and local cytokine profiles in 41 Japanese patients with CIN. Cervicovaginal microbiota were identified using universal 16S rRNA gene (rDNA) bacterial primers for the V3/4 region by PCR of genomic DNA, followed by MiSeq sequencing. We found that Atopobium vaginae was significantly decreased (p < 0.047), whereas A. ureaplasma (p < 0.022) increased after surgery. Cytokine levels in cervical mucus were measured by multiplexed bead-based immunoassays, revealing that IL-1β (p < 0.006), TNF-α (p < 0.004), MIP-1α (p < 0.045) and eotaxin (p < 0.003) were significantly decreased after surgery. Notably, the level of eotaxin decreased in parallel with HPV clearance after surgery (p < 0.028). Thus, local surgery affected the cervicovaginal microbiome, status of HPV infection and immune response. Changes to the cervicovaginal microbiota and cervical cytokine profile following surgery for cervical intraepithelial neoplasia may be important for understanding the pathogenesis of CIN in future.


Spinal stability with anterior or posterior ray threaded fusion cages.
The authors conducted a study to determine if the rigidity supplied to the spine by posterior placement of the Ray threaded fusion cage (TFC) is further enhanced by the placement of pedicle screws and, additionally, if bilateral anteriorly placed TFCs render the spine more rigid than a single anteriorly placed TFC. Ten human cadaveric spinal specimens (L2-S1) were affixed within a testing frame. Loads of 1.5, 3, 4.5, and 6 Nm were applied to the spine in six degrees of freedom: flexion-extension, right and left lateral bending, and right and left axial rotation. Motion in an x, y, and z cartesian axis system was tracked using dual video cameras following light-emitting diodes attached to the spine and base plate. Load testing of the spines was performed in the intact mode, following which the spinal segments were randomized to receive anterior or posterior instrumentation. In five spine specimens we performed posterior discectomy, posterior lumbar interbody fusion (PLIF) with placement of femoral rings and pedicle screws, PLIF with bilateral TFCs, and bilateral TFCs with pedicle screws. Five other spines underwent anterior-approach discectomy, followed by implantation of a unilateral cage and bilateral cages. Load testing was performed after each step. Spines in which PLIF with pedicle screws and TFCs with pedicle screws were placed were more rigid than after discectomy in all directions of motion except flexion. Anterior discectomy provided significantly (p < or = 0.05) less stability in left and right axial rotation than the intact spines and following posterior discectomy. Following anterior implantation of bilateral TFCs, spines were significantly more rigid than after discectomy in all directions except extension.


Korean red ginseng improves testicular ineffectiveness in aging rats by modulating spermatogenesis-related molecules.
Korean red ginseng (Panax ginseng Meyer) is known to rejuvenate testicular effectiveness and the sperm maturation process by regulating redox proteins in aged rats. This study was performed to investigate the effect of Korean red ginseng water extract (KRG-WE) on the expression level of spermatogenesis-related key biomolecules and sex hormone receptors as well as enzymes regulating oxidation, histone deacetylation, and growth-related activities in aged rat testis. KRG-WE (200mg/kg) mixed with a regular pellet diet was administered to 12-month-old rats for 6months (KRG-AC), whereas the young (YC, 2months) and aged (AC, 12months) controls received the vehicle only. The results showed that the expression levels of spermatogenesis-related key biomolecules (inhibin-α, nectin-2, and cyclic adenosine monophosphate [cAMP] responsive element binding protein [CREB]-1), sex hormone receptors (androgen, luteinizing- and follicle-stimulating hormone receptors [AR, LHR, and FSHR, respectively]), and antioxidant enzymes (glutathione S-transferase mu [GSTm]-5, glutathione peroxidase [GPx]-4, peroxiredoxin [PRx]-3), as well as histone deactylation (silent mating type information regulation 2 homolog 1, SIRT1) and growth-related (mammalian target of rapamycin complex 1, mTORC1) molecules were significantly altered in the AC group rat testes compared with those of the YC group. However, KRG-WE treatment of the AC group significantly (p<0.05) attenuated these molecular changes. From these results, it can be concluded that long-term administration of KRG-WE significantly delayed the aging-induced testicular dysfunction.


