Disseminated histiocytic sarcoma with hemophagocytosis in a rabbit.
A 7-year-old female domestic rabbit suffered from labored respiration, poor appetite, mild anemia and thrombocytopenia. Radioscopic examination revealed masses in multiple locations including the intrapleural cavity and spleen. Forty-three days after the first visit to a private veterinary clinic, the rabbit died of severe respiratory distress. Microscopically, all of the masses were composed of round to polygonal neoplastic cells with distinct cell borders that were arranged in a sheet pattern. Multinucleated giant neoplastic cells were often observed. Some neoplastic cells had phagocytozed one or more erythrocytes. Immunohistochemical staining revealed that the neoplastic cells expressed vimentin, CD204, Iba-1 and lysozyme, but not CD163. Based on the morphological and immunohistochemical findings, this case was diagnosed as disseminated histiocytic sarcoma with hemophagocytosis.


Optimization of RGD-Containing Cyclic Peptides against αvβ3 Integrin.
We have previously reported the use of one-bead-one-compound (OBOC) combinatorial technology to develop a disulfide cyclic, Arg-Gly-Asp-containing octapeptide LXW7 (cGRGDdvc), that targets αvβ3 integrin with high affinity and specificity. αvβ3 integrin is known to be overexpressed in many cancers and in tumor vasculature, and it has been established as a cancer therapeutic target. To further optimize LXW7, we have performed systematic structure-activity relationship studies. On the basis of the results, two highly focused OBOC peptide libraries were designed, synthesized, and screened against αvβ3 integrin-transfected K562 cells. One of the best ligands, LXW64, was found to have 6.6-fold higher binding affinity than LXW7, and showed preferential binding to cells expressing αvβ3 integrin. In addition to binding strongly to U-87MG glioblastoma cells in vitro, LXW64 also targets U-87MG xenografts implanted in nude mice, indicating that it is an excellent vehicle for the delivery of cytotoxic payload to tumors and tumor blood vessels that overexpress αvβ3 integrin. Mol Cancer Ther; 15(2); 232-40. ©2015 AACR.


Decrement of compound muscle action potential is related to mutation type in myotonia congenita.
Decrement of the compound muscle action potential (CMAP) during 10-HZ repetitive nerve stimulation is thought to be an unusual finding in dominant myotonia congenita, and has not previously been reported in patients with the genetically verified disorder. It was the purpose of the present study to elucidate the relation between decrement and CLCN1 mutation type in myotonia congenita. Decrement and genotypes were studied in eight Danish families with myotonia congenita. Six patients with the known dominant mutation P480L had decrements of 30-84%. Patients heterozygous for the R894X mutation had decrements of 20-47%. Three novel CLCN1 mutations (two dominant and one recessive) were found segregating with the Thomsen/Becker phenotypes. In families with the novel dominant mutations M128V and E193K, decrement was absent in all family members tested. In conclusion, CMAP decrement may be pronounced in dominant myotonia congenita, and the presence of decrement is related to mutation type.


Tissue-specific control of glandular kallikreins.
Glandular kallikreins are kinin-generating serine proteases found in the salivary glands, pancreas, reproductive organs, and kidney and in their secretions. They are physico-chemically, enzymatically, and immunologically identical but it is not known whether they perform similar functions at these separate anatomical sites. A specific radioimmunoassay was used to measure immunoreactive kallikrein in these tissues of the rat after various stimuli. Salt depletion significantly increased kallikrein in the kidney from 2.35 +/- 0.17 to 4.11 +/- 0.27 microgram/g tissue (P less than 0.01, 16 DF) and in the salivary glands from 16.8 +/- 2.1 to 24.2 +/- 0.9 mg/g tissue (P less than 0.01, 16 DF), but did not change pancreatic kallikrein. Deoxycorticosterone (2.4 mg s.c. over 8 days) led to a doubling in kidney kallikrein, from 2.35 +/- 0.17 to 5.27 +/- 0.56 microgram/g tissue (P less than 0.01, 18 DF), without changing salivary gland or pancreatic kallikrein, whereas testosterone (240 micrograms/day s.c. over 15 days) significantly increased salivary gland kallikrein from 26.6 +/- 2.1 to 42.2 +/- 1.8 mg/g tissue (P less than 0.01, 18 DF) with no increase in kidney or pancreatic kallikrein. Accordingly, the glandular kallikreins in these tissues vary independently, which suggests they are under different electrolyte and endocrine control and may perform different physiological functions at each anatomical site.


Herb and Flowers of Achillea millefolium subsp. millefolium L.: Structure and Histochemistry of Secretory Tissues and Phytochemistry of Essential Oils.
Achillea millefolium L. herb and flowers have high biological activity; hence, they are used in medicine and cosmetics. The aim of this study was to perform morpho-anatomical analyses of the raw material, including secretory tissues, histochemical assays of the location of lipophilic compounds, and quantitative and qualitative analysis of essential oil (EO). Light and scanning electron microscopy techniques were used to analyse plant structures. The qualitative analyses of EO were carried out using gas chromatography-mass spectrometry (GC/MS). The results of this study showed the presence of exogenous secretory structures in the raw material, i.e., conical cells (papillae) on the adaxial surface of petal teeth and biseriate glandular trichomes on the surface flowers, bracts, stems, and leaves. Canal-shaped endogenous secretory tissue was observed in the stems and leaves. The histochemical assays revealed the presence of total, acidic, and neutral lipids as well as EO in the glandular trichome cells. Additionally, papillae located at the petal teeth contained neutral lipids. Sesquiterpenes were detected in the glandular trichomes and petal epidermis cells. The secretory canals in the stems were found to contain total and neutral lipids. The phytochemical assays demonstrated that the A. millefolium subsp. millefolium flowers contained over 2.5-fold higher amounts of EO (6.1 mL/kg) than the herb (2.4 mL/kg). The EO extracted from the flowers and herb had a similar dominant compounds: β-pinene, bornyl acetate, (E)-nerolidol, 1,8-cineole, borneol, sabinene, camphor, and α-pinene. Both EO samples had greater amounts of monoterpenes than sesquiterpenes. Higher amounts of oxygenated monoterpenes and oxygenated sesquiterpenoids were detected in the EO from the herb than from the flowers.


The positively charged region of the myosin IIC non-helical tailpiece promotes filament assembly.
The motor protein, non-muscle myosin II (NMII), must undergo dynamic oligomerization into filaments to participate in cellular processes such as cell migration and cytokinesis. A small non-helical region at the tail of the long coiled-coil region (tailpiece) is a common feature of all dynamically assembling myosin II proteins. In this study, we investigated the role of the tailpiece in NMII-C self-assembly. We show that the tailpiece is natively unfolded, as seen by circular dichroism and NMR experiments, and is divided into two regions of opposite charge. The positively charged region (Tailpiece(1946-1967)) starts at residue 1946 and is extended by seven amino acids at its N terminus from the traditional coiled-coil ending proline (Tailpiece(1953-1967)). Pull-down and sedimentation assays showed that the positive Tailpiece(1946-1967) binds to assembly incompetent NMII-C fragments inducing filament assembly. The negative region, residues 1968-2000, is responsible for NMII paracrystal morphology as determined by chimeras in which the negative region was swapped between the NMII isoforms. Mixing the positive and negative peptides had no effect on the ability of the positive peptide to bind and induce filament assembly. This study provides molecular insight into the role of the structurally disordered tailpiece of NMII-C in shifting the oligomeric equilibrium of NMII-C toward filament assembly and determining its morphology.


Indications and results of pancreatic stump duct occlusion after duodenopancreatectomy.
Severe post-operative complications after pancreaticoduodenectomy (PD) are largely due to pancreatic fistula onset. The occlusion of the main pancreatic duct using synthetic glue may prevent these complications. Aim of this study is to describe this technique and to report short- and long-term results as well as the post-operative endocrine and exocrine insufficiency. Two hundred and four patients who underwent PD with occlusion of the main pancreatic duct in a period of 15 years were retrospectively analyzed. Post-operative complications and their management were the main aim of the study with particular focus on pancreatic fistula incidence and its treatment. At 1-year follow-up endocrine and exocrine functions were analyzed. We observed a 54 % pancreatic fistula incidence, most of which (77/204 patients) were a grade A fistula with little change in medical management. Twenty-eight patients developed a grade B fistula while only 2 % of patients (5/204) developed a grade C fistula. Nine patients required re-operation, 5 of whom had a post-operative grade C fistula. Post-operative mortality was 3.4 %. At 1-year follow-up, 31 % of patients developed a post-operative diabetes while exocrine insufficiency was encountered in 88 % of patients. The occlusion of the main pancreatic duct after PD can be considered a relatively safe and easy-to-perform procedure. It should be reserved to selected patients, especially in case of soft pancreatic texture and small pancreatic duct and in elderly patients with comorbidities, in whom pancreatic fistula-related complications could be life threatening.


Isolation and characterization of SSEA-4-positive subpopulation of human deciduous dental pulp cells.
It is well accepted that stage-specific embryonic antigen (SSEA)-4 is an antigen that is useful to isolate adult stem cells analogous to embryonic stem cells. Therefore, in the present study, we investigated whether SSEA-4 can also be used as a marker to identify human deciduous dental pulp (D-DP) stem cells. Intact deciduous teeth were collected from healthy patients who were undergoing orthodontic treatment at Okayama University Hospital. Immunofluorescence analysis, flow cytometric analysis, and multilineage differentiation assay were performed to characterize SSEA-4+ D-DP cells. The D-DP cells had the characteristics of mesenchymal stem cells (MSCs), namely plastic adherence, specific surface antigen expression, and multipotent differentiation potential. SSEA-4 expression was detected in D-DP cells in vitro and ex vivo samples. A flow cytometric analysis demonstrated that 21.2 % of the D-DP cells were positive for SSEA-4. The SSEA-4+ clonal D-DP cells showed multilineage differentiation potential toward adipocytes, osteoblasts, and chondrocytes in vitro. In fact, 26.1 % (6/23) of the SSEA-4+ clonal D-DP cells showed adipogenic potential, 91.3 % (21/23) showed osteogenic potential, 91.3 % (21/23) showed chondrogenic potential, and 87.0 % (20/23) showed both osteogenic and chondrogenic potential. Thus, the majority of SSEA-4+ D-DP cells had the potential for multilineage differentiation. Hence, SSEA-4 appears to be a specific marker that can be used to identify D-DP stem cells. SSEA-4+ D-DP cells appear to be a promising source of stem cells for regenerative therapy.


Temperature biofeedback in the treatment of migraine headaches: a controlled evaluation.
After an initial four-week baseline phase, during which daily records of headache frequency and intensity and daily medication records were kept, 30 patients with frequent (at least one per month) migraine headaches were randomly assigned to three conditions: (1) temperature biofeedback, autogenic training, and regular home practice; (2) progressive relaxation with regular home practice; and (3) a waiting-list control condition. Comparisons of headache data from the four weeks of baseline and last two weeks of treatment showed that both the relaxation and biofeedback groups improved significantly on total headache activity, duration of headaches, and peak headache intensity and reduced consumption of analgesic medication, while the waiting list control group did not. All three groups showed significant decreases in headache frequency. Although the relaxation training was more effective than biofeedback training at the last week of treatment, follow-up data at one, two, and three months showed no differences between the two treated groups on any dependent measure.


Quantum non-demolition readout of an electron spin in silicon.
While single-shot detection of silicon spin qubits is now a laboratory routine, the need for quantum error correction in a large-scale quantum computing device demands a quantum non-demolition (QND) implementation. Unlike conventional counterparts, the QND spin readout imposes minimal disturbance to the probed spin polarization and can therefore be repeated to extinguish measurement errors. Here, we show that an electron spin qubit in silicon can be measured in a highly non-demolition manner by probing another electron spin in a neighboring dot Ising-coupled to the qubit spin. The high non-demolition fidelity (99% on average) enables over 20 readout repetitions of a single spin state, yielding an overall average measurement fidelity of up to 95% within 1.2 ms. We further demonstrate that our repetitive QND readout protocol can realize heralded high-fidelity (>99.6%) ground-state preparation. Our QND-based measurement and preparation, mediated by a second qubit of the same kind, will allow for a wide class of quantum information protocols with electron spins in silicon without compromising the architectural homogeneity.


Virus inhibition induced by polyvalent nanoparticles of different sizes.
The development of antiviral agents is one of the major challenges in medical science. So far, small monovalent molecular drugs that inhibit the late steps in the viral replication cycle, i.e., virus budding, have not worked well which emphasizes the need for alternative approaches. Polyvalently presented viral receptors, however, show potential as good inhibitors of virus-cell binding, which is the first step in the viral infection cycle. By gradually increasing the size of ligand functionalized gold nanoparticles, up to virus-like dimensions, we are now able to quantify the polyvalent enhancement of virus-cell binding inhibition and to identify varying mechanisms of virus inhibition with different efficacies: by employing a new binding assay we found that surface area-normalized polysulfated gold nanoparticles of diameters equal to and larger than the virus diameter (>50 nm) more efficiently inhibit the binding of vesicular stomatitis virus (VSV) to cells than smaller particles. On a per particle basis, larger sized gold nanoparticles were surprisingly shown to inhibit the viral infection up to two orders of magnitude more efficiently than smaller particles, which suggests different mechanisms of virus inhibition. Based on complementary electron microscopic data, we noticed that larger gold nanoparticles act as efficient cross-linkers between virions, whereas smaller gold nanoparticles decorate the surface of individual virus particles. Our systematic study accentuates the need for the design of biodegradable, virus-sized inhibitors capitalizing on polyvalent binding.


Evaluation of radiography as a screening method for detection and characterisation of congenital vertebral malformations in dogs.
Congenital vertebral malformations (CVM) are common in brachycephalic 'screw-tailed' dogs; they can be associated with neurological deficits and a genetic predisposition has been suggested. The purpose of this study was to evaluate radiography as a screening method for congenital thoracic vertebral malformations in brachycephalic 'screw-tailed' dogs by comparing it with CT. Forty-nine dogs that had both radiographic and CT evaluations of the thoracic vertebral column were included. Three observers retrospectively reviewed the images independently to detect CVMs. When identified, they were classified according to a previously published radiographic classification scheme. A CT consensus was then reached. All observers identified significantly more affected vertebrae when evaluating orthogonal radiographic views compared with lateral views alone; and more affected vertebrae with the CT consensus compared with orthogonal radiographic views. Given the high number of CVMs per dog, the number of dogs classified as being CVM free was not significantly different between CT and radiography. Significantly more midline closure defects were also identified with CT compared with radiography. Malformations classified as symmetrical or ventral hypoplasias on radiography were frequently classified as ventral and medial aplasias on CT images. Our results support that CT is better than radiography for the classification of CVMs and this will be important when further evidence of which are the most clinically relevant CVMs is identified. These findings are of particular importance for designing screening schemes of CVMs that could help selective breeding programmes based on phenotype and future studies.


The prevalence of migraine and tension-type headaches among adolescents in Norway. The Nord-Trøndelag Health Study (Head-HUNT-Youth), a large population-based epidemiological study.
The aim of this study was to examine the prevalence of headache and primary headache disorders like migraine and tension-type headaches among adolescents, and to explore the differences in headache prevalence and frequency by gender and age. This cross-sectional study was conducted in Nord-Trøndelag county, Norway, during the years 1995-97. In total, 8984 (88%) out of 10 202 invited adolescents aged 12-19 years participated in the youth part of the Nord-Trøndelag Health Study [Helseundersøkelsen i Nord-Trøndelag (HUNT)]. The total study population in this study consisted of 8255 individuals after exclusion of invalid questionnaires and students outside the target range of 13-18 years of age. The students completed a comprehensive questionnaire, and one of the questions was whether the students had experienced any headaches during the last 12 months. In addition, 5847 of these students were also subject to an interview in which they were asked whether they had experienced recurring headaches during the last year and, if so, were they classified as migraine (MI), tension-type headache (TTH) or non-classifiable headache. In the total questionnaire-based population, 76.8% reported having had headaches during the last 12 months (69.4% boys and 84.2% girls). Among those who also were interviewed, 29.1% reported having recurrent headaches (21.0% boys and 36.5% girls). The overall 1-year prevalence of migraine was 7%, of tension-type headache 18%, and of non-classifiable headache 4.8%. Higher prevalence rates were found for girls in all age groups and for all headache categories. The overall frequency of recurrent headaches did not vary significantly with age, but girls had significantly more frequent headaches than boys. We concluded that headache in general, and recurrent primary headache disorders like migraine and tension-type headaches, are common somatic complaints among Norwegian adolescents, especially among girls.


Thoracic endovascular aortic repair for traumatic aortic injuries: insight from literature and practical recommendations.
Thoracic endovascular aortic repair (TEVAR) for treatment of blunt traumatic aortic injuries (BTAIs) is nowadays the gold standard technique in adult patients, replacing gradually the use of open repair (OR). Although randomized controlled trials will never be performed comparing TEVAR to OR for BTAIs management, trauma and vascular societies guidelines today primarily recommend the former for BTAI patients with a suitable anatomy. The aim of this review was to describe past and recent data published in literature regarding pros and cons of TEVAR treatment in BTAI, and to analyze some debated issues and future perspectives. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and Scale for the Assessment of Narrative Review Articles (SANRA) were used to obtain and describe selected articles on TEVAR in BTAI. Young (<50 years) men were the most operated population. The use of TEVAR increased over the years, with a progressive reduction in mortality and overall postoperative complication rates when compared with OR. Lack of information remains about the percentage of urgent cases. TEVAR is considered nowadays the treatment of choice in BTAI patients. In case of aortic rupture (grade IV) the treatment is mandatory, while intimal tear (grade I) and intramural hematoma (grade II) can be safely managed with no operative management (NOM). Debate is still ongoing on grade III (pseudoaneurysms). Unfortunately, several aspects remain not yet clarified, including disease classification, type and grade to treat, timing (urgent versus elective), priority of vascular injuries in polytrauma patients, and TEVAR use in pediatrics and young patients.


Potential use of radiolabeled glucuronide prodrugs with auger and/or alpha emitters in combined chemo- and radio-therapy of cancer.
Nowadays, the scientists from different disciplines have focused their attentions to new anticancer drug design for cancer chemotherapy. An effective anticancer drug should ensure the selective drug incorporation into the targeted tumor cells without principally incorporation into the normal cells. So, the targeted tumor cells can selectively be damaged by the cytotoxic effectiveness of the drug. The basic principles of drug design have involved "prodrug" concept, which means a chemical agent which is not itself active as an anticancer drug, but it can be transformed to an active form after its administration. Prodrugs can finally be activated onto the tumor cells by some kind of enzymes. In this context, the activation of glucuronide prodrugs by b-glucuronidase have a large potential applications in cancer chemotherapy. On the other hand, combined chemo- and radio-therapy of cancer (CCRTC) concept aims to combine the cytotoxicity of an aglycone with the radiotoxicity of an appropriate radionuclide on the same prodrug. So, the cytotoxic and radiotoxic effectiveness' will be able to be concentrated into the same tumor cell to increase obviously its damage. For experimental realization of this concept an effective anticancer prodrug should be radiolabeled with a radionuclide having high level of radiotoxic effectiveness such as Auger and/or alpha-emitter radionuclides. Iodine-125 and astatine-211 are very interesting radionuclides as being effective Auger and/or alpha-emitters. Briefly, the glucuronide prodrugs radiolabeled with iodine-125 or astatine-211 promise to be designed very effective anticancer agents in the future applications of cancer chemotherapy.


Discovery and Optimization of wt-RET/KDR-Selective Inhibitors of RETV804M Kinase.
A combination of focused library and virtual screening, hit expansion, and rational design has resulted in the development of a series of inhibitors of RETV804M kinase, the anticipated drug-resistant mutant of RET kinase. These agents do not inhibit the wild type (wt) isoforms of RET or KDR and therefore offer a potential adjunct to RET inhibitors currently undergoing clinical evaluation.


Posture-related oscillations in human cerebellar thalamus in essential tremor are enabled by voluntary motor circuits.
The mechanism of essential tremor (ET) is unclear. Animal models of tremor and functional imaging studies in ET predict that the cerebellum and a cerebellar recipient thalamic nucleus (ventral intermediate, Vim) should exhibit oscillatory activity during rest and during tremor due to abnormal olivo-cerebellar activity. Physiologic responses of 152 single neurons were recorded during awake mapping of the ventral thalamus in seven patients with ET prior to thalamotomy. During postural tremor, spectral cross-correlation analysis demonstrated that 51% of the neurons studied exhibited a concentration of power at tremor frequency that was correlated with electromyography, i.e., tremor neurons. During rest, thalamic neurons did not exhibit tremor-frequency activity. Among the three thalamic nuclei surveyed, Vim had a significantly higher proportion of tremor neurons than did the principal somatic sensory nucleus (ventral caudal, Vc) or a pallidal recipient thalamic nucleus (ventral oral posterior, Vop). Neurons related to active movement (voluntary neurons) had significantly greater tremor-related activity than did nonvoluntary neurons. These findings are not consistent with a model of continuous olivo-cerebellar driving of the motor cortex through thalamic connections. Instead ET may be facilitated by motor circuits that enable tremor-related thalamic activity during voluntary movement. Additionally, a subgroup of tremor neurons with proprioceptive inputs were identified that may allow sensory feedback to access the central tremor network.


The Discovery of RNA Aptamers that Selectively Bind Glioblastoma Stem Cells.
Glioblastoma (GBM) is the most aggressive primary brain tumor in adults. Despite progress in surgical and medical neuro-oncology, prognosis for GBM patients remains dismal, with a median survival of only 14-15 months. The modest benefit of conventional therapies is due to the presence of GBM stem cells (GSCs) that cause tumor relapse and chemoresistance and, therefore, that play a key role in GBM aggressiveness and recurrence. So far, strategies to identify and target GSCs have been unsuccessful. Thus, the development of an approach for GSC detection and targeting would be fundamental for improving the survival of GBM patients. Here, using the cell-systematic evolution of ligand by exponential (SELEX) methodology on human primary GSCs, we generated and characterized RNA aptamers that selectively bind GSCs versus undifferentiated GBM cells. We found that the shortened version of the aptamer 40L, which we have called A40s, costained with CD133-labeled cells in human GBM tissue, suggestive of an ability to specifically recognize GSCs in fixed human tissues. Of note, both 40L and A40s were rapidly internalized by cells, allowing for the delivery of the microRNA miR-34c and the anti-microRNA anti-miR-10b, demonstrating that these aptamers can serve as selective vehicles for therapeutics. In conclusion, the aptamers 40L and A40s can selectively target GSCs. Given the crucial role of GSCs in GBM recurrence and therapy resistance, these aptamers represent innovative drug delivery candidates with a great potential in the treatment of GBM.


Comparison of two Norepinephrine rescue bolus for Management of Post-spinal Hypotension during Cesarean Delivery: a randomized controlled trial.
Data on the best norepinephrine bolus dose for management of hypotension are limited. The aim of this study was to compare the efficacy and safety of two norepinephrine bolus doses in the rescue management of maternal hypotension during cesarean delivery. This randomized, controlled trial included mothers scheduled for cesarean delivery with spinal anesthesia with a prophylactic norepinephrine infusion. Following spinal anaesthesia administration, a participant was considered hypotensive if systolic blood pressure was ≤80% compared to the baseline reading. Participants were allocated to receive either 6 mcg or 10 mcg norepinephrine bolus for the management of hypotensive episodes. The hemodynamic response after administration of norepinephrine bolus was recorded. The episode was considered successfully managed if systolic blood pressure returned to within 80% from the baseline reading within 2 min after norepinephrine bolus administration, and did not drop again within 6 min after the norepinephrine bolus. The primary outcome was the incidence of successful management of the first hypotensive episode. Other outcomes included systolic blood pressure, heart rate, incidence of maternal bradycardia, and reactive hypertension. One hundred and ten mothers developed hypotensive episodes and received norepinephrine boluses for management. The number of successfully managed first hypotensive episodes was 50/57 (88%) in the 6 mcg-treated episodes and 45/53 (85%) in the 10 mcg-treated episodes (p = 0.78). Systolic blood pressure was comparable after administration of either bolus dose. Heart rate was lower after administration of 10 mcg bolus compared to 6 mcg bolus, without significant bradycardia requiring atropine administration. The incidence of reactive hypertension was comparable between both groups. In mothers undergoing elective cesarean delivery under prophylactic norepinephrine infusion at 0.05 mcg/kg/min, there was no advantage to the use of 10 mcg norepinephrine bolus over 6 mcg norepinephrine bolus for the rescue management of first hypotensive episode. Neither of the 2 bolus doses reached a 100% success rate. The incidences of bradycardia and reactive hypertension were comparable between both norepinephrine doses. At clinicaltrial.gov registry system on January 4, 2019 Clinical trial identifier: NCT03792906.


Clinicopathologic outcomes of curative resection for sarcomatoid carcinoma of the lung.
Sarcomatoid carcinoma of the lung is a very rare and aggressive subtype of non-small cell lung cancer. We explored the clinicopathologic characteristics and surgical outcome of this tumor. Among 4,212 patients who underwent curative resection for non-small cell lung cancer from September 1994 to December 2009, 99 patients had sarcomatoid carcinoma. Medical records of patients were reviewed retrospectively. The mean follow-up period was 16.07 months. Thirty-six patients had pathologic stage I disease, and 63 had more advanced disease. Surgery included 2 wedge resections, 67 lobectomies, 17 bilobectomies, and 13 pneumonectomies. There were 90 pleomorphic carcinomas, 6 spindle cell carcinomas, 1 giant cell carcinoma, 1 carcinosarcoma, and 1 pulmonary blastoma. Overall 5-year survival was 54.3%. Forty-three patients experienced recurrence and 42 of these died of the cancer. Pathologic T stage as defined by the 7th TNM staging system was significantly associated with survival and recurrence (p = 0.004 and 0.002, respectively). Mean positron emission tomography uptake was significantly higher than in other types of lung cancer (p < 0.0001). Our results implied that surgery for sarcomatoid carcinoma must be carefully planned after extensive preoperative evaluation. Efforts should be made for accurate preoperative histological diagnosis of large peripheral tumor with exceedingly high positron emission tomography uptake.


MiRNA Profiles of Extracellular Vesicles Secreted by Mesenchymal Stromal Cells-Can They Predict Potential Off-Target Effects?
The cardioprotective properties of extracellular vesicles (EVs) derived from mesenchymal stromal cells (MSCs) are currently being investigated in preclinical studies. Although microRNAs (miRNAs) encapsulated in EVs have been identified as one component responsible for the cardioprotective effect of MSCs, their potential off-target effects have not been sufficiently characterized. In the present study, we aimed to investigate the miRNA profile of EVs isolated from MSCs that were derived from cord blood (CB) and adipose tissue (AT). The identified miRNAs were then compared to known targets from the literature to discover possible adverse effects prior to clinical use. Our data show that while many cardioprotective miRNAs such as miR-22-3p, miR-26a-5p, miR-29c-3p, and miR-125b-5p were present in CB- and AT-MSC-derived EVs, a large number of known oncogenic and tumor suppressor miRNAs such as miR-16-5p, miR-23a-3p, and miR-191-5p were also detected. These findings highlight the importance of quality assessment for therapeutically applied EV preparations.


The persistence of vertically transmitted fungi in grass metapopulations.
Theory predicts that (i) vertical transmission of parasites (i.e. when they are passed directly from a host to its offspring) selects for benign association with the host and that (ii) vertically transmitted parasites that lower their hosts' fitness cannot persist if they are not able to infect horizontally (i.e. contagiously) other host individuals in the population. In this paper, we develop a mathematical model to examine whether mutualism is a prerequisite for persistence of exclusively vertically transmitted (from maternal plant to offspring via seeds) fungal endophytes in structured grass metapopulations. Interestingly, endophyte survival does not require plant mutualism, even in a metapopulation consisting of qualitatively identical patches, if vertical transmission of the fungus is perfect, i.e. if all established seedlings in offspring of the endophyte-infected plant are infected. In more realistic situations, when the metapopulation consists of qualitatively different patches, endophyte-infected plants may persist at the metapopulation level even if the vertical transmission is imperfect (due to hyphae inviability or failure to grow into all seeds) and the endophyte decreases the host grass fitness in certain environments. These results have biological importance because they (i) question the requirement of a mutualistic nature in exclusively vertically transmitted symbionts and (ii) emphasize the importance of habitat diversity in relation to symbiont success in vertical transmission.


Appeal rating and visual attention associated with youth-appealing cannabis packaging: An eye-tracking experiment.
Cannabis-infused edibles have grown in popularity particularly among young people in the United States. Youth-appealing cannabis packaging is common and associated with concerns on its public health impacts. This study aims to assess associations of youth-appealing cannabis edible package attributes with appeal ratings and visual attention of young adults. Seventy-two young adults participated in an eye-tracking experiment, in which each participant viewed seven randomly ordered cannabis edible package images with varying youth-appealing attributes, including a cartoon character, a young adult model, bubble font, berry flavor, and gummy bear shape. Two primary outcomes were assessed: 1) appeal ratings elicited on a scale from 0 to 10 based on self-reporting, and 2) fixation durations on predefined areas of interest in the package images based on eye-tracking data. Multivariate linear regressions were conducted to assess associations. Packages containing a cartoon character, bubble font, berry flavor, or gummy bear shape received higher appeal ratings than the package with no youth-appealing attributes. Youth-appealing attributes received longer fixation durations than non-youth-appealing attributes. The presence of any youth-appealing attribute is associated with reduced fixation durations on the warning label, with the largest reduction in the package with multiple youth-appealing attributes. Youth-appealing attributes on cannabis edible packages are associated with higher appeal ratings, more visual attention towards those attributes, and less visual attention towards warning labels among young adults in the United States. Regulations banning youth-appealing attributes may be effective in reducing appeal of cannabis edibles and increasing attention towards warning labels.


KCNH2A561V Heterozygous Mutation Inhibits KCNH2 Protein Expression via The Activation of UPR Mediated by ATF6.
The potassium channel protein KCNH2 is encoded by KCNH2 gene, and there are more than 300 mutations of KCNH2. Unfolded protein response (UPR) is typically initiated in response to an accumulation of unfolded and/or misfolded proteins in the endoplasmic reticulum (ER). The present study aimed to explore the UPR process and the role of activating transcription factor 6 (ATF6) in the abnormal expression of potassium voltage-gated channel subfamily H member 2 (KCNH2)A561V. The wild-type (wt) KCNH2 and A561V mutant KCNH2 was constructed with his-tag. The 293 cells were used and divided into KCNH2wt+KCNH2A561V, KCNH2wt and KCNH2A561V groups. The expression levels of ATF6 and KCNH2 in different groups were detected by Western blotting, reverse transcription-quantitative PCR, immunofluorescence and immuno-coprecipitation assays. The protein types and abundance of immuno-coprecipitation samples were analyzed by mass spectrometry. The proteomic analysis of the mass spectrometry results was carried out by using the reactome database and GO (Gene Ontology) tool. The mRNA expression levels of KCNH2 and ATF6 in the KCNH2wt+KCNH2A561V group were higher compared with the KCNH2A561V group. However, the full-length protein expression of ATF6 was inhibited, indicating that ATF6 was highly activated and a substantial number of ATF6 was sheared in KCNH2wt+KCNH2A561V group compared with control group. Furthermore, A561V-KCNH2 mutation leading to the accumulation of the immature form of KCNH2 (135 kDa bands) in ER, resulting in the reduction of the ratio of 155 kDa/135 kDa. In addition, the abundance of UPR-related proteins in the KCNH2A561V group was higher compared with the KCNH2wt+KCNH2A561V group. The 'cysteine biosynthetic activity' of GO:0019344 process and the 'positive regulation of cytoplasmic translation activity' of GO:2000767 process in the KCNH2A561V group were higher compared with the KCNH2wt+KCNH2A561V group. Hence, co-expression of wild-type and A561V mutant KCNH2 in 293 cells activated the UPR process, which led to the inhibition of protein translation and synthesis, in turn inhibiting the expression of KCNH2. These results provided a theoretical basis for clinical treatment of Long QT syndrome.


Deferred parathyroid autografts with cryopreserved tissue after reoperative parathyroid surgery.
Between August 1975 and March 1981, 12 patients underwent forearm parathyroid autotransplantation with cryopreserved tissue following reoperative parathyroid surgery. Tissue had been cryopreserved two to 18 months. Follow-up ranged from four to 66 months (median, 18 months) following autotransplantation. All patients required calcium supplementation as a condition for autografting; six patients were no longer receiving calcium supplementation at most recent follow-up and in one patient the dosage was being tapered. The presence of a parathyroid hormone gradient of 2 : 1 or greater correlated well with freedom from calcium supplementation. Of seven patients with preautograft and postautograft urinary cyclic adenosine monophosphate (cAMP) determinations, three with increases following transplantation did not require calcium, three without increases continued to require calcium, and the patient whose dosage was being tapered had increased urinary cAMP levels.


Evaluation of recombinant Salmonella expressing CD154 for persistence and enhanced antibody response in commercial turkeys.
Foodborne illness due to Salmonella is a worldwide public health concern and epidemiological evidence has identified poultry and poultry products as a significant source of human Salmonella infection. To discover an effective vaccine that protects poultry against multiple Salmonella serotypes, several novel attenuated Salmonella Enteritidis strains (DeltaSE) were developed to express variations of a potential immune-enhancing CD154 peptide sequence on the outer membrane protein lamB in association with a M2e (marker) epitope. The 3 CD154 peptide sequences evaluated in this study correspond to those naturally occurring in turkeys, humans, and chickens. In 3 separate trials, poults were immunized with 10(7) to 10(8) cfu/poult of the appropriate recombinant Salmonella strains (DeltaSE-M2e, DeltaSE-M2e-T/CD154, DeltaSE-M2e-H/CD154, DeltaSE-M2e-C/CD154) via oral gavage on day of hatch and again on 21 d posthatch. Liver, spleen, and cecal tonsils were aseptically removed on d 7, 14, 21, 28, 35, and 42 posthatch for detection of Salmonella and blood samples were obtained at these same time points for determination of an M2e-specific antibody response. In all 3 trials, DeltaSE strains exhibited significantly less invasion of the liver and spleen at d 7 when compared with Salmonella Enteritidis phage type 13A (P < 0.05). In 2 of the 3 trials, the DeltaSE strains expressing a CD154 peptide sequence further decreased invasion of the liver and spleen. Similarly, colonization of the cecal tonsils was also decreased in the poults immunized with the DeltaSE strains. However, there were no differences in colonization or invasion due to the amino acid sequence of the CD154 insert in all 3 trials. By d 21, the DeltaSE strains exhibited a significantly higher M2e-specific antibody response when compared with the negative control and SE13A groups (P < 0.05). However, no significant differences in M2e-specific antibody responses were observed between any of the DeltaSE candidate vaccine strains expressing CD154 throughout the study. Overall, these data suggest that oral live attenuated Salmonella-vectored vaccines expressing a foreign peptide sequence are able to elicit a humoral immune response in commercial poults and may contribute to a reduction in Salmonella organ invasion and colonization.


Treatment of depression in the medically ill.
Most studies on treatment methods in elderly depressive patients have included primarily patients in good physical health, excluding medical comorbidity, despite the fact that depression with medical comorbidity is the norm rather than the exception. In addition, depression is known to increase disability and mortality among the medically ill. This, therefore, becomes an extremely important issue. Although data are limited, the available evidence suggests that depression concomitant with medical illness can be treated. One or more of the selective serotonin reuptake inhibitors have demonstrated potential usefulness in depressed patients with ischemic heart disease, diabetes, dementia, and Parkinson's disease and in patients after stroke and after myocardial infarction. Large-scale trials are needed to assess not only the safety and effectiveness of agents for the treatment of depression in comorbid illness, but also the effects of depression on the course of the medical illness itself.


Sex and Race Differences in the Association of Incident Ischemic Stroke With Risk Factors.
Race-specific and sex-specific stroke risk varies across the lifespan, yet few reports describe sex differences in stroke risk separately in black individuals and white individuals. To examine incidence and risk factors for ischemic stroke by sex for black and white individuals. This prospective cohort study included participants 45 years and older who were stroke-free from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) cohort, enrolled from the continental United States 2003 through 2007 with follow-up through October 2016. Data were analyzed from March 2018 to September 2018. Sex and race. Physician-adjudicated incident ischemic stroke, self-reported race/ethnicity, and measured and self-reported risk factors. A total of 25 789 participants (14 170 women [54.9%]; 10 301 black individuals [39.9%]) were included. Over 222 120 person-years of follow-up, 939 ischemic strokes occurred: 159 (16.9%) in black men, 326 in white men (34.7%), 217 in black women (23.1%), and 237 in white women (25.2%). Between 45 and 64 years of age, white women had 32% lower stroke risk than white men (incidence rate ratio [IRR], 0.68 [95% CI, 0.49-0.94]), and black women had a 28% lower risk than black men (IRR, 0.72 [95% CI, 0.52-0.99]). Lower stroke risk in women than men persisted at age 65 through 74 years in white individuals (IRR, 0.71 [95% CI, 0.55-0.94]) but not in black individuals (IRR, 0.94 [95% CI, 0.68-1.30]); however, the race-sex interaction was not significant. At 75 years and older, there was no sex difference in stroke risk for either race. For white individuals, associations of systolic blood pressure (women: hazard ratio [HR], 1.13 [95% CI, 1.05-1.22]; men: 1.04 [95% CI, 0.97-1.11]; P = .099), diabetes (women: HR, 1.84 [95% CI, 1.35-2.52]; men: 1.13 [95% CI, 0.86-1.49]; P = .02), and heart disease (women: HR, 1.76 [95% CI, 1.30-2.39]; men, 1.26 [95% CI, 0.99-1.60]; P = .09) with stroke risk were larger for women than men, while antihypertensive medication use had a smaller association in women than men (women: HR, 1.17 [95% CI, 0.89-1.54]; men: 1.61 [95% CI, 1.29-2.03]; P = .08). In black individuals, there was no evidence of a sex difference for any risk factors. For both races, at age 45 through 64 years, women were at lower stroke risk than men, and there was no sex difference at 75 years or older; however, the sex difference pattern may differ by race from age 65 through 74 years. The association of risk factors on stroke risk differed by race-sex groups. While the need for primordial prevention, optimal management, and control of risk factors is universal across all age, racial/ethnic, and sex groups, some demographic subgroups may require earlier and more aggressive strategies.


Rapid Induction of Long-Lasting Systemic and Mucosal Immunity via Thermostable Microneedle-Mediated Chitosan Oligosaccharide-Encapsulated DNA Nanoparticles.
Most existing vaccines, delivered by intramuscular injection (IM), are typically associated with stringent storage requirements under cold-chain distribution and professional administration by medical personnel and often result in the induction of weak mucosal immunity. In this context, we reported a microneedle (MN) patch to deliver chitosan oligosaccharide (COS)-encapsulated DNA vaccines (DNA@COS) encoding spike and nucleocapsid proteins of SARS-CoV-2 as a vaccination technology. Compared with IM immunization, intradermal administration via the MN-mediated DNA vaccine effectively induces a comparable level of neutralizing antibody against SARS-CoV-2 variants. Surprisingly, we found that MN-mediated intradermal immunization elicited superior systemic and mucosal T cell immunity with enhanced magnitude, polyfunctionality, and persistence. Importantly, the DNA@COS nanoparticle vaccine loaded in an MN patch can be stored at room temperature for at least 1 month without a significant decrease of its immunogenicity. Mechanically, our strategy enhanced dendritic cell maturation and antiviral immunity by activating the cGAS-STING-mediated IFN signaling pathway. In conclusion, this work provides valuable insights for the rapid development of an easy-to-administer and thermostable technology for mucosal vaccines.


[Factors associated with prolonged hospital stay in infants].
To evaluate factors present on newborn admission to a neonatal intensive care and associated with a prolonged hospital stay. Non-matched case-control study, with 555 infants, 111 with more than 7 days of hospital stay and 444 who stayed hospitalized between 1 and 7 days, between 2005 and 2010. Pre hospitalization maternal factors (age, pregnancy, health insurance, education, prenatal care, marital status, history of preeclampsia, prolonged rupture of membranes, chorioamnionitis infection) and neonatal ones (age at admission, gestational age, birth weight, gender, delivery practice, route of admission, Apgar and type of resuscitation) that were associated with prolonged hospital stay were analyzed. Analyses were conducted using STATA 11.0 and logistic regression in the multivariate analysis. Maternal factors such as prenatal care with less than 5 doctor visits (AOR 2.7, 95% CI 1.3-5.5), lack of social health insurance (AOR 1.9, 95% CI 1.4-29), pregnant three or more times (AOR 1.7, 95% CI 1.1-2.7), neonatal birth weight under 2,000 g (AOR 4.2, 95% CI 1.9-9.5), need for cardiopulmonary resuscitation (AOR 4.2, 95% CI 2-9.1), gestational age less than 36 weeks (AOR 3.9, 95% CI 2-7.7) and admission to the neonatal unit through emergency room or referral from another hospital (AOR 2.8, 95% CI 1.7-4.6) were associated with hospital stays longer than 7 days. In-hospital complications that affect a prolonged stay at the health center were social health insurance, maternal education and prenatal care, and these should be considered in the evaluation of the hospital care quality indicators.


Assessing the contribution of bacteria to the heat tolerance of experimentally evolved coral photosymbionts.
Coral reefs are extremely vulnerable to ocean warming, which triggers coral bleaching-the loss of endosymbiotic microalgae (Symbiodiniaceae) from coral tissues, often leading to death. To enhance coral climate resilience, the symbiont, Cladocopium proliferum was experimentally evolved for >10 years under elevated temperatures resulting in increased heat tolerance. Bacterial 16S rRNA gene metabarcoding showed the composition of intra- and extracellular bacterial communities of heat-evolved strains was significantly different from that of wild-type strains, suggesting bacteria responded to elevated temperatures, and may even play a role in C. proliferum thermal tolerance. To assess whether microbiome transplantation could enhance heat tolerance of the sensitive wild-type C. proliferum, we transplanted bacterial communities from heat-evolved to the wild-type strain and subjected it to acute heat stress. Microbiome transplantation resulted in the incorporation of only 30 low-abundance strains into the microbiome of wild-type cultures, while the relative abundance of 14 pre-existing strains doubled in inoculated versus uninoculated samples. Inoculation with either wild-type or heat-evolved bacterial communities boosted C. proliferum growth, although no difference in heat tolerance was observed between the two inoculation treatments. This study provides evidence that Symbiodiniaceae-associated bacterial communities respond to heat selection and may contribute to coral adaptation to climate change.


A survey questionnaire evaluating physical activity patterns and determinants in patients with chronic liver disease.
Physical activity can reduce the risk of morbidity and mortality in patients with chronic liver disease (CLD), whereas physical inactivity adversely affects clinical outcomes. Since data on physical activity in CLD are scarce, we conducted a questionnaire survey to assess the physical activity patterns and determinants in patients with CLD. We surveyed 437 patients from outpatient clinics at Gifu University Hospital about their physical activity patterns and determinants in 2022 using a validated questionnaire. The primary objective was to examine the proportion of patients who exercised and the clinical characteristics of patients who achieved high levels of physical activity. The secondary objectives were to explore the types, motivations, barriers, and preferences for physical activity. Among the 397 eligible patients (median age 68 years; 51% men; and median Model for End-Stage Liver Disease score 6), 55.4% reported performing physical activity less than once a week. Physical activity frequency was not associated with sex, body mass index, comorbidities, or hepatic reserve. Among the respondents, 60.4% expressed concern regarding physical strength, and 80.6% expressed concern regarding physical inactivity. The main barriers to physical activity were work, household chores, and health problems. However, many respondents expressed their willingness to increase their physical activity frequency with some promotional policies. Walking was the most common physical activity practiced in the past year and the activity most respondents wanted to try in the future. Patients with CLD are insufficiently active and need physical activity interventions, especially regarding walking.


Organizational silence and hidden threats to patient safety.
Organizational silence refers to a collective-level phenomenon of saying or doing very little in response to significant problems that face an organization. The paper focuses on some of the less obvious factors contributing to organizational silence that can serve as threats to patient safety. Converging areas of research from the cognitive, social, and organizational sciences and the study of sociotechnical systems help to identify some of the underlying factors that serve to shape and sustain organizational silence. These factors have been organized under three levels of analysis: (1) individual factors, including the availability heuristic, self-serving bias, and the status quo trap; (2) social factors, including conformity, diffusion of responsibility, and microclimates of distrust; and (3) organizational factors, including unchallenged beliefs, the good provider fallacy, and neglect of the interdependencies. Finally, a new role for health care leaders and managers is envisioned. It is one that places high value on understanding system complexity and does not take comfort in organizational silence.


Detection of biological macromolecules on a biochip dedicated to UV specific absorption.
This work describes an ultraviolet biosensing technique based on specific molecular absorption detected with a previously developed spectrally selective aluminum gallium nitride (AlGaN) based detector. Light absorption signal of DNA and proteins, respectively at 260 nm and 280 nm, is used to image biochips. To allow detection of protein or DNA monolayers at the surface of a biochip, we develop contrast-enhancing multilayer substrates. We analyze them through models and experiments and validate the possibility of measuring absorptions of the order of 10(-3). These multilayer structures display a high reflectivity, and maximize the interaction of the electric field with the biological element at the chip surface. Optimization of the experimental absorption, which includes effects such as roughness of the biochip, spectral and angular resolution of the optics, illumination, etc., is carried out with an inorganic ultraviolet absorber (titanium dioxide) deposit. We obtained an induced absorption contrast enhanced by a factor of 4.0, conferring enough sensitivity to detect monolayers of DNA or proteins. Experimental results on an Escherichia coli histidine-tagged methionyl-tRNA synthetase protein before and after complexation with an anti-polyHis specific antibody validate our biosensing technique. This label-free optical method may be helpful in controlling biochip coatings, and subsequent biological coupling at the surface of a biochip.


Renormalization of oscillator lattices with disorder.
A real-space renormalization transformation is constructed for lattices of nonidentical oscillators with dynamics of the general form dvarphi_{k}/dt=omega_{k}+g summation operator_{l}f_{lk}(varphi_{l},varphi_{k}) . The transformation acts on ensembles of such lattices. Critical properties corresponding to a second-order phase transition toward macroscopic synchronization are deduced. The analysis is potentially exact but relies in part on unproven assumptions. Numerically, second-order phase transitions with the predicted properties are observed as g increases in two structurally different two-dimensional oscillator models. One model has smooth coupling f_{lk}(varphi_{l},varphi_{k})=phi(varphi_{l}-varphi_{k}) , where phi(x) is nonodd. The other model is pulse coupled, with f_{lk}(varphi_{l},varphi_{k})=delta(varphi_{l})phi(varphi_{k}) . Lower bounds for the critical dimensions for different types of coupling are obtained. For nonodd coupling, macroscopic synchronization cannot be ruled out for any dimension D> or =1 , whereas in the case of odd coupling, the well-known result that it can be ruled out for D<3 is regained.


SARS-CoV-2 vaccination responses in untreated, conventionally treated and anticytokine-treated patients with immune-mediated inflammatