[Place of transurethral contact nephrolithotripsy in the treatment of patients with kidney stones].
Currently, the question of choosing the optimal treatment for patients with large (> 20 mm) concretions is still open. Extracorporeal shock wave lithotripsy (ESWL) and percutaneous nephrolitholapaxy (PNL) are the main methods for removing of such concretions, with efficiency of 45-63, and 86-100%, respectively. Development of semirigid and flexible endoscopes, the creation of new types of contact lithotriptors have expanded the possibilities for use of transurethral treatment of urolithiasis. Results of treatment of 63 patients who underwent transurethral nephrolithotripsy (TUNL) for the large concretions in pelvicalyceal system (PCS) were analyzed. Selection of energy type for contact lithotripsy depended on the location, size, density of stone and type of uretherorenoscope. According to ultrasound and urography data after 30 days, stones and their fragments in the urinary tract were not found in 36 (57.1%) patients, clusters of small residual fragments were identified in 21 (33.3%) patients. In these cases, the stent was removed. During re-examination at 3 months, the full discharge of the fragments was observed in 19 (90.5%) of 21 patients. A separate group consisted of 6 (9.52%) patients, in whom residual concrements in PCS of operated kidneys were found after 30 days. In this group, two patients underwent one session of ESWL; repeated endoscopic interventions were performed in other patients, culminating in the complete removal of stone from PCS. According to the ultrasound and x-ray examinations, 55 (87.3%) patients achieved full exemption from concretions in PCS and urinary tract after 60 days. Thus, TUNL in the treatment of large and multiple kidney stones is comparable with ESWL and PNL on clinical efficacy, and in some clinical situations can be considered as a method of choice for surgical treatment of nephrolithiasis.


Plasma Total Homocysteine Level Is Related to Unfavorable Outcomes in Ischemic Stroke With Atrial Fibrillation.
Background Unlike patients with stroke caused by other mechanisms, the effect of elevated plasma total homocysteine (tHcy) on the prognosis of patients with both ischemic stroke and atrial fibrillation (AF) is unknown. This study aimed to evaluate the association between tHcy level and the functional outcome of patients with AF-related stroke. Methods and Results We included consecutive patients with AF-related stroke between 2013 and 2015 from the registry of a real-world prospective cohort from 11 large centers in South Korea. A 3-month modified Rankin Scale score ≥3 was considered an unfavorable outcome. Since tHcy is strongly affected by renal function, we performed a subgroup analysis according to the presence of renal dysfunction. A total of 910 patients with AF-related stroke were evaluated (mean age, 73 years; male sex, 56.0%). The mean tHcy level was 11.98±8.81 μmol/L. In multivariable analysis, the tHcy level (adjusted odds ratio, 1.04; 95% CI, 1.01-1.07, per 1 μmol/L) remained significantly associated with unfavorable outcomes. In the subgroup analysis based on renal function, tHcy values above the cutoff point (≥14.60 μmol/L) showed a close association with the unfavorable outcome only in the normal renal function group (adjusted odds ratio, 3.10; 95% CI, 1.60-6.01). In patients with renal dysfunction, tHcy was not significantly associated with the prognosis of AF-related stroke. Conclusions A higher plasma tHcy level was associated with unfavorable outcomes in patients with AF-related stroke. This positive association may vary according to renal function but needs to be verified in further studies.


Cutting edge: generation of effector cells that localize to mucosal tissues and form resident memory CD8 T cells is controlled by mTOR.
Mucosal tissues are subject to frequent pathogen exposure and are major sites for transmission of infectious disease. CD8 T cells play a critical role in controlling mucosa-acquired infections even though their migration into mucosal tissues is tightly regulated. The mechanisms and signals that control the formation of tissue-resident memory CD8 T cells are poorly understood; however, one key regulator of memory CD8 T cell differentiation, mammalian target of rapamycin kinase, can be inhibited by rapamycin. We report that, despite enhancing the formation of memory CD8 T cells in secondary lymphoid tissues, rapamycin inhibits the formation of resident memory CD8 T cells in the intestinal and vaginal mucosa. The ability of rapamycin to block the formation of functional resident CD8 T cells in mucosal tissues protected mice from a model of CD8 T cell-mediated lethal intestinal autoimmunity. These findings demonstrate an opposing role for mammalian target of rapamycin in the formation of resident versus nonresident CD8 T cell immunity.


Environmental transmission of norovirus gastroenteritis.
The advent of molecular techniques and their increasingly widespread use in public health laboratories and research studies has transformed the understanding of the burden of norovirus. Norovirus is the most common cause of community-acquired diarrheal disease across all ages, the most common cause of outbreaks of gastroenteritis, and the most common cause of foodborne disease in the United States. They are a diverse group of single-stranded RNA viruses that are highly infectious and stable in the environment; both symptomatic and asymptomatic infections are common. Through shedding in feces and vomit, norovirus can be transmitted directly through an array of routes: person-to-person, food or the environment. The relative importance of environmental transmission of virus is yet to be fully quantified but is likely to be substantial and is an important feature that complicates control.


Exposure to phagolysosomal simulated fluid altered the cytotoxicity of PET micro(nano)plastics to human lung epithelial cells.
The occurrence of micro(nano)plastics into various environmental and biological settings influences their physicochemical and toxic behavior. Simulated body fluids are appropriate media for understanding the degradation, stability, and interaction with other substances of any material in the human body. When the particles enter the human body via inhalation, which is one of the avenues for micro(nano)plastics, they first come into contact with the lung lining fluid under neutral conditions and then are phagocytosed under acidic conditions to be removed. Therefore, it is important to examine the physicochemical transformation and toxicity characteristics after interaction with phagolysosomal simulant fluid (PSF). Here, we focused on exploring how the physicochemical differences (e.g. surface chemistry, elemental distribution, and surface charge) of micro(nano)plastics under pH 4.5 phagolysosome conditions impact cytotoxicity and the oxidative characteristics of lung epithelia cells. The cytotoxicity of lung epithelia cells to those treated with PSF and non-treated micro(nano)plastics was tested by various viability indicators including cell counting kit-8 (CCK-8), MTT, and LDH. Furthermore, the cytotoxicity background was examined through the oxidative processes (e.g. reactive oxygen species, antioxidant, superoxide dismutase (SOD), catalase, and reduced glutathione). The results showed that all tested surface physicochemical characteristics were significantly influenced by the phagolysosome conditions. The staged responses were observed with the treatment duration, and significant changes were calculated in carbonyl, carbon-nitrogen, and sulfonyl groups. Moreover, the negativity of the zeta potentials declined between exposure of 2-40 h and then increased at 80 h compared to control owing to the chemical functional groups and elemental distribution of the plastic particles. The tested viability indicators showed that the micro(nano)plastics treated with PSF were cytotoxic to the lung epithelia cells compared to non-treated micro(nano)plastics, and SOD was the dominant enzyme triggering cytotoxicity due to the particle degradation and instability.


The latent structure of posttraumatic stress disorder: a taxometric investigation of reactions to extreme stress.
Mental health professionals have debated whether posttraumatic stress disorder (PTSD) can be qualitatively distinguished from normal reactions to traumatic events. This debate has been fueled by indications that many trauma-exposed individuals evidence partial presentations of PTSD that are associated with significant impairment and help-seeking behavior. The authors examined the latent structure of PTSD in a large sample of male combat veterans. Three taxometric procedures-MAMBAC, MAXEIG, and L-Mode-were performed with 3 indicator sets drawn from a clinical interview and a self-report measure of PTSD. Results across procedures, consistency tests, and analysis of simulated comparison data all converged on a dimensional solution, suggesting that PTSD reflects the upper end of a stress-response continuum rather than a discrete clinical syndrome.


Percutaneous, Transtrapezial Fixation without Bone Graft Leads to Consolidation in Selected Cases of Delayed Union of the Scaphoid Waist.
Purpose We evaluated clinical and radiographic outcome of percutaneous transtrapezial fixation of the scaphoid delayed union or nonunion using a headless bone screw without bone grafting. Methods Sixteen patients with delayed union or nonunion of the scaphoid were included in this retrospective study between 2006 and 2011. All patients had a delayed presentation of scaphoid fracture, and none of them was treated conservatively elsewhere. Patients with bone graft, sclerotic bone debridement, or displacement of the fragment at the nonunion site were excluded. A percutaneous transtrapezial fixation technique was used in all cases. Patients were reviewed until clinical and radiographic union was observed. At the final follow-up, DASH (Disabilities of the Arm, Shoulder and Hand) and PRWHE (Patient-Rated Wrist and Hand Evaluation) outcome scores were completed. Results Radiographic union was obtained in 15 out of 16 patients (94%) at an average follow-up of 36 months (range: 12-98 months). No complications from the percutaneous technique were noted. The average DASH score was 6 (range: 0-39) and the average PRWHE score was 10 (range: 0-56). No statistical significant difference in range of motion and grip strength was found between the operated side and the contralateral side. Conclusion Percutaneous transtrapezial screw fixation for delayed or nonunion of selected scaphoid fractures without bone grafting is promising. At a mean of 4 months, 94% union was obtained with good functional results when there was no sclerosis, minimal osteolysis, and no displacement at the scaphoid nonunion site. Type of Study Therapeutic study. Level of Evidence IV.


Estimated prevalence and patterns of presumed osteoporosis among older Americans based on Medicare data.
Estimates of osteoporosis (OP) prevalence based on bone mineral density testing and fracture occurrence may be imprecise for small demographic groups. Medicare data are a useful supplemental source of information on OP. We studied people ages > or = 65 years covered by Medicare 2005. Cases of presumed OP were beneficiaries with physician services or inpatient claims for OP or for an associated fracture (hip, distal forearm, spine) in 1999-2005. Among 911,327 beneficiaries with 6 or 7 years of Medicare coverage, the overall prevalence of OP and associated fractures was 29.7%. Prevalence was four times higher for women than men, increased with age, and was two times higher for whites, Hispanic Americans, and Asian Americans than African Americans. Among people with OP-associated fracture claims, the proportion with an OP diagnosis was 49.7% overall (women, 57.1%; men, 21.9%) and was lower for men than women and for African Americans than other ethnic groups. The low proportion of beneficiaries who had an OP-associated fracture and also had an OP diagnosis, particularly among men and African American women, suggests suboptimal recognition and management of OP. Study limitations included lack of validation of our definition of OP and potential misclassification of race/ethnicity.


Use of the bnx/hu xenograft model of human hematopoiesis to optimize methods for retroviral-mediated stem cell transduction (Review).
The potentiality of primitive human hematopoietic cells can be profoundly affected by in vitro culture. Due to the growing number of protocols proposed for stem cell gene therapy and ex vivo expansion, it is crucial to define methods to preserve the generative capacity of human stem cells in culture while promoting self-renewal divisions. Stem cell division, homing, and subsequent lineage development can only be studied definitively by marking of pluripotent cells, followed by tracking and clonal analysis of the progeny in a long-term transplantation system. We have developed a bnx/hu xenograft model, in which transduced human hematopoietic cells can be individually tracked into different lineages over the course of one year post-transplantation. The tracking is accomplished by single cell cloning of individual T lymphoid and myeloid progenitors recovered from the marrow of the mice, and clonal integration analysis by the sensitive technique of single-colony inverse PCR. All cells derived from a stem cell transduced by a retroviral vector will carry the unique restriction fragment length polymorphism (RFLP) created by the random integration event. We have used the bnx/hu xenograft system coupled with single-colony inverse PCR to determine that human stem cells require stromal support, fibronectin support with cytokines, or the presence of Flt3 ligand during a 72-h ex vivo culture to maintain the ability to sustain long-term multilineage hematopoiesis.


Investigating Various Thresholds as Immunohistochemistry Cutoffs for Observer Agreement.
Clinical translation of immunohistochemistry (IHC) biomarkers requires reliable and reproducible cutoffs or thresholds for interpretation of immunostaining. Most IHC biomarker research focuses on the clinical relevance (diagnostic, prognostic, or predictive utility) of cutoffs, with less emphasis on observer agreement using these cutoffs. From the literature, we identified 3 commonly used cutoffs of 10% positive epithelial cells, 20% positive epithelial cells, and moderate to strong staining intensity (+2/+3 hereafter) to use for investigating observer agreement. A series of 36 images of microarray cores stained for 4 different IHC biomarkers, with variable staining intensity and percentage of positive cells, was used for investigating interobserver and intraobserver agreement. Seven pathologists scored the immunostaining in each image using the 3 cutoffs for positive and negative staining. Kappa (κ) statistic was used to assess the strength of agreement for each cutoff. The interobserver agreement between all 7 pathologists using the 3 cutoffs was reasonably good, with mean κ scores of 0.64, 0.59, and 0.62, respectively, for 10%, 20%, and +2/+3 cutoffs. A good agreement was observed for experienced pathologists using the 10% cutoff, and their agreement was statistically higher than for junior pathologists (P=0.02). In addition, the mean intraobserver agreement for all 7 pathologists using the 3 cutoffs was reasonably good, with mean κ scores of 0.71, 0.60, and 0.73, respectively, for 10%, 20%, and +2/+3 cutoffs. For all 3 cutoffs, a positive correlation was observed with perceived ease of interpretation (P<0.003). Finally, cytoplasmic-only staining achieved higher agreement using all 3 cutoffs than mixed staining patterns. All 3 cutoffs investigated achieve reasonable strength of agreement, modestly decreasing interobserver and intraobserver variability in IHC interpretation. These cutoffs have previously been used in cancer pathology, and this study provides evidence that these cutoffs can be reproducible between practicing pathologists.


Investigation of neovascularization in three-dimensional porous scaffolds in vivo by a combination of multiscale photoacoustic microscopy and optical coherence tomography.
It is a grand challenge to visualize and assess in vivo neovascularization in a three-dimensional (3D) scaffold noninvasively, together with high spatial resolution and deep penetration depth. Here we used multiscale photoacoustic microscopy (PAM), including acoustic-resolution PAM (AR-PAM) and optical-resolution PAM (OR-PAM), to chronically monitor neovascularization in an inverse opal scaffold implanted in a mouse model up to 6 weeks by taking advantage of the optical absorption contrast intrinsic to hemoglobin molecules in red blood cells. By combining with optical coherence tomography (OCT) based on optical scattering contrast, we also demonstrated the capability to simultaneously image and analyze the vasculature and the scaffold in the same mouse. The hybrid system containing OR-PAM and OCT offered a fine lateral resolution of ∼5 μm and a penetration depth of ∼1 mm into the scaffold/tissue construct. AR-PAM further extended the penetration depth up to ∼3 mm at a lateral resolution of ∼45 μm. By quantifying the 3D PAM data, we further examined the effect of pore size (200 vs. 80 μm) of a scaffold on neovascularization. The data collected from PAM were consistent with those obtained from traditional invasive, labor-intensive histologic analyses.


Isolation and Characterization of Lactobacillus brevis Phages.
Lactobacillus brevis has been widely used in industry for fermentation purposes. However, it is also associated with the spoilage of foods and beverages, in particular, beer. There is an increasing demand for natural food preservation methods, and in this context, bacteriophages possess the potential to control such spoilage bacteria. Just a few studies on phages infecting Lactobacillus brevis have been performed to date and in the present study, we report the isolation and characterization of five virulent phages capable of infecting Lb. brevis strains. The analysis reveals a high diversity among the isolates, with members belonging to both, the Myoviridae and Siphoviridae families. One isolate, designated phage 3-521, possesses a genome of 140.8 kb, thus representing the largest Lb. brevis phage genome sequenced to date. While the isolated phages do not propagate on Lb. brevis beer-spoiling strains, phages showed activity against these strains, impairing the growth of some Lb. brevis strains. The results highlight the potential of bacteriophage-based treatments as an effective approach to prevent bacterial spoilage of beer.


An unusual banded structure in Ewing's sarcoma.
In a largely haemorrhagic and necrotic specimen of Ewing's sarcoma we found banded structures (periodicity of banding about 250 nm) of a type hitherto not known to occur in any normal or pathological tissue. Morphological appearances suggested that these structures had evolved from the fibrin which was always closely associated with them. However, this idea was abandoned because the periodicity of banding of these structures is about ten times greater than the known periodicity of banding of fibrin. These structures have the same periodicity of banding as fibrous long-spacing collagen produced in vitro and about twice the periodicity of banding of fibrous long-spacing collagen found in vivo. However, they lack the fine striations or minor bands of the in vitro fibrous long-spacing collagen. We therefore conclude that the banded structures in this tumour represent a new form of fibrous long-spacing collagen which shares the features of in vitro and in vivo types of fibrous long-spacing collagen.


Injection granuloma mimicking soft tissue sarcoma following seasonal influenza vaccine administration: A case report.
Soft tissue masses are common within the general population with a minority diagnosed as soft tissue neoplasms. Differing between benign and malignant soft tissue processes can be a challenge given the overlapping clinical and imaging characteristics. We present the case of a 69-year-old female referred to the Orthopaedic Oncology Service for evaluation of a suspected soft tissue sarcoma in the upper arm. She reported a mass localized over the deltoid with associated tenderness 1 month after influenza vaccination. After thorough consideration of the patient's clinical course, history, advanced imaging, and physical examination, the diagnosis of injection granuloma associated with recent influenza vaccination was considered. Biopsy was deferred and close interval follow-up with clinical and imaging evaluation revealed a resolving process. The patient was followed until complete resolution of all symptoms, which occurred 5 months after initial presentation. It was hypothesized that due the patient's body habitus, the injection contents intended for intramuscular administration remained in the subcutaneous tissues and elicited a granulomatous reaction. This case highlights several important factors for physicians to consider in the work up of suspicious masses for which injection granuloma is on the differential diagnosis.


Crystal structure of elongation factor P from Thermus thermophilus HB8.
Translation elongation factor P (EF-P) stimulates ribosomal peptidyltransferase activity. EF-P is conserved in bacteria and is essential for cell viability. Eukarya and Archaea have an EF-P homologue, eukaryotic initiation factor 5A (eIF-5A). In the present study, we determined the crystal structure of EF-P from Thermus thermophilus HB8 at a 1.65-A resolution. EF-P consists of three beta-barrel domains (I, II, and III), whereas eIF-5A has only two domains (N and C domains). Domain I of EF-P is topologically the same as the N domain of eIF-5A. On the other hand, EF-P domains II and III share the same topology as that of the eIF-5A C domain, indicating that domains II and III arose by duplication. Intriguingly, the N-terminal half of domain II and the C-terminal half of domain III of EF-P have sequence homologies to the N- and C-terminal halves, respectively, of the eIF-5A C domain. The three domains of EF-P are arranged in an "L" shape, with 65- and 53-A-long arms at an angle of 95 degrees, which is reminiscent of tRNA. Furthermore, most of the EF-P protein surface is negatively charged. Therefore, EF-P mimics the tRNA shape but uses domain topologies different from those of the known tRNA-mimicry translation factors. Domain I of EF-P has a conserved positive charge at its tip, like the eIF-5A N domain.


Induction of tibial dyschondroplasia in turkeys by tetramethylthiuram disulfide (thiram).
Tibial dyschondroplasia (TD) is a prevalent skeletal abnormality associated with rapid growth rate in many avian species; it causes enormous economic losses and is an animal welfare problem. Tibial dyschondroplasia is characterized by the presence of a nonvascularized, nonmineralized lesion that extends from the epiphyseal growth plate into the metaphysis of the proximal tibiotarsal bones. The mechanisms underlying TD development are not known, although they have been extensively studied in broilers using different induction models. However, an effective model for TD induction in turkeys has never been described. The objective of this study was to establish such a model by using tetramethylthiuram disulfide (thiram), an agent that is frequently used in broilers to induce TD. We found that dramatically longer exposures to much higher concentrations of thiram were required to induce TD in turkeys vs. broilers. In contrast to broilers, in which 50 mg/kg of thiram induces a high incidence of severe TD within 10 d, in turkeys, an exposure to 400 mg/kg of thiram for 11 wk was necessary for the development of severe TD lesions. These results show different mechanisms for TD induction in these 2 closely related species, suggesting differences in TD etiology between them.


Effect of Neuromodulation of Short-term Plasticity on Information Processing in Hippocampal Interneuron Synapses.
Neurons in a micro-circuit connected by chemical synapses can have their connectivity affected by the prior activity of the cells. The number of synapses available for releasing neurotransmitter can be decreased by repetitive activation through depletion of readily releasable neurotransmitter (NT), or increased through facilitation, where the probability of release of NT is increased by prior activation. These competing effects can create a complicated and subtle range of time-dependent connectivity. Here we investigate the probabilistic properties of facilitation and depression (FD) for a presynaptic neuron that is receiving a Poisson spike train of input. We use a model of FD that is parameterized with experimental data from a hippocampal basket cell and pyramidal cell connection, for fixed frequency input spikes at frequencies in the range of theta (3-8 Hz) and gamma (20-100 Hz) oscillations. Hence our results will apply to micro-circuits in the hippocampus that are responsible for the interaction of theta and gamma rhythms associated with learning and memory. A control situation is compared with one in which a pharmaceutical neuromodulator (muscarine) is employed. We apply standard information-theoretic measures such as entropy and mutual information, and find a closed form approximate expression for the probability distribution of release probability. We also use techniques that measure the dependence of the response on the exact history of stimulation the synapse has received, which uncovers some unexpected differences between control and muscarine-added cases.


Two-Stage Shape Memory Alloy Identification Based on the Hammerstein-Wiener Model.
Thanks to characteristics, such as high force and light weight, a good biocompatibility, noiseless operation and simplicity, and relatively low-cost compared with other conventional actuators, actuators based on shape memory alloy are currently one of the most interesting research topics. They have been introduced in applications such robotics, medicine, automation, and so on. For a good actuator integration of these types of applications, proper control is needed, which seems to be a difficult task due to the hysteresis, dilatory response, and non-linear behavior. This work presents a new form of modeling of this type of actuator based on Hammerstein-Wiener model. This has been identified in two stages of the operation. When the activation temperature for the actuator is obtained by the Joule effect, electrically energy is transformed into thermal energy. In the second stage, the thermal energy is transformed into mechanical work. To fulfill this objective, experimental data [e.g., the input signal (pulse-width modulation), temperature signal, and position signal] from the two stages was obtained for a specific shape memory alloy wire and for specific environmental conditions. This data was used in the modeling process. The final model consists of a combination of the models from the two stages, which represent the behavior of the shape memory alloy actuator where the input signal is the pulse-width modulation signal and the output signal are the position of the actuator. Our results indicate that our model has a very similar response to the behavior of the real actuator. This model can be used to tune different control algorithms, simulate the entry system before manufacture and test on real devices.


CHMP4B and VSP4A reverse GSDMD-mediated pyroptosis by cell membrane remodeling in endometrial carcinoma.
In advanced and recurrent endometrial carcinoma (EC), the current state of immuno- or targeted therapy remains in the clinical research phase. Our study aimed to explore the role of the ESCRT machinery in maintaining cell membrane integrity and reversing pyroptotic cell death. Immunohistochemistry, western blotting, and co-immunoprecipitation were performed to determine the expression and relationship between GSDMD, CHMP4B, and VPS4A. We employed techniques such as FITC Annexin V/propidium iodide staining, Ca2+ fluorescence intensity, IL-1β enzyme-linked immunosorbent assay, and lactate dehydrogenase release assay to detect pyroptosis in endometrial cancer cells. Plasma membrane perforations and CHMP4B/VPS4A puncta were observed through electron and fluorescence confocal microscopy. We showed that GSDMD, CHMP4B, and VPS4A were differentially expressed in the pyroptotic EC xenograft mouse model group, as well as high, moderate, and mild expression in EC cells treated with LPS and nigericin compared to endometrial epithelial cells. Co-IP confirmed the interaction between GSDMD, CHMP4B, and VPS4A. We found that GSDMD knockdown reduced PI-positive cells, Ca2+ efflux, IL-1β, and LDH release, while CHMP4B and VPS4A depletion enhanced these indicators in HEC1A and AN3CA cells. Electron microscopy showed membrane perforations correspondingly decreased with inactivated GSDMD and increased or decreased after CHMP4B and VPS4A depletion or overexpression in EC cells. Fluorescence confocal microscopy detected CHMP4B protein puncta associated with VPS4A at the injured plasma membrane in GSDMDNT cells. We preliminary evidenced that CHMP4B and VPS4A reverses GSDMD-mediated pyroptosis by facilitating cell membrane remodeling in endometrial carcinoma. Targeting CHMP4B related proteins may promote pyroptosis in endometrial tumors.


Identification of an antisense transcript to ZIM2 in the primate lineage.
In this study, we identified an antisense transcript to ZIM2 (zinc finger imprinted gene 2) in the human, called ZIM2as. Sequence analysis of the 110 kb region spanned by this transcript revealed a cluster of tandemly repeated sequence in the human, orangutan, and chimpanzee as well as a loss of approximately 70 kb from the corresponding region in the rhesus. The homologous region in most mammals contains a cluster of olfactory receptor (OLFR) genes, but this gene cluster has been lost from the primate lineage. Expression analyses confirmed that ZIM2as is expressed in the human brain and testis. Two CpG islands near the promoter region of ZIM2as showed different methylation patterns in these three species. The CpG island distal to ZIM2as showed an allele-specific DNA methylation pattern in the human testis, while the CpG island proximal to the ZIM2as promoter showed a mosaic methylation pattern in the chimpanzee. The methylation status of several nearby zinc finger genes was unchanged among the primates tested. Overall, this study reports the presence of a previously unreported primate-specific antisense transcript in the PEG3 imprinted domain, suggesting that the formation of this transcript may coincide with the loss of the OLFR cluster.


A comparative study on the knowledge levels of artificial intelligence programs in diagnosing ophthalmic pathologies and intraocular tumors evaluated their superiority and potential utility.
This study aimed to test the knowledge levels of ChatGPT, Bing, and Bard artificial intelligence chatbots, which have been released by three different manufacturers, about ophthalmic pathologies and intraocular tumors, to test their usability and to investigate the presence of superiority to each other. Thirty-six questions were obtained from the American Academy and Ophthalmology 2022-2023 Basic and Clinical Science Course Ophthalmic Pathology and Intraocular Tumor study questions section. Each question was asked separately for the ChatGPT, Bing, and Bard artificial intelligence programs. Answers to the questions were categorized as correct or incorrect. The statistical relationship between the correct and incorrect response rates of the artificial intelligence programs was determined. From the artificial intelligence chatbots, ChatGPT gave the correct answer to 58.6% of the questions asked, Bing gave the correct answer to 63.9%, and Bard gave the correct answer to 69.4%. No statistical significance was found between the rates of correct answers to the questions in all 3 artificial intelligence programs (p = 0.705, Pearson Chi-square test). Artificial intelligence chatbots can be used to access information related to ophthalmic pathologies and intraocular tumors. However, in the evaluation of the data, it should be noted that not all questions can be answered correctly. Care should be taken when examining the answers.


Abscisic acid biosynthesis and catabolism.
The level of abscisic acid (ABA) in any particular tissue in a plant is determined by the rate of biosynthesis and catabolism of the hormone. Therefore, identifying all the genes involved in the metabolism is essential for a complete understanding of how this hormone directs plant growth and development. To date, almost all the biosynthetic genes have been identified through the isolation of auxotrophic mutants. On the other hand, among several ABA catabolic pathways, current genomic approaches revealed that Arabidopsis CYP707A genes encode ABA 8'-hydroxylases, which catalyze the first committed step in the predominant ABA catabolic pathway. Identification of ABA metabolic genes has revealed that multiple metabolic steps are differentially regulated to fine-tune the ABA level at both transcriptional and post-transcriptional levels. Furthermore, recent ongoing studies have given new insights into the regulation and site of ABA metabolism in relation to its physiological roles.


Towards the Development of Novel Hybrid Composite Steel Pipes: Electrochemical Evaluation of Fiber-Reinforced Polymer Layered Steel against Corrosion.
Corrosion remains one of the major and most costly challenges faced by the steel industry. Various fiber-reinforced polymer coating systems have been proposed to protect metallic piping distribution networks against corrosion. Despite increasing interest among scientific and industrial communities, there is only limited predictive capability for selecting the optimum composite system for a given corrosive condition. In this study, we present a comprehensive evaluation of the electrochemical behavior of two different fiber-reinforced polymer composite systems against the corrosion of carbon steel pipes under a wide range of acidic and corrosive solutions. The composites were made of glass and Kevlar fibers with an epoxy resin matrix and were subjected to corrosive solutions of 0.5 M NaCl, 0.5 M HCl, and 0.5 M H2SO4. The kinetics of the corrosion reactions were evaluated using potentiodynamic polarization (PDP) tests. In addition, electrochemical impedance spectroscopy (EIS) tests were carried out at open circuit potentials (OCPs). It was demonstrated that the glass fiber-reinforced polymer coating system offered the best protection against corrosion, with a high stability against deterioration when compared with epoxy and Kevlar fiber-reinforced polymer coating systems. Scanning electron microscopy images revealed cracks and deteriorated embedded fibers due to acid attack, sustained/assisted by the diffusion of the corrosion species.


Telerehabilitation use and experiences in occupational and physical therapy through the early stages of the COVID-19 pandemic.
Telehealth has helped to increase access to rehabilitative services such as occupational and physical therapy. The early COVID-19 pandemic amplified the need for remote access to care, and the rapid implementation of telehealth systems provided a unique opportunity to learn from clinicians' experiences adopting telehealth for telerehabilitation applications. To understand these experiences, a self-administered online survey was conducted to capture perspectives on ease of telerehabilitation use and adoption from occupational and physical therapists. The survey captured retrospective views on telerehabilitation use pre-pandemic as well as real-time perspectives on telerehabilitation during the early stages of the pandemic (July to August 2020). The survey gathered information on clinician demographics (N = 109), clinicians' experiences with adopting or utilizing telerehabilitation systems, and their perceptions on remotely performing cognitive, emotional, and physical assessments via video-conferencing (a common mode of telehealth). Responses demonstrated a modest increase in telerehabilitation as a care setting (rate increase from 3.4% to 19.3%), and telerehabilitation was more generally tried during the early stages of the pandemic (41 clinicians explicitly reported telerehabilitation use). However, technology access and acceptance remained low, with 38 clinicians (35%) expressing concerns that technology was ineffective or impractical, unavailable, not covered by insurance, or not desired by their patients. Video-conferencing technology was perceived as generally ill-equipped to support clinicians in performing remote assessment tasks. Physical assessment tasks were considered particularly difficult, with 55% of clinicians rating their ability to perform these tasks in the range of moderately difficult to unable to perform. To address these difficulties and better augment clinical care, clinicians require more robust assessment methods that may combine video, mobile, and wearable technologies that would be accessible to a patient at home. When designing future telerehabilitation tools, information captured through these modes must be task-relevant, standardized, and understandable to a remote clinician.


Innate immune response to Anaplasma phagocytophilum contributes to hepatic injury.
In mice, Anaplasma phagocytophilum control is independent of phagocyte oxidase (phox), inducible NO synthase (NOS2), tumor necrosis factor (TNF), and MyD88 Toll-like receptor signaling. We show that despite evasion of these host responses, phox, NOS2, TNF, and MyD88 are activated and contribute to inflammation and hepatic injury more than A. phagocytophilum itself.


Organocatalyzed ring-opening copolymerization of α-bromo-γ-butyrolactone with ε-caprolactone for the synthesis of functional aliphatic polyesters - pre-polymers for graft copolymerization.
Diphenyl phosphate (DPP) was exploited as an organocatalyst to synthesize copolymers by ring-opening polymerization with α-bromo-γ-butyrolactone (αBrγBL) and ε-caprolactone (εCL) as monomers and polyethylene glycol (PEG) as initiator. The conversion rates of monomers and molecular weights of copolymers synthesized under different conditions were determined by 1H-NMR. The 1H-NMR results showed that the copolymers of αBrγBL and εCL initiated by PEG (PEGCB) were successfully synthesized and the conversions of εCL were relatively high (>70%), while the conversions of αBrγBL were relatively low (<26%). The highest molar ratio of αBrγBL to εCL units in these copolymers is 0.17, when the copolymerization was carried out at 100℃ for 17h. The bromine atoms hanged on the chain of the copolymers PEGCB provide a good opportunity to construct graft copolymers via atom transfer radical polymerization (ATRP). The subsequent grafting of 2-(dimethylamino)ethyl methacrylate (DMAEMA) was conducted by using PEGCB3 as macroinitiator, CuBr/N,N',N',N",N"- pentamethyldiethylenetriamine (PMDETA) as catalysts and toluene/anisole as solvents via ATRP. According to the analysis of 1H-NMR, the grafting efficiency, grafting ratio and grafting frequency were 22.4%, 160.7% and 1133.8, respectively.


Catalytic stereospecific O-glycosylation.
A new simple protocol, using TMSNTf2 or Tf2NH as the catalyst, for the activation of trichloroacetimidate donors is described. This O-glycosylation proceeds with stereospecific inversion of the donor configuration. The scope of the protocol has been investigated using common glycosyl donors reacting with simple alcohols as well as sugar acceptors.


Viability of Rhizobium bacteroids.
Bacteroids prepared from nodules of soybean and bean were tested for viability. Contrary to the prevailing view that bacteroids are nonviable, it was found that bacteroids averaged 90% viability, irrespective of Rhizobium strain, nodule age, or nodule environment.


Effects of a virtual reality video game exercise program on upper extremity function and daily living activities in stroke patients.
[Purpose] This study examined the effects of training using virtual reality games on stroke patients' functional recovery. [Paticipants and Methods] Twenty-four hemiplegia patients whose disease duration was longer than six months participated in this study. The participants were divided at random into a control group (n=12), which received traditional rehabilitation therapy, and an experimental group (n=12), which received both traditional rehabilitation therapy and training using virtual reality games. The program lasted for a total of 12 weeks. To examine the participants' functional recovery, their upper limb function was measured using the Fugl-Meyer Assessment and Manual Function Test before and after they completed the training and their daily living activities were measured using the Stroke Impact Scale before and after they completed the training. [Results] The experimental group participants' daily living activities improved after training. In addition, the experimental group scored significantly higher on all the tests than the control group, but upper extremity function between the groups was not significantly different. [Conclusion] Stroke patients who completed the additional training using virtual reality games showed significantly greater improvement in their daily living activities than those who only received traditional rehabilitation therapy.


High performance solar-selective absorbers using coated sub-wavelength gratings.
Spectral control of the emissivity of surfaces is essential for efficient conversion of solar radiation into heat. We investigated surfaces consisting of sub-wavelength V-groove gratings coated with aperiodic metal-dielectric stacks. The spectral behavior of the coated gratings was modeled using rigorous coupled-wave analysis (RCWA). The proposed absorber coatings combine impedance matching using tapered metallic features with the excellent spectral selectivity of aperiodic metal-dielectric stacks. The aspect ratio of the V-groove can be tailored in order to obtain the desired spectral selectivity over a wide angular range. Coated V-groove gratings with optimal aspect ratio are predicted to have thermal emissivity below 6% at 720K while absorbing >94% of the incident light. These sub-wavelength gratings would have the potential to significantly increase the efficiency of concentrated solar thermal systems.


Documentation of fatty acid profiles in lamb meat and lamb-based infant foods.
Lamb meat, when used in the weaning diet of children, is presumed to have a lower allergenicity than other forms of red meat. In children with atopic dermatitis and multiple food hypersensitivities, consumption of lamb meat has also resulted in significant clinical improvements in the severity of the eczematous lesions. Lamb meat is also of special interest in infant nutrition because it provides a somewhat unique fatty acid (FA) profile that mirrors what is thought to be optimal for neonatal growth and development. However, very little is known about how the processing of fresh meat (FM) into prepared infant foods influences its FA composition. In this study, we compared the FA profile of FM from suckling lambs with those of homogenized (HO) and lyophilized (LIO) baby foods prepared primarily with lamb meat. The results show that the content of total omega-3 polyunsaturated FAs was the highest in FM (more than 3-fold) compared to commercial baby food, due to largely higher contents of α-linolenic acid (1.5-fold higher), eicosapentaenoic acid (6-fold higher), and docosahexaenoic acid (10-fold higher). Furthermore, arachidonic acid was more than 6-fold higher in FM compared to LIO and HO. Results from this study suggest the possibility of enhancing the FA profile of commercial baby food based on meat by using lamb meat, but care should be taken during processing so that important FAs are not lost. In this article, we have documented that meat from the suckling lamb is an interesting and potentially important source of omega-3-FAs, especially some of the long-chain polyunsaturated FAs (LC-PUFAs) that are essential for optimal neonatal growth and development. These results may have special implications to the infant food industry, in that products made using meat from suckling lambs may provide not only exceptional amounts of these FAs, but also other limiting essential nutrients such as iron. This may be especially important in regions of the world, such as Italy, where use of lamb meat as a weaning food is common during infancy.


The proteasomal subunit S6 ATPase is a novel synphilin-1 interacting protein--implications for Parkinson's disease.
Synphilin-1 is linked to Parkinson's disease (PD), based on its role as an alpha-synuclein (PARK1)-interacting protein and substrate of the ubiquitin E3 ligase Parkin (PARK2) and because of its presence in Lewy bodies (LB) in brains of PD patients. We found that overexpression of synphilin-1 in cells leads to the formation of ubiquitinated cytoplasmic inclusions supporting a derangement of the ubiquitin-proteasome system in PD. We report here a novel specific interaction of synphilin-1 with the regulatory proteasomal protein S6 ATPase (tbp7). Functional characterization of this interaction on a cellular level revealed colocalization of S6 and synphilin-1 in aggresome-like intracytoplasmic inclusions. Overexpression of synphilin-1 and S6 in cells caused reduced proteasomal activity associated with a significant increase in inclusion formation compared to cells expressing synphilin-1 alone. Steady-state levels of synphilin-1 in cells were not altered after cotransfection of S6 and colocalization of synphilin-1-positive inclusions with lysosomal markers suggests the presence of an alternative lysosomal degradation pathway. Subsequent immunohistochemical studies in brains of PD patients identified S6 ATPase as a component of LB. This is the first study investigating the physiological role of synphilin-1 in the ubiquitin proteasome system. Our data suggest a direct interaction of synphilin-1 with the regulatory complex of the proteasome modulating proteasomal function.


Trends of HIV-Related Cancer Mortality between 2001 and 2018: An Observational Analysis.
The burden of AIDS-defining cancers has remained relatively steady for the past two decades, whilst the burden of non-AIDS-defining cancer has increased. Here, we conduct a study to describe mortality trends attributed to HIV-associated cancers in 31 countries. We extracted HIV-related cancer mortality data from 2001 to 2018 from the World Health Organization Mortality Database. We computed age-standardized death rates (ASDRs) per 100,000 population using the World Standard Population. Data were visualized using Locally Weighted Scatterplot Smoothing (LOWESS). Data for females were available for 25 countries. Overall, there has been a decrease in mortality attributed to HIV-associated cancers among most of the countries. In total, 18 out of 31 countries (58.0%) and 14 out of 25 countries (56.0%) showed decreases in male and female mortality, respectively. An increasing mortality trend was observed in many developing countries, such as Malaysia and Thailand, and some developed countries, such as the United Kingdom. Malaysia had the greatest increase in male mortality (+495.0%), and Canada had the greatest decrease (-88.5%). Thailand had the greatest increase in female mortality (+540.0%), and Germany had the greatest decrease (-86.0%). At the endpoint year, South Africa had the highest ASDRs for both males (16.8/100,000) and females (19.2/100,000). The lowest was in Japan for males (0.07/100,000) and Egypt for females (0.028/100,000).


Improving the Laser-Induced Breakdown Spectroscopy for Highly Efficient Trace Measurement of Hazardous Components in Waste Oils.
Improper disposal of waste oils containing hazardous components damages the environment and the ecosystem, posing a significant threat to human life and health. Here, we present a method of discharge-assisted laser-induced breakdown spectroscopy combined with filter paper sampling (DA-LIBS-FPS) to detect hazardous components and trace the source of polluting elements. DA-LIBS-FPS significantly enhances spectral intensity by 1-2 orders of magnitude due to the discharge energy deposition into the laser-induced plasma and the highly efficient laser-sample interaction on the filter paper, when compared to single-pulse LIBS with silica wafer sampling (SP-LIBS-SWS). Additionally, the signal-to-noise ratio and the signal-to-background ratio are both significantly increased. Resultantly, indiscernible lines, such as CN and Cr I, are well distinguished. In contrast with DA-LIBS combined with silica wafer sampling (DA-LIBS-SWS), the spectral signal fluctuations in DA-LIBS-FPS are reduced by up to 33%, because of the homogeneous distribution of the oil layer on the filter paper in FPS. Further examination indicates that the limit of detection for Ba is reduced from a several parts per million level in SP-LIBS-SWS to a dozens of parts per billion level in DA-LIBS-FPS, i.e., nearly 2 orders of magnitude enhancement in analysis sensitivity. This improvement is attributed to the extended plasma lifespan in DA-LIBS and the increasing electron density and plasma temperature in FPS. DA-LIBS-FPS provides a low-cost, handy, rapid, and highly sensitive avenue to analyze the hazardous components in waste oils with great potential in environmental and ecological monitoring.


p53 expression and tumor proliferative activity in testicular germ-cell tumors.
We evaluated p53 expression and tumor proliferative activity (TPA) using monoclonal antibodies to Ki-67 and proliferating cell nuclear antigen (PCNA) in 26 patients with seminomatous and nonseminomatous testicular germ-cell tumors (GCTs). Correlation between p53 expression and TPA, as well as the clinical correlation with the expression of these proteins were also assessed. There were eight cases of pure seminoma and 18 cases of nonseminomatous GCTs, collectively consisting of 45 tumors or tumor components. The nonseminomatous GCTs were mixed or pure and included choriocarcinoma (CC), embryonal carcinoma (EC), immature teratoma (IMT), mature teratoma (MT), seminoma, and yolk sac tumor (YST). The ages of the patients with seminomatous GCTs ranged from 24 to 47 years (mean, 34 years) and those for patients with nonseminomatous GCTs ranged from 17 to 43 years (mean, 29 years). Sixteen (44%) of the 36 nonseminomatous GCTs or tumor components were positive for p53 protein. Ten (91%) of eleven ECs, three (38%) of eight YSTs, two (20%) of ten MTs, and the single case of CC were positive for p53 protein. All nine seminomas and three of six IMTs were only focally positive for p53 protein. The p53 expression in ECs and YSTs was significantly higher than that in IMTs, MTs, and seminomas (P=0.0001). TPA was present in the majority of the seminomatous and nonseminomatous GCTs, and was significantly higher in ECs and YSTs than in seminomas, MTs, and IMTs (Ki-67, P=0.0001; PCNA, P=0.0006). In the majority of the cases PCNA expression was higher than Ki-67 expression (P=0.0001). The mean TPA percentage was significantly higher in the p53-positive tumors or tumor components (EC and YST) when compared with the mean TPA percentage in those neoplasms that were focally positive or negative for p53 protein (Ki-67, P=0.003; PCNA, P=0.046). p53 expression was also associated with histologically aggressive tumors (ECs and YSTs) that also exhibit high TPA. No relationship appears to exist between the three tumor markers and the clinical stage or the patients' follow-up and outcome in this small series. Further studies are necessary to elucidate the roles of p53 and proliferation markers in testicular tumorigenesis and as prognostic markers.


Mapping regional grey and white matter atrophy in relapsing-remitting multiple sclerosis.
We aimed to investigate the regional distribution of grey matter (GM) and white matter (WM) atrophy in patients with relapsing-remitting (RR) MS and their relationship with gender, clinical findings, and T2 lesions. Clinical and magnetic resonance imaging assessments were obtained from 78 patients with RRMS and 88 controls. GM and WM atrophy were estimated using voxel-based morphometry (SPM8). Patients with RRMS experienced atrophy of the deep GM nuclei, and several cortical regions mainly located in the fronto-parietal lobes. WM atrophy involved posterior regions of the brain, including the cerebellum and brainstem. Compared with men, affected women showed atrophy of several WM tracts, while gender did not impact GM atrophy. Disease duration > 5 years was associated with atrophy of the thalami and inferior frontal gyrus, while WM atrophy was already prominent in patients with disease duration ≤ 5 years. Expanded Disability Status Scale score > 3.0 was associated with diffuse WM atrophy and basal ganglia and precentral gyrus atrophy. T2 lesions were marginally associated to focal atrophy. In RRMS, GM and WM atrophy have distinct patterns of regional distribution, with a sparing of GM infratentorial regions. Gender, disease duration and disability affect differently the topography of GM/WM atrophy, while T2 lesions play a modest role.


Role of KCC2-dependent potassium efflux in 4-Aminopyridine-induced Epileptiform synchronization.
A balance between excitation and inhibition is necessary to maintain stable brain network dynamics. Traditionally, seizure activity is believed to arise from the breakdown of this delicate balance in favor of excitation with loss of inhibition. Surprisingly, recent experimental evidence suggests that this conventional view may be limited, and that inhibition plays a prominent role in the development of epileptiform synchronization. Here, we explored the role of the KCC2 co-transporter in the onset of inhibitory network-induced seizures. Our experiments in acute mouse brain slices, of either sex, revealed that optogenetic stimulation of either parvalbumin- or somatostatin-expressing interneurons induced ictal discharges in rodent entorhinal cortex during 4-aminopyridine application. These data point to a proconvulsive role of GABAA receptor signaling that is independent of the inhibitory input location (i.e., dendritic vs. somatic). We developed a biophysically realistic network model implementing dynamics of ion concentrations to explore the mechanisms leading to inhibitory network-induced seizures. In agreement with experimental results, we found that stimulation of the inhibitory interneurons induced seizure-like activity in a network with reduced potassium A-current. Our model predicts that interneuron stimulation triggered an increase of interneuron firing, which was accompanied by an increase in the intracellular chloride concentration and a subsequent KCC2-dependent gradual accumulation of the extracellular potassium promoting epileptiform ictal activity. When the KCC2 activity was reduced, stimulation of the interneurons was no longer able to induce ictal events. Overall, our study provides evidence for a proconvulsive role of GABAA receptor signaling that depends on the involvement of the KCC2 co-transporter.


Assays for metabolic alpha-hydroxylation of N'-nitrosonornicotine and N-nitrosopyrrolidine and the influence of modifying factors.
High-pressure liquid chromatographic methods were developed to study microsomal alpha-hydroxylation, which is likely to be an activation mechanism for N-nitrosopyrrolidine (NPYR) and N'-nitrosonornicotine (NNN). The effects of ethanol, phenobarbital and 3-methylcholanthrene pretreatment on the alpha-hydroxylation of NPYR and NNN were determined using F-344 rats and Syrian golden hamsters. In the rat, 3-methylcholanthrene pretreatment decreased the rates of alpha-hydroxylation of NPYR and 5'-hydroxylation of NNN, but increased the rate of 2'-hydroxylation of NNN. Phenobarbital pretreatment of rats did not markedly affect rates of alpha-hydroxylation of NPYR or NNN. In the hamster, 3-methylcholanthrene pretreatment increased the rate of alpha-hydroxylation of NPYR, but did not affect the rates of alpha-hydroxylation of NNN. Phenobarbital or ethanol pretreatment of hamsters resulted in increased rates of alpha-hydroxylation of NPYR and 5'-hydroxylation of NNN. The induction of alpha-hydroxylation of NNN and NPYR by ethanol suggests that these nitrosamines may be more carcinogenic in alcohol-treated animals.


Auto detecting deliveries in elite cricket fast bowlers using microsensors and machine learning.
Cricket fast bowlers are at a high risk of injury occurrence, which has previously been shown to be correlated to bowling workloads. This study aimed to develop and test an algorithm that can automatically, reliably and accurately detect bowling deliveries. Inertial sensor data from a Catapult OptimEye S5 wearable device was collected from both national and international level fast bowlers (n = 35) in both training and matches, at various intensities. A machine-learning based approach was used to develop the algorithm. Outputs were compared with over 20,000 manually recorded events. A high Matthews correlation coefficient (r = 0.945) showed very good agreement between the automatically detected bowling deliveries and manually recorded ones. The algorithm was found to be both sensitive and specific in training (96.3%, 98.3%) and matches (99.6%, 96.9%), respectively. Rare falsely classified events were typically warm-up deliveries or throws preceded by a run. Inertial sensors data processed by a machine-learning based algorithm provide a valid tool to automatically detect bowling events, whilst also providing the opportunity to look at performance metrics associated with fast bowling. This offers the possibility to better monitor bowling workloads across a range of intensities to mitigate injury risk potential and maximise performance.


Cost-effectiveness of apixaban compared to other anticoagulants in patients with atrial fibrillation in the real-world and trial settings.
Randomized clinical trials (RCTs) and real-world data (RWD) in patients with atrial fibrillation have shown that-compared to vitamin K antagonists (VKAs)-non-VKA oral anticoagulants (NOACs) are at least as effective in the prevention of ischaemic stroke, while decreasing the risk of bleeding. We aim to evaluate the cost-effectiveness of the NOAC apixaban versus other NOACs (dabigatran, edoxaban and rivaroxaban) and VKA, for stroke prevention in patients with atrial fibrillation by including the available data both from RCT and real-world analyses of all NOACs into one integrative previously published model. The model was updated to the current Dutch healthcare situation. The incremental cost-effectiveness ratio was calculated using either efficacy/effectiveness and safety data derived from a network meta-analysis (NMA) synthesizing NOAC RCTs or RWD. We conducted a systematic literature search to identify eligible publication to best inform the RWD-based analysis. Additional sensitivity and scenario analyses were conducted to test the robustness of the outcomes. In the NMA-based analysis, apixaban appeared to be cost-effective compared to VKA (€3,506 per quality adjusted life-year) and dominant (cost-saving and more effective) over dabigatran 110 mg, dabigatran 150 mg, edoxaban and rivaroxaban. In the RWD-based analysis, apixaban was dominant over all other anticoagulants. In the scenario analysis apixaban appeared to be not cost-effective compared to dabigatran 150 mg, when using equal event-unrelated treatment discontinuation rates for each drug. In all other scenarios apixaban is cost-effective or cost-saving compared to VKA and other NOACs. Based on RCTs as well as RWD, we conclude that apixaban is generally cost-effective or even cost-saving (less costly and more effective) compared to VKA and other NOACs in the overall population of patients with atrial fibrillation.


Outcome after early thrombotic occlusion of arteriovenous fistulas.
Arteriovenous fistulas (AVFs) are considered the first choice for venous access in end-stage renal disease patients, however, they are also known to have a high primary failure rate (early thrombosis and maturation failure). Of these, the outcome of thrombosed immature AVFs is not well known. This study aimed to investigate the outcome of AVFs with early thrombosis. Patients who underwent AVF creation from January 2009 to December 2019 at Seoul National University Hospital or Seoul Metropolitan Government - Seoul National University Boramae Medical Center were retrospectively reviewed. Patients who received salvage operations due to early thrombosis within 30 days after access creation were analyzed. During the study period, a total of 45 patients (radiocephalic 26; brachiocephalic 19) developed early thrombosis and underwent salvage operations. The median age of patients was 61.0 (54.5-69.5) years, and 51.1% were male. The first salvage operation was performed on the median 1.0 (0.0-4.5) day after AVF creation. The most common cause for early thrombosis was venous stenosis (64.4%) and followed by poor arterial inflow (28.9%), especially in radiocephalic AVFs. About 20 AVFs were salvaged to maturation (46.5%). Post-salvage primary patency and secondary patency at 1 year was 72.6% and 100%. In a multivariate logistic regression, significant risk factors for maturation failures were minimum venous outflow diameter ⩽2.5 mm (OR, 4.433; 95% CI, 1.039-18.921; p = 0.044) and lower in patients with hypertension (OR, 0.064; 95% CI, 0.006-0.637; p = 0.019). Thrombosed immature AVFs are associated with a high failure rate after salvage operation. However, if the salvage operation is successfully performed, it is associated with an acceptable 1-year outcome.


Obesity, adipokines, and prostate cancer in a prospective population-based study.
The purpose of this investigation was to examine the association of obesity and the adipokines leptin, adiponectin, and interleukin-6 (IL-6) with prostate cancer risk and aggressiveness. One hundred twenty-five incident prostate cancer cases and 125 age-matched controls were sampled from among participants in the original San Antonio Center for Biomarkers of Risk of Prostate Cancer cohort study. The odds ratios (OR) of prostate cancer and high-grade disease (Gleason sum >7) associated with the WHO categories of body mass index (kg/m(2)) and with tertiles of serum concentrations of adiponectin, leptin, and IL-6 were estimated using multivariable conditional logistic regression models. Body mass index was not associated with either incident prostate cancer [obese versus normal; OR, 0.75; 95% confidence interval (95% CI), 0.38-1.48; P(trend) = 0.27] or high-grade versus low-grade disease (OR, 1.17; 95% CI, 0.39-3.52; P(trend) = 0.62). Moreover, none of the three adipokines was statistically significant associated with prostate cancer risk or high-grade disease, respectively: leptin (highest versus lowest tertile; OR, 0.77; 95% CI, 0.28-1.37; P(trend) = 0.57; OR, 1.20; 95% CI, 0.48-3.01; P(trend) = 0.85); adiponectin (OR, 0.87; 95% CI, 0.46-1.65; P(trend) = 0.24; OR, 1.93; 95% CI, 0.74-5.10; P(trend) = 0.85); IL-6 (OR, 0.84; 95% CI, 0.46-1.53; P(trend) = 0.98; OR, 0.84; 95% CI, 0.30-2.33; P(trend) = 0.17). Findings from this nested case-control study of men routinely screened for prostate cancer and who had a high prevalence of overweight and obesity do not provide evidence to support that prediagnostic obesity or factors elaborated by fat cells strongly influence prostate cancer risk or aggressiveness. However, due to the small sample population, a small or modest effect of obesity and adipokines on these outcomes cannot be excluded.


The three-dimensional landscape of cortical chromatin accessibility in Alzheimer's disease.
To characterize the dysregulation of chromatin accessibility in Alzheimer's disease (AD), we generated 636 ATAC-seq libraries from neuronal and nonneuronal nuclei isolated from the superior temporal gyrus and entorhinal cortex of 153 AD cases and 56 controls. By analyzing a total of ~20 billion read pairs, we expanded the repertoire of known open chromatin regions (OCRs) in the human brain and identified cell-type-specific enhancer-promoter interactions. We show that interindividual variability in OCRs can be leveraged to identify cis-regulatory domains (CRDs) that capture the three-dimensional structure of the genome (3D genome). We identified AD-associated effects on chromatin accessibility, the 3D genome and transcription factor (TF) regulatory networks. For one of the most AD-perturbed TFs, USF2, we validated its regulatory effect on lysosomal genes. Overall, we applied a systematic approach to understanding the role of the 3D genome in AD. We provide all data as an online resource for widespread community-based analysis.


Identification of putative negative regulators of yeast signaling through a screening for protein phosphatases acting on cell wall integrity and mating MAPK pathways.
The lack of signaling through MAPK pathways leads to a defective cellular response to the corresponding stimulus, but an improper hyperactivation of these routes results in deleterious effects as well. Protein phosphorylation is an activating modification for signal transmission through components of MAPK pathways and thus, protein phosphatases are key negative regulators of these cellular routes by limiting excessive signaling activity. However, in contrast to most of the protein kinases operating in MAPK pathways, protein phosphatases usually exhibit redundancy and promiscuity, which has limited the identification of their function. In order to identify new putative phosphatases operating in Saccharomyces cerevisiae MAPK signaling, we have taken advantage of growth inhibition promoted by overproduction of constitutively active components of the mating and cell wall integrity (CWI) pathways to perform a screen with a collection of 43 protein phosphatases or phosphatase-regulatory proteins. The phosphatases able to alleviate the induced growth inhibition when overproduced were further studied by testing their capacity to downregulate expression of mating and CWI responsive promoters and the consequences of their removal on MAPK signaling. Epistasis analysis placed the Ser/Thr protein phosphatase Ppq1 as a regulator of the mating MAPK module downstream the MAPKKK Ste11. The dual specificity phosphatase Yvh1 was found to be important for the maintenance of cell wall integrity and appropriate signaling through the CWI pathway. Moreover, we have found that Ptc2 and Ptc4 bind to the CWI MAPK Slt2. Together with known phosphatases of the mating and CWI pathway, as Msg5 or Ptp2, other putative negative regulators of both pathways that came up in the screening were Ptc2, Oca2 and Ptp1. We show that Ptp1 physically interacts with Slt2 and the mating MAPK Fus3. Elimination of Ptp1 results in increased signaling through these pathways, suggesting that this tyrosine phosphatase, like Ptp2 and Ptp3, plays a downregulatory role on both MAPKs.


The value of FeNO measurement in childhood asthma: uncertainties and perspectives.
Asthma is considered an heterogeneous disease, requiring multiple biomarkers for diagnosis and management. Fractional exhaled nitric oxide in exhaled breath (FeNO) was the first useful non-invasive marker of airway inflammation in asthma and still is the most widely used. The non-invasive nature and the relatively easy use of FeNO technique make it an interesting tool to monitor airway inflammation and rationalize corticosteroid therapy in asthmatic patients, together with the traditional clinical tools (history, physical examination and lung function tests), even if some controversies have been published regarding the use of FeNO to support the management of asthma in children. The problem of multiple confounding factors and overlap between healthy and asthmatic populations preclude the routine application of FeNO reference values in clinical practice and suggest that it would be better to consider an individual "best", taking into account the context in which the measurement is obtained and the clinical history of the patient. Besides, there is still disagreement about the role of FeNO as a marker of asthma control, due to the complexity of balance among the different items involved in its determination and the lack of homogeneity in the population groups studied in the few studies conducted so far. Heterogeneity of problematic severe asthma greatly limits utility of FeNO alone as a biomarker of inflammation to optimize the disease management on an individual basis. None of the studies conducted so far demonstrated that the use of FeNO was better than current asthma guidelines in controlling asthma exacerbations. In summary, there is a large variation in FeNO levels between individuals, which may reflect the natural heterogeneity in baseline epithelial nitric oxide synthase activity and/or the contribution of other noneosinophilic factors to epithelial nitric oxide synthase activity. FeNO is a promising biomarker, but at present some limits are highlighted. We would recommend that further research can be carried out by organizing studies aimed to obtain reliable reference values of FeNO and in order to better interpret FeNO measurements in clinical settings, taking also into account the influence of genetic and environmental factors.


Use of Imputation and Decision Modeling to Improve Diagnosis and Management of Patients at Risk for New-Onset Diabetes After Transplantation.
BACKGROUND New-onset diabetes after transplantation (NODAT) is a complication of solid organ transplantation. We sought to determine the extent to which NODAT goes undiagnosed over the course of 1 year following transplantation, analyze missed or later-diagnosed cases of NODAT due to poor hemoglobin A1c (HbA1c) and fasting blood glucose (FBG) collection, and to estimate the impact that improved NODAT screening metrics may have on long-term outcomes. MATERIAL AND METHODS This was a retrospective study utilizing 3 datasets from a single center on kidney, liver, and heart transplantation patients. Retrospective analysis was supplemented with an imputation procedure to account for missing data and project outcomes under perfect information. In addition, the data were used to inform a simulation model used to estimate life expectancy and cost-effectiveness of a hypothetical intervention. RESULTS Estimates of NODAT incidence increased from 27% to 31% in kidney transplantation patients, from 31% to 40% in liver transplantation patients, and from 45% to 67% in heart transplantation patients, when HbA1c and FBG were assumed to be collected perfectly at all points. Perfect screening for kidney transplantation patients was cost-saving, while perfect screening for liver and heart transplantation patients was cost-effective at a willingness-to-pay threshold of $100 000 per life-year. CONCLUSIONS Improved collection of HbA1c and FBG is a cost-effective method for detecting many additional cases of NODAT within the first year alone. Additional research into both improved glucometric monitoring as well as effective strategies for mitigating NODAT risk will become increasingly important to improve health in this population.


Serum enterolactone concentration is not associated with prostate cancer risk in a nested case-control study.
The lignan enterolactone, produced by the intestinal microflora from dietary precursors, has been hypothesized to protect against hormone-dependent cancers and cardiovascular diseases. We conducted a nested case-control study to examine the relationship between serum enterolactone concentration and prostate cancer. Enterolactone concentrations were measured by time-resolved fluoroimmunoassay in serum collected at baseline in the alpha-Tocopherol, beta-Carotene Cancer Prevention Study from 214 men with prostate cancer diagnosed during a 6-year follow-up and from 214 controls matched by age, date of baseline blood collection, intervention group, and local study area. Mean serum enterolactone concentration (in nmol/liter) did not differ significantly between case and control subjects [15.9 (SD, 15.2) versus 16.9 (SD, 14.9), respectively (P = 0.42)]. Odds ratios for prostate cancer risk estimated by conditional logistic regression for increasing quartiles of enterolactone concentration were 1.00 (referent), 0.72 [95% confidence interval (CI), 0.43-1.23], 0.98 (95% CI, 0.58-1.68), and 0.71 (95% CI, 0.42-1.21). Our findings do not support the hypothesis that enterolactone is involved in the development of prostate cancer.


Effectiveness and safety of fluocinolone acetonide intravitreal implant in diabetic macular edema patients considered insufficiently responsive to available therapies (REACT): a prospective, non-randomized, and multicenter study.
To assess the effectiveness and safety of the intravitreal fluocinolone-acetonide implant (FAc-i) in patients with chronic diabetic macular edema who did not sufficiently respond to other available therapies. This was a multicenter, prospective, non-randomized, and phase-IV observational study conducted on patients with recurrent-DME who were insufficient responders to currently available therapies (REACT-Study). The primary end-point was the mean change in best-corrected-visual-acuity from baseline to month-24 values. Thirty-one eyes from 31 patients were included in the study. Mean age was 68.0 ± 7.7 years, and 10 (32.3%) were women. Study patients had received 5.3 ± 7.3 previous DME treatments before starting the study. In the overall study sample, BCVA improved from 56.1 ± 12.3 letters at baseline to 62.4 ± 17.0 letters at month-24 (p = 0.0510). The eyes with a baseline BCVA < 70 ETDRS letters had a significant improvement in BCVA from 53.2 ± 10.2 letters at baseline to 61.5 ± 17.9 letters at month-24 (p = 0.0165). In the overall study population, central-subfoveal-thickness (CST) was significantly reduced from 474.0 ± 135.1 µm at baseline to 333.4 ± 135.6 at month-24 (p < 0.0001). Similarly, macular-volume (MV) was significantly reduced from 10.7 ± 2.7 mm3 at baseline to 9.6 ± 2.9 mm3 (p = 0.0027) at month-24. Among the 31 study eyes, 19 (61.3%) required an additional treatment for DME. Throughout the study, 9 (29.0%) eyes required ocular hypotensive medication for controlling their intraocular-pressure and 5 (16.1%) eyes underwent cataract surgery. In DME eyes who did not sufficiently respond to previous therapies, the FAc-i was associated with an improvement in visual and anatomic outcomes. There were no unexpected adverse-events. EudraCT identifier: 2016-001680-37.


A simple approach for protein covalent grafting on conducting polymer films.
Covalent immobilization of biomolecules, such as proteins, on conducting polymer films is critical to organic bioelectronics to create tailored interfaces with biological systems. In this study, we propose a simple approach to graft proteins on films of the conducting polymer poly(3,4-ethylenedioxythiophene) doped with poly(styrenesulfonate) (PEDOT:PSS). PEDOT:PSS is a biocompatible and easy to process conducting polymer, widely used in bioelectronics. However, it does not possess any chemical reactive groups available for protein grafting. By mixing a commercial PEDOT:PSS suspension with the modified biopolymer carboxymethylated dextran (CMD), we obtained films displaying carboxyl (-COOH) groups allowing for covalent grafting of proteins via amide bonds, without any further functionalization step. By fine-tuning the concentration of CMD as well as those of a conductivity enhancer (glycerol) and a crosslinking agent (glycidoxypropyltrimethoxysilane, GOPS) in the film processing mixture, we were able to produce COOH-functionalized PEDOT:PSS films displaying excellent electrical conductivity and high stability in an aqueous environment.


Expanded endoscopic endonasal approach for treatment of clival chordomas: early results in 12 patients.
We report our recent experience with an expanded purely endoscopic endonasal approach for the treatment of clival chordomas. Twelve patients underwent an expanded endoscopic approach for excision of cranial base chordomas at Toronto Western Hospital. Two patients had undergone a previous craniotomy for excision of a significant lateral intracranial extension of the tumor. All other patients had mainly centrally located lesions. Three patients had recurrent tumors. This study focused on the surgical approach, results, and complications associated with this approach. Diplopia caused by VIth nerve palsy was the most common presenting symptom and was observed in seven patients. Gross total resection of the tumor was achieved in seven patients (58%). Four patients had complete recovery of their preoperative diplopia. One patient (8%) presented with new hemiparesis postoperatively. Four patients (33%) had a cerebrospinal fluid leak postoperatively; two were treated by lumbar drainage, and two required a secondary surgical repair. All newly diagnosed patients underwent adjuvant radiotherapy. There was no mortality. The short-term outcome was excellent in all but one patient. No recurrence was observed at the median follow-up period of 16 months. The expanded endoscopic endonasal approach is a valid minimally invasive alternative for the treatment of centrally located clival chordomas or as an adjunct for the central part of chordomas with lateral extension. The early results of this technique indicate at least equivalency to more extensive open approaches, and its versatility may widen the horizon of surgical management of these aggressive lesions. The challenge with the cerebrospinal fluid leakage is being addressed with novel local flap repair techniques. This approach should be in the armamentarium of cranial base surgeons as an option in the management of clival chordomas.


Racial/ethnic variation in the reliability of DSM-IV pathological gambling disorder.
Racial/ethnic disparities in mental disorders, including pathological gambling disorder (PGD), may be either real or artifacts of how they are conceptualized and measured. We aimed to assess racial/ethnic variation in the reliability of self-reported lifetime PGD determined by meeting > or = 5 criteria of the Diagnostic and Statistical Manual of Mental Disorders. Using community advertising, we recruited 15-85-year-old Caucasians (n = 225) and African (American/other minorities (n = 87), who had gambled more than 5 times lifetime), for 2 interviews, held 1 week apart, about gambling and associated behaviors. Results indicate substantial to almost-perfect DSM-IV PGD reliability for Caucasians (kappa = 0.82) and African Americans/other minorities (kappa = 0.68). Reliability for symptoms and for game-specific disorders was fair to almost perfect (kappa = 0.37-0.90). After adjusting results for confounding variables and multiple comparisons, racial/ethnic variation in PGD and game-specific reliability failed to persist. Implications exist for increased attention to screening and prevention efforts critical to reducing racial/ethnic disparities in PGD prevalence.


Multi-objective optimisation of material properties and strut geometry for poly(L-lactic acid) coronary stents using response surface methodology.
Coronary stents for treating atherosclerosis are traditionally manufactured from metallic alloys. However, metal stents permanently reside in the body and may trigger undesirable immunological responses. Bioresorbable polymer stents can provide a temporary scaffold that resorbs once the artery heals but are mechanically inferior, requiring thicker struts for equivalent radial support, which may increase thrombosis risk. This study addresses the challenge of designing mechanically effective but sufficiently thin poly(L-lactic acid) stents through a computational approach that optimises material properties and stent geometry. Forty parametric stent designs were generated: cross-sectional area (post-dilation), foreshortening, stent-to-artery ratio and radial collapse pressure were evaluated computationally using finite element analysis. Response surface methodology was used to identify performance trade-offs by formulating relationships between design parameters and response variables. Multi-objective optimisation was used to identify suitable stent designs from approximated Pareto fronts and an optimal design is proposed that offers comparable performance to designs in clinical practice. In summary, a computational framework has been developed that has potential application in the design of high stiffness, thin strut polymeric stents.


Do Prosthetic Joint Infections Worsen the Functional Ambulatory Outcome of Patients with Joint Replacements? A Retrospective Matched Cohort Study.
To assess the effect on the functional ambulatory outcome of postoperative joint infection (PJI) cured at the first treatment attempt versus not developing PJI in patients with hip and knee prostheses. In a single-hospital retrospectively matched cohort study, each patient with PJI between 2007 and 2016 was matched on age, sex, type of prosthesis and year of implantation with two other patients with uninfected arthroplasties. The definition of a PJI cure included infection eradication, no further surgical procedures, no PJI-related mortality and no suppressive antibiotics. Functional ambulatory status evaluated one year after the last surgery was classified into four simple categories: able to walk without assistance, able to walk with one crutch, able to walk with two crutches, and unable to walk. Patients with total hip arthroplasties (THA), total knee arthroplasties (TKA) and partial hip arthroplasty (PHA) were analysed separately. A total of 109 PJI patients (38 TKA, 41 THA, 30 PHA) and 218 non-PJI patients were included. In a model adjusted for clinically relevant variables, PJI was associated with a higher risk of needing an assistive device for ambulation (vs. walking without aid) among THA (adjusted odds ratio (OR) 3.10, 95% confidence interval (95% CI) 1.26-7.57; p = 0.014) and TKA patients (OR 5.40, 95% CI 2.12-13.67; p < 0.001), and with requiring two crutches to walk or being unable to walk (vs. walking unaided or with one crutch) among PHA patients (OR 3.05, 95% CI 1.01-9.20; p = 0.047). Ambulatory outcome in patients with hip and knee prostheses with postoperative PJI is worse than in patients who do not have PJI.


The GacS-GacA two-component regulatory system of Pseudomonas fluorescens: a bacterial two-hybrid analysis.
The two-component regulatory system comprised of the sensor kinase, GacS, and its response regulator, GacA, is involved in regulation of secondary metabolism and many other aspects of bacterial physiology. Although it is known that the sensor kinases RetS and LadS feed into the GacS/GacA system, the mechanism through which this occurs is unknown, as are the protein-protein interactions in this system. To characterize and define these interactions, we utilized a bacterial two-hybrid system to study the interactions of GacS and GacA from Pseudomonas fluorescens CHA0. Domains of GacA and GacS, identified through bioinformatics, were subcloned and their ability to interact in vivo was investigated. We found that the entire GacA molecule is required for GacA to interact with itself or GacS. Furthermore, the HisKA/HATPase/REC domains of GacS together are responsible for GacS interacting with GacA, while the HAMP domain of GacS is responsible for GacS interacting with itself. In addition, homologs of Pseudomonas aeruginosa hybrid sensor kinases, RetS and LadS, were identified in P. fluorescens, and shown to interact with GacS, but not GacA.


Antifeedant and Antifungal Activities of Metabolites Isolated from the Coculture of Endophytic Fungus Aspergillus tubingensis S1120 with Red Ginseng.
A new globoscinic acid derivative, aspertubin A (1) along with four known compounds, were obtained from the co-culture of Aspergillus tubingensis S1120 with red ginseng. The chemical structures of compounds were characterized by using spectroscopic methods, the calculated and experimental electronic circular dichroism. Panaxytriol (2) from red ginseng, and asperic acid (4) showed significant antifeedant effect with the antifeedant rates of 75 % and 80 % at the concentrations of 50 μg/cm2 . Monomeric carviolin (3) and asperazine (5) displayed weak attractant activity on silkworm. All compounds were assayed for antifungal activities against phytopathogens A. tubingensis, Nigrospora oryzae and Phoma herbarum and the results indicated that autotoxic aspertubin A (1) and panaxytriol (2) possessed selective inhibition against A. tubingensis with MIC values at 8 μg/mL. The co-culture extract showed higher antifeedant and antifungal activities against P. herbarum than those of monoculture of A. tubingensis in ordinary medium. So the medicinal plant and endophyte showed synergistic effect on the plant disease resistance by active compounds from the coculture of A. tubingensis S1120 and red ginseng.


An efficient dynamic system for real-time robot-path planning.
This paper presents a simple yet efficient dynamic-programming (DP) shortest path algorithm for real-time collision-free robot-path planning applicable to situations in which targets and barriers are permitted to move. The algorithm works in real time and requires no prior knowledge of target or barrier movements. In the case that the barriers are stationary, this paper proves that this algorithm always results in the robot catching the target, provided it moves at a greater speed than the target, and the dynamic-system update frequency is sufficiently large. Like most robot-path-planning approaches, the environment is represented by a topologically organized map. Each grid point on the map has only local connections to its neighboring grid points from which it receives information in real time. The information stored at each point is a current estimate of the distance to the nearest target and the neighbor from which this distance was determined. Updating the distance estimate at each grid point is done using only the information gathered from the point's neighbors, that is, each point can be considered an independent processor, and the order in which grid points are updated is not determined based on global knowledge of the current distances at each point or the previous history of each point. The robot path is determined in real time completely from the information at the robot's current grid-point location. The computational effort to update each point is minimal, allowing for rapid propagation of the distance information outward along the grid from the target locations. In the static situation, where both the targets and the barriers do not move, this algorithm is a DP solution to the shortest path problem, but is restricted by lack of global knowledge. In this case, this paper proves that the dynamic system converges in a small number of iterations to a state where the minimal distance to a target is recorded at each grid point and shows that this robot-path-planning algorithm can be made to always choose an optimal path. The effectiveness of this algorithm is demonstrated through a number of simulations.


Correlation of electrical and contractile activities of the cricopharyngeus muscle in the cat.
We correlated the electrical and contractile activities of the cricopharyngeus (CP) to better understand the function of the CP and the upper esophageal sphincter (UES). In 40 decerebrate cats, we recorded resting and active tension of the CP and CP force and electromyographic (EMG) activity simultaneously during electrical stimulation of the pharyngoesophageal (PE) nerve, esophageal distension, or swallowing. In six intact cats, the change in diameter of the UES during food swallows was determined in two planes using videofluoroscopy. We found that resting tension of the CP developed quickly with stretch, and the strain-energy function, y = 6.5e3.4(z-1), fit (r = 0.94 +/- 0.06) this relationship. Active tension peaked at 1.68 +/- 0.03 times resting length, which is greater than the maximum distension during swallowing. Activation and relaxation of the CP occurred in approximately 50 and 120 ms, respectively. PE nerve stimulation bilaterally caused a force equal to approximately 90% of the summed force generated by separate stimulation of each PE nerve. The magnitude of the EMG response of the contralateral CP was approximately 18% of the ipsilateral response to unilateral PE nerve stimulation. We conclude that the CP exhibits tension throughout its physiological range of stretch. The CP functions more like a bilateral than a single contiguous muscle, and more like cardiac than striated muscle with regard to its passive elastic properties.


Antithrombotic Treatment in Patients With Hemophilia: an EHA-ISTH-EAHAD-ESO Clinical Practice Guidance.
Cardiovascular disease is an emerging medical issue in patients with hemophilia (PWH) and its prevalence is increasing up to 15% in PWH in the United States. Atrial fibrillation, acute and chronic coronary syndromes, venous thromboembolism, and cerebral thrombosis are frequent thrombotic or prothrombotic situations, which require a careful approach to fine-tune the delicate balance between thrombosis and hemostasis in PWH when using both procoagulant and anticoagulant treatments. Generally, PWH could be considered as being naturally anticoagulated when clotting factors are <20 IU/dL, but specific recommendations in patients with very low levels according to the different clinical situations are lacking and mainly based on the anecdotal series. For PWH with baseline clotting factor levels >20 IU/dL in need for any form of antithrombotic therapy, usually treatment without additional clotting factor prophylaxis could be used, but careful monitoring for bleeding is recommended. For antiplatelet treatment, this threshold could be lower with single-antiplatelet agent, but again factor level should be at least 20 IU/dL for dual antiplatelet treatment. In this complex growing scenario, the European Hematology Association in collaboration with the International Society on Thrombosis and Haemostasis, the European Association for Hemophilia and Allied Disorders, the European Stroke Organization, and a representative of the European Society of Cardiology Working Group on Thrombosis has produced this current guidance document to provide clinical practice recommendations for health care providers who care for PWH.


Serum C-reactive protein concentrations in dogs with structural and idiopathic epilepsy.
C-reactive protein (CRP) is an acute-phase protein produced by the liver during systemic inflammation. In humans, some epilepsies are associated with increased serum CRP (sCRP) concentrations, but this has yet to be proven in veterinary studies. Dogs with structural epilepsy (SE) and normal interictal neurological examination are hard to distinguish from dogs with idiopathic epilepsy (IE) without the use of advanced imaging. The study included eight dogs with SE and 12 dogs with IE from a referral hospital population. This was a retrospective observational cohort study. The Mann-Whitney test was used to compare the sCRP concentrations within 24 hours of the last epileptic seizure between dogs with SE or IE. Dogs with SE had higher sCRP concentrations than dogs with IE (8.9 [range <2.2-53.2] mg/L vs. <2.2 [range <2.2-6.9] mg/L; p = 0.043). Five of the eight (62%) dogs with SE had an sCRP concentration above the reference interval, compared with none of the 12 dogs with IE. The small sample size was the major limitation of this study. Other inflammatory causes were also not exclusively ruled out, although further clinical investigations were not indicated. This study found that sCRP concentrations were higher in this cohort of dogs with SE than in those with IE. Further studies with larger cohorts of dogs are warranted to validate if sCRP can be used as an additional biomarker for SE.


Biomechanics of slow running and walking with a rocker shoe.
Evidence suggests a link between the loading of the Achilles tendon and the magnitude of the ankle internal plantar flexion moment during late stance of gait, which is clinically relevant in the management of Achilles tendinopathy. Some studies showed that rocker shoes can reduce the ankle internal plantar flexion moment. However, the existing evidence is not conclusive and focused on walking and scarce in running. Sixteen healthy runners participated in this study. Lower extremity kinetics, kinematics and electromyographic (EMG) signals of triceps surae and tibialis anterior were quantified for two types of shoes during running and walking. The peak ankle plantar flexion moment was reduced significantly in late stance of running (0.27 Nm/kg; p<0.001) and walking (0.24 Nm/kg; p<0.001) with the rocker shoe compared to standard shoe. The ankle power generation and plantar flexion moment impulse were also reduced significantly when running and walking with the rocker shoe (p<0.001). No significant changes in the knee and hip moments were found in running and walking. A significant delay of the EMG peak, approximately 2% (p<0.001), was present in the triceps surae when walking with rocker shoes. There were no significant changes in the EMG peak amplitude of triceps surae in running and walking. The peak amplitude of tibialis anterior was significantly increased (64.7 μV, p<0.001) when walking with rocker shoes. The findings show that rocker shoes reduce the ankle plantar flexion moment during the late stance phase of running and walking in healthy people.


Malaria Molecular Epidemiology: An Evolutionary Genetics Perspective.
Malaria is a vector-borne disease that involves multiple parasite species in a variety of ecological settings. However, the parasite species causing the disease, the prevalence of subclinical infections, the emergence of drug resistance, the scale-up of interventions, and the ecological factors affecting malaria transmission, among others, are aspects that vary across areas where malaria is endemic. Such complexities have propelled the study of parasite genetic diversity patterns in the context of epidemiologic investigations. Importantly, molecular studies indicate that the time and spatial distribution of malaria cases reflect epidemiologic processes that cannot be fully understood without characterizing the evolutionary forces shaping parasite population genetic patterns. Although broad in scope, this review in the Microbiology Spectrum Curated Collection: Advances in Molecular Epidemiology highlights the need for understanding population genetic concepts when interpreting parasite molecular data. First, we discuss malaria complexity in terms of the parasite species involved. Second, we describe how molecular data are changing our understanding of malaria incidence and infectiousness. Third, we compare different approaches to generate parasite genetic information in the context of epidemiologically relevant questions related to malaria control. Finally, we describe a few Plasmodium genomic studies as evidence of how these approaches will provide new insights into the malaria disease dynamics. *This article is part of a curated collection.


Patient-Reported Outcomes in Orphan Drug Labels Approved by the US Food and Drug Administration.
In recent years, there has been increasing recognition of the need to assess treatment benefit from the patient's perspective. The extent of patient-reported outcome (PRO) data included in labeling for rare disease treatment is largely unknown. The objective of this study was to review trends over time for PRO-based labeling granted by the US Food and Drug Administration (FDA) for orphan drugs. Review of FDA package inserts. Products included in this analysis were all new molecular entities (NMEs) and biologic license applications (BLAs) with orphan designations approved by the FDA from 2002 through 2017. For identified products, package inserts were reviewed to determine the number and type of PRO claim(s) granted, endpoint status, and PRO measure named. Two trends were analyzed: (1) over all years 2002 to 2017 and (2) 2002 to 2017 stratified into 3 periods (before draft FDA PRO guidance [2006], between draft and final guidance release, and after final guidance [2009] release. A total of 156 NMEs and BLAs with orphan designations were approved between 2002 and 2017. Of these, 13 products (8.3%) had PRO-based labeling, and 7 of 13 were symptom-related. The percent of orphan drugs approved with PRO-based labeling between 2002 and 2005, 2006 and 2008, and 2009 and 2017 was 0, 10.5, and 9.9, respectively. In FDA-approved labeling for orphan therapies, PRO measures used as primary and secondary endpoints increased after draft FDA PRO guidance release but remained relatively low thereafter. It is important to understand barriers to PRO measure use to ensure that treatments capture perspectives of patients with rare diseases.


The effect of sodium, potassium and ammonium ions on the conformation of the dimeric quadruplex formed by the Oxytricha nova telomere repeat oligonucleotide d(G(4)T(4)G(4)).
The DNA sequence d(G(4)T(4)G(4)) [Oxy-1.5] consists of 1.5 units of the repeat in telomeres of Oxytricha nova and has been shown by NMR and X-ray crystallographic analysis to form a dimeric quadruplex structure with four guanine-quartets. However, the structure reported in the X-ray study has a fundamentally different conformation and folding topology compared to the solution structure. In order to elucidate the possible role of different counterions in this discrepancy and to investigate the conformational effects and dynamics of ion binding to G-quadruplex DNA, we compare results from further experiments using a variety of counterions, namely K(+), Na(+)and NH(4)(+). A detailed structure determination of Oxy-1.5 in solution in the presence of K(+)shows the same folding topology as previously reported with the same molecule in the presence of Na(+). Both conformations are symmetric dimeric quadruplexes with T(4)loops which span the diagonal of the end quartets. The stack of quartets shows only small differences in the presence of K(+)versus Na(+)counterions, but the T(4)loops adopt notably distinguishable conformations. Dynamic NMR analysis of the spectra of Oxy-1.5 in mixed Na(+)/K(+)solution reveals that there are at least three K(+)binding sites. Additional experiments in the presence of NH(4)(+)reveal the same topology and loop conformation as in the K(+)form and allow the direct localization of three central ions in the stack of quartets and further show that there are no specific NH(4)(+)binding sites in the T(4)loop. The location of bound NH(4)(+)with respect to the expected coordination sites for Na(+)binding provides a rationale for the difference observed for the structure of the T(4)loop in the Na(+)form, with respect to that observed for the K(+)and NH(4)(+)forms.