[Percutaneous exclusion of traumatic abdominal aortic pseudoaneurysm from a brachial approach].
Abdominal aortic pseudoaneurysm (AAP) is a rare lesion, although traumatic aortic injury is described as one of the main causes; both the rupture as the surgical treatment of the defect has high morbidity and mortality. Therefore, endovascular treatment either by chemical embolization or exclusion of defect with devices has emerged as an alternative treatment. However, there are risks such as occlusion of visceral vessels near the neck of the defect, embolization material or aortic rupture. Therefore, the choice of material and method of approach should be planned carefully in each case. We report a patient who ten years after abdominal wound firearm was diagnosed with AAP 17 x 13 cm, with short neck originated close to the ostium of the celiac trunk at an acute angle with the aortic axis. We perform the exclusion of the defect with a device designed for closing atrial septal defect from the left brachial access due to the angulation of the neck defect. There were no complications. At 72 hours was granted discharge. A month later, CT scan control showed the false aneurysm of equal size and no residual flow. The monitoring to date is five months and the patient remained asymptomatic.


Mycobacterium bovis BCG Interferes with miR-3619-5p Control of Cathepsin S in the Process of Autophagy.
Main survival mechanism of pathogenic mycobacteria is to escape inimical phagolysosomal environment inside the macrophages. Many efforts have been made to unravel the molecular mechanisms behind this process. However, little is known about the involvement of microRNAs (miRNAs) in the regulation of phagolysosomal biosynthesis and maturation. Based on a bottom up approach, we searched for miRNAs that were involved in phagolysosomal processing events in the course of mycobacterial infection of macrophages. After infecting THP-1 derived macrophages with viable and heat killed Mycobacterium bovis BCG (BCG), early time points were identified after co-localization studies of the phagosomal marker protein LAMP1 and BCG. Differences in LAMP1 localization on the phagosomes of both groups were observed at 30 min and 4 h. After in silico based pre-selection of miRNAs, expression analysis at the identified time points revealed down-regulation of three miRNAs: miR-3619-5p, miR-637, and miR-324-3p. Consequently, most likely targets were predicted that were supposed to be mutually regulated by these three studied miRNAs. The lysosomal cysteine protease Cathepsin S (CTSS) and Rab11 family-interacting protein 4 (RAB11FIP4) were up-regulated and were considered to be connected to lysosomal trafficking and autophagy. Interaction studies verified the regulation of CTSS by miR-3619-5p. Down-regulation of CTSS by ectopic miR-3619-5p as well as its specific knockdown by siRNA affected the process of autophagy in THP-1 derived macrophages.


Demonstration of an electrogenic Na+-K+ pump in mouse spleen macrophages.
The effect of ouabain on the membrane potential of cultured mouse spleen macrophages was examined. Ouabain (10(-3) M) induced a membrane depolarization (6.6 mV) in 18 of 19 cells studied that occurred within several minutes after exposure and was not associated with significant changes in current-voltage relationships. In related studies, cells were placed in K+-free medium in the cold for 2 h to block pump activity. Subsequent exposure to K+ at 37 degrees C resulted in a membrane hyperpolarization. However, addition of K+ also enhanced inward rectification. To differentiate between the effect of K+ on the Na+-K+ pump and its action on inward rectification, two types of experiments were done. Studies performed in the presence of barium, which blocks inward rectification, demonstrated a K+-induced hyperpolarization with no changes in rectification. Additional studies examined the effects of rubidium on Na+-loaded cells. Rubidium, which blocks inward rectification but substitutes for K+ in activating the Na+-K+ pump, induced membrane hyperpolarizations that were reversed by addition of ouabain. These data indicate that macrophages exhibit an electrogenic Na+-K+ pump, which probably contributes to the resting membrane potential under steady-state conditions and can be activated under conditions designed to Na+ load the cells. In addition, they demonstrate that increasing extracellular K+ enhances inward rectification in macrophages.


Nulp1, a novel basic helix-loop-helix protein expressed broadly during early embryonic organogenesis and prominently in developing dorsal root ganglia.
The basic helix-loop-helix (bHLH) proteins control differentiation and development of a variety of organs. We have isolated the complementary DNA (cDNA) of a novel class of bHLH transcription factors. The previously uncharacterized bHLH messenger RNA (mRNA) was identified by RNA fingerprinting by comparing embryonic and adult mRNA. The reading frame sequence predicts a new class of bHLH family. Northern blotting of embryonic stages demonstrated a 3.2-kb transcript present in several embryonic tissues, including kidney, brain, heart, and lung, in a fashion confirmatory with the RNA-fingerprinting data. In situ hybridization of cryosections detected strong signals in the dorsal root ganglia of 14-day-old mouse embryos (E14). Transient transfection of human embryonic kidney cells with Nulp1-EGFP demonstrated nuclear localization. The complex expression pattern and unique protein sequence, including an acidic amino terminal and putative transcription activation domain, suggests that Nulp1 may have a distinct role in embryonic development of many organs, including the adult brain.


Effect of Femtosecond Laser-Irradiated Titanium Plates on Enhanced Antibacterial Activity and Preservation of Bacteriophage Stability.
Titanium (Ti) is widely recognized for its exceptional properties and compatibility with medical applications. In our study, we successfully formed laser-induced periodic surface structures (LIPSS) on Ti plates with a periodicity of 520-740 nm and a height range of 150-250 nm. To investigate the morphology and chemical composition of these surfaces, we employed various techniques, including field emission scanning electron microscopy, energy dispersive X-ray spectroscopy, atomic force microscopy, X-ray photoelectron spectroscopy, and Raman spectroscopy. Additionally, we utilized a drop-shape analyzer to determine the wetting properties of the surfaces. To evaluate the antibacterial activity, we followed the ISO 22196:2011 standard, utilizing reference bacterial cultures of Gram-positive Staphylococcus aureus (ATCC 25923) and Gram-negative Escherichia coli (ATCC 25922). The results revealed enhanced antibacterial properties against Staphylococcus aureus by more than 99% and Escherichia coli by more than 80% in comparison with non-irradiated Ti. Furthermore, we conducted experiments using the Escherichia coli bacteriophage T4 (ATCC 11303-B4) and the bacterial host Escherichia coli (ATCC 11303) to investigate the impact of Ti plates on the stability of the bacteriophage. Overall, our findings highlight the potential of LIPSS on Ti plates for achieving enhanced antibacterial activity against common bacterial strains while maintaining the stability of bacteriophages.


[Cholestatic viral hepatitis: is it an easy diagnosis?].
Three cases of acute cholestatic viral hepatitis are presented. A discussion is made regarding the difficulties encountered and the methods used for certifying this not always easy diagnosis: one patient with virus A and two presumed cases of non-A, non-B virus. The most noteworthy laboratory findings are observed in the very slight transaminase changes or their abrupt descent over a short period whereas bilirubin and cholestatic parameters increase. Due to the particular characteristics observed in the first case, a doubt still exists regarding the possibility of an occult systemic disease existing even though 17 months have passed since the onset of symptoms. The possibility of Hodgkin's disease has been virtually ruled out since it seldom presents such long term hyperbilirubinemia and such high alkaline phosphatase levels.


Modification of the Epworth Sleepiness Scale in Central China.
The well-known excessive daytime sleepiness (EDS) assessment, Epworth Sleepiness Scale (ESS), is not consistently qualified for patients with diverse living habits. This study is aimed to build a modified ESS (mESS) and then to verify its feasibility in the assessment of EDS for patients with suspected sleep-disordered breathing (SDB) in central China. A Ten-item Sleepiness Questionnaire (10-ISQ) was built by adding two backup items to the original ESS. Then the 10-ISQ was administered to 122 patients in central China with suspected SDB [among them, 119 cases met the minimal diagnostic criteria for obstructive sleep apnea by sleep study, e.g., apnea and hypopnea index (AHI) ≥ 5 h(-1)] and 117 healthy central Chinese volunteers without SDB. Multivariate exploratory techniques were used for item validation. The unreliable item in the original ESS was replaced by the eligible backup item, thus a modified ESS (mESS) was built, and then verified. Item 8 proved to be the only unreliable item in central Chinese patients, with the least factor loading on the main factor and the lowest item-total correlation both in the 10-ISQ and in the original ESS, deletion of it would increase the Cronbach's alpha (from 0.86 to 0.87 in the 10-ISQ; from 0.83 to 0.85 in the original ESS). The mESS was subsequently built by replacing item 8 in the original ESS with item 10 in the 10-ISQ. Verification with patients' responses revealed that the mESS was a single-factor questionnaire with good internal consistency (Cronbach's alpha = 0.86). The sum score of the mESS not only correlated with AHI (P < 0.01) but was also able to discriminate the severity of obstructive apnea (P < 0.01). Nasal CPAP treatment for severe OSA reduced the score significantly (P < 0.001). The performance of the mESS was poor in evaluating normal subjects. The mESS improves the validity of ESS for our patients. Therefore, it is justified to use it instead of the original one in assessment of EDS for patients with SDB in central China.


Bioprinting of 3D hydrogels.
Three-dimensional (3D) bioprinting has recently emerged as an extension of 3D material printing, by using biocompatible or cellular components to build structures in an additive, layer-by-layer methodology for encapsulation and culture of cells. These 3D systems allow for cell culture in a suspension for formation of highly organized tissue or controlled spatial orientation of cell environments. The in vitro 3D cellular environments simulate the complexity of an in vivo environment and natural extracellular matrices (ECM). This paper will focus on bioprinting utilizing hydrogels as 3D scaffolds. Hydrogels are advantageous for cell culture as they are highly permeable to cell culture media, nutrients, and waste products generated during metabolic cell processes. They have the ability to be fabricated in customized shapes with various material properties with dimensions at the micron scale. 3D hydrogels are a reliable method for biocompatible 3D printing and have applications in tissue engineering, drug screening, and organ on a chip models.


Nanogel-based nasal vaccines for infectious and lifestyle-related diseases.
Because the mucosa is the major entry route for most pathogens, the development of mucosal vaccines is a rational approach for protecting against these undesired agents. Mucosal administration of vaccine antigen is useful for non-infectious chronic diseases as well, because of its advantages over injection routes, including comparable efficacy in the induction of systemic immune responses, less pain, and no risk of adverse events at the injection site. However, because it is difficult to effectively induce and regulate antigen-specific mucosal and systemic immune responses when antigen alone is mucosally administered, an appropriate form of mucosal delivery vehicle must be used. Antigen delivery systems involving nanogels, which act as artificial chaperones and mucosal adhesives, are a promising approach to overcoming this problem. Here, we introduce current perspectives regarding the development of nanogel-based nasal vaccines for both infectious and lifestyle-related diseases.


The development of visual P3a and P3b.
The relationship of visual P3a and P3b to age and neuropsychological performance was investigated in 26 healthy children (6.8-15.8 years) and 129 adult volunteers (20.0-88.8 years). Within the sample of children, an effect of age on midline topography was observed, with higher frontal amplitudes in the youngest compared to the oldest children. Increasing age was associated with lower P3a and P3b amplitude and shorter P3b latency at Fz. Performance on neuropsychological tests (matrix reasoning from WASI, digit span from WAIS, word order and hand movement from Kaufman) was only weakly associated with measures of P3a and P3b. The analyses were then repeated with the full life-span sample (n = 155). It was found that for P3a, amplitude decreased and latency increased with age. For P3b, the pattern was more complex, with a nonlinear amplitude reduction and no latency change with age. It appears that the development of P3a in children represents the start of processes that later continue in the adult life-span, but that the automatic processes indexed by P3a seems to mature earlier than the controlled processes reflected by P3b. Finally, it was demonstrated that the relationships between neuropsychological test scores (matrix reasoning, digit span) and P3 parameters were complex, following a mix of linear and nonlinear patterns. It is suggested that the neuropsychological significance of the different P3a and P3b parameters may change from childhood to the adult life-span.


Development and validation of a nomogram for predicting ongoing pregnancy in single vitrified-warmed blastocyst embryo transfer cycles.
The global adoption of the "freeze-all strategy" has led to a continuous increase in utilization of single vitrified-warmed blastocyst embryo transfer (SVBT) owing to its clinical effectiveness. Accurate prediction of clinical pregnancy is crucial from a patient-centered perspective. However, this remains challenging, with inherent limitations due to the absence of precise and user-friendly prediction tools. Thus, this study primarily aimed to develop and assess a nomogram based on quantitative clinical data to optimize the efficacy of personalized prognosis assessment. We conducted a retrospective cohort analysis of ongoing pregnancy data from 658 patients with infertility who underwent SVBT at our center between October 17, 2017, and December 18, 2021. Patients were randomly assigned to the training (n=461) or validation (n=197) cohort for nomogram development and testing, respectively. A nomogram was constructed using the results of the multivariable logistic regression (MLR), which included clinical covariates that were assessed for their association with ongoing pregnancy. The MLR identified eight significant variables that independently predicted ongoing pregnancy outcomes in the study population. These predictors encompassed maternal physiology, including maternal age at oocyte retrieval and serum anti-Müllerian hormone levels; uterine factors, such as adenomyosis; and various embryo assessment parameters, including the number of fertilized embryos, blastocyst morphology, blastulation day, blastocyst re-expansion speed, and presence of embryo string. The area under the receiver operating characteristic curve in our prediction model was 0.675 (95% confidence interval [CI], 0.622-0.729) and 0.656 (95% CI, 0.573-0.739) in the training and validation cohorts, respectively, indicating good discrimination performance in both cohorts. Our individualized nomogram is a practical and user-friendly tool that can provide accurate and useful SVBT information for patients and clinicians. By offering this model to patients, clinical stakeholders can alleviate uncertainty and confusion about fertility treatment options and enhance patients' confidence in making informed decisions.


Expression of Tumor Suppressor FHIT Is Regulated by the LINC00173-SNAIL Axis in Human Lung Adenocarcinoma.
Long non-coding RNAs (lncRNAs) play a critical role in a variety of human diseases such as cancer. Here, to elucidate a novel function of a lncRNA called LINC00173, we investigated its binding partner, target gene, and its regulatory mechanism in lung adenocarcinoma, including the A549 cell line and patients. In the A549 cell line, RNA immunoprecipitation (RIP) assays revealed that LINC00173 efficiently binds to SNAIL. RNA-seq and RT-qPCR analyses revealed that the expression of FHIT was decreased upon LINC00173 depletion, indicating that FHIT is a target gene of LINC00173. Overexpression of SNAIL suppressed and depletion of SNAIL increased the expression of FHIT, indicating that SNAIL negatively regulates FHIT. The downregulation of FHIT expression upon LINC00173 depletion was restored by additional SNAIL depletion, revealing a LINC00173-SNAIL-FHIT axis for FHIT regulation. Data from 501 patients with lung adenocarcinoma also support the existence of a LINC00173-SNAIL-FHIT axis, as FHIT expression correlated positively with LINC00173 (p = 1.75 × 10-6) and negatively with SNAIL (p = 7.00 × 10-5). Taken together, we propose that LINC00173 positively regulates FHIT gene expression by binding to SNAIL and inhibiting its function in human lung adenocarcinoma. Thus, this study sheds light on the LINC00173-SNAIL-FHIT axis, which may be a key mechanism for carcinogenesis and progression in human lung adenocarcinoma.


Self-stigma and empowerment in combined-CMHA and consumer-run services: two controlled trials.
Self-help agencies (SHAs) are consumer-operated service organizations managed as participatory democracies involving members in all management tasks. Hierarchically organized board- and staff-run consumer-operated service programs (BSR-COSPs) are consumer managed, but they afford members less decision-making power. This study considered the relative effectiveness of SHAs and BSR-COSPs working jointly with community mental health agencies (CMHAs) and the role of organizational empowerment in reducing self-stigma. Clients seeking CMHA services were assigned in separate randomized controlled trials to a trial of combined SHA and CMHA services versus regular CMHA services (N=505) or to a trial of combined BSR-COSP and CMHA services versus regular CMHA services (N=139). Self-stigma, organizational empowerment, and self-efficacy were assessed at baseline and eight months with the Attitudes Toward Persons With Mental Illness Scale, the Organizationally Mediated Empowerment Scale, and the Self-Efficacy Scale. Outcomes were evaluated with fully recursive path analysis models. SHA-CMHA participants experienced greater positive change in self-stigma than CMHA-only participants, a result attributable to participation in the combined condition (b=1.20, p=.016) and increased organizational empowerment (b=.27, p=.003). BSR-COSP-CMHA participants experienced greater negative change in self-stigma than CMHA-only participants, a result attributable to participation in the combined service (b=-4.73, p=.031). In the SHA-CMHA trial, participants showed positive change in self-efficacy, whereas the change among BSR-COSP-CMHA participants was negative. Differential organizational empowerment efforts in the SHA and BSR-COSP appeared to account for the differing outcomes. Members experienced reduced self-stigma and increases in self-efficacy when they were engaged in responsible roles.


The role of playgrounds in the development of children's fundamental movement skills: A scoping review.
Fundamental movement skills (FMS) are the basic skills children should develop but are low in children from high-income countries. Literature indicates that playgrounds can play an important role challenging children's balance, agility, and coordination. However, knowledge on the influence of playgrounds on children's FMS development is fragmented. The aim of the present scoping review was to create an overview of all research that is relevant when studying the influence of unstructured playground play on children's FMS. Four electronic databases (Scopus, Web of Science, SportDiscus, and PsycInfo) were searched systematically in May 2022 and October 2023 following the PRISMA guidelines, leading to a final set of 14 publications meeting the inclusion criteria. The results of these publications indicate that it is important to design playgrounds with various features targeting balance, climbing, throwing, and catching to provide opportunities for children to enhance each FMS (i.e., stability, locomotor skills, and object control skills). Also, spreading features over a large area of the playground seems to ensure ample space per child, stimulate children to use locomotor skills by moving to and from features, and to play active games without equipment. Possibly, also natural play settings develop children's FMS. These findings, however, should be read with caution. More experimental studies using objective and standardized FMS tests are needed in this research field for a more robust conclusion.


Detection of EGFR-SEPT14 fusion in cell-free DNA of a patient with advanced gastric cancer: A case report.
Gastric cancer is the fifth most diagnosed cancer worldwide and the third most common cause of cancer-related death. In recent decades, increasing application of next-generation sequencing has enabled detection of molecular aberrations, including fusions. In cases where tissue is difficult to obtain, cell-free DNA (cfDNA) is used for detecting mutations to identify the molecular profile of cancer. Here, we report a rare case of EGFR-SEPT14 fusion detected from cfDNA analysis in a patient with gastric cancer. A 49-year-old female diagnosed with advanced gastric cancer in July 2019 received capecitabine and then combination chemotherapy of ramucirumab and paclitaxel, but ascites was detected. The therapy was switched to nivolumab, but disease progression was observed on a positron emission tomography/computed tomography scan in May 2020. Therapy was discontinued, and cfDNA next-generation sequencing was immediately evaluated. All genomic variants, including fusions, were analyzed from cfDNA. The following somatic alterations were detected from the patient's cfDNA: an APC frameshift mutation (NM_000038.5:c.6579del, p.V2194fs) with variant allele frequency of 0.5%, an EGFR amplification with a copy number of 17.3, and an EGFR-SEPT14 fusion with variant allele frequency of 45.3%. The site of the fusion was exon 24 of EGFR fused to exon 10 of SEPT14. The fusion was in-frame and considered to be protooncogenic. Although the patient refused to continue therapy, we suggest that EGFR-targeted therapies be tried in such future cases. The expanded applications of the cfDNA assay may open a new horizon in treatment of patients with advanced gastric cancer.


Cardiovascular risk and acute coronary syndrome in giant cell arteritis: a population-based retrospective cohort study.
To assess the occurrence of acute coronary syndrome (ACS) in patients with giant cell arteritis (GCA) compared to subjects without GCA. We retrospectively reviewed a population-based incidence cohort of Olmsted County, Minnesota residents with GCA diagnosed in 1950-2009. We compared this cohort with a cohort of patients without GCA of similar age, sex, and calendar year from the same population. The study included 245 patients with GCA and 245 non-GCA subjects. The mean ± SD Framingham cardiovascular risk score was 30% ± 19% in GCA patients and 34% ± 23% in non-GCA subjects (P = 0.096) at the incidence/index date. Diabetes mellitus was significantly less common in GCA patients than non-GCA subjects at the index date. The mean high-density lipoprotein was higher and triglycerides were lower, with fewer patients taking lipid-lowering medications in the GCA cohort compared to the non-GCA cohort at the index date. During followup, no difference between the 2 cohorts was noted in the overall rate of ACS events (hazard ratio 0.74, 95% confidence interval 0.44-1.26). Overall thrombosis in myocardial infarction scores were similar in both cohorts. Revascularization procedures were done less frequently in GCA than in non-GCA subjects (19% versus 50%; P = 0.015). Post-ACS hospital length of stays and complications were similar in both cohorts. Multiple cardiovascular risk factors are less atherogenic at incidence of GCA. There is no overall increased risk of ACS in patients with GCA.


In silico modeling to optimize interpretation of liver safety biomarkers in clinical trials.
Current strategies to delineate the risk of serious drug-induced liver injury associated with drugs rely on assessment of serum biomarkers that have been utilized for many decades. In particular, serum alanine aminotransferase and total bilirubin levels are typically used to assess hepatic integrity and function, respectively. Parallel measurement of these biomarkers is utilized to identify patients with drug-induced hepatocellular jaundice ("Hy's Law" cases) which carries at least a 10% risk of death or liver transplant. However, current guidelines regarding use of these biomarkers in clinical trials can put study subjects at risk for life-threatening drug-induced liver injury, or result in over estimation of risk that may halt development of safe drugs. In addition, pharmaceutical companies are increasingly being required to conduct large and expensive clinical trials to "defend" the safety of their new drug when results from smaller trials are inconclusive. Innovative approaches and some novel biomarkers are now being employed to maximize the value of traditional biochemical tests. DILIsym®, a product of the DILIsim Initiative, utilizes serial serum alanine aminotransferase values, along with serum biomarkers of apoptosis vs necrosis, to estimate percent hepatocyte loss and total bilirubin elevations resulting from loss of global liver function. The results from analyses conducted with DILIsym have been reported to the FDA to support the safety of entolimod and cimaglermin alfa after elevations in serum alanine aminotransferase and/or bilirubin halted clinical development. DILIsym can also be utilized to determine whether rises in serum conjugated and unconjugated bilirubin are consistent with mechanisms unrelated to toxicity ( i.e. inhibition of bilirubin transport or metabolism). In silico modeling of traditional and novel drug-induced liver injury biomarker data obtained in clinical trials may be the most efficient and accurate way to define the liver safety profile of new drug candidates. Impact statement Blood tests used in clinical trials to detect and monitor drug-induced liver injury (DILI) have not changed in half a century. These tests have several shortcomings: their use has not completely prevented clinical trial participants from risk of life-threatening DILI, they can give false positive results that halt the development of safe drug candidates, and they can create liver safety "concerns" that require large additional clinical trials to accurately define DILI risk. This review highlights the use of in silico modeling to improve interpretation of the blood tests currently available to detect DILI risk in new drug candidates. This approach is increasingly being applied in clinical trials to more precisely assess the degree of hepatocellular injury and its functional impact. This new approach holds the promise of more accurately defining DILI risk in smaller clinical trials.


Impact of the community-based newborn care package in Nepal: a quasi-experimental evaluation.
To evaluate the impact of the community-based newborn care package (CBNCP) on six essential practices to improve neonatal health. CBNCP pilot districts were matched to comparison districts using propensity scores. Impact on birth preparedness, antenatal care seeking, antenatal care quality, delivery by skilled birth attendant, immediate newborn care and postnatal care within 48 hours were assessed using Demographic and Health Survey (DHS) and Health Management Information System (HMIS) data through difference-in-differences and multivariate logistic regression analyses. Changes over time in intervention and comparison areas were similar in difference-in-differences analysis of DHS and HMIS data. Logistic regression of DHS data also did not reveal any significant improvement in combined outcomes: birth preparedness, adjusted OR (aOR)=0.8 (95% CI 0.4 to 1.7); antenatal care seeking, aOR=1.0 (0.6 to 1.5); antenatal care quality, aOR=1.4 (0.9 to 2.1); delivery by skilled birth attendant, aOR=1.5 (1.0 to 2.3); immediate newborn care, aOR=1.1 (0.7 to 1.9); postnatal care, aOR=1.3 (0.9 to 1.9). Health providers' knowledge and skills in intervention districts were fair but showed much variation between different providers and districts. This study, while representing an early assessment of impact, did not identify significant improvements in newborn care practices and raises concerns regarding CBNCP implementation. It has contributed to revisions of the package and it being merged with the Integrated Management of Neonatal and Childhood Illness programme. This is now being implemented in 35 districts and carefully monitored for quality and impact. The study also highlights general challenges in evaluating the impacts of a complex health intervention under 'real life' conditions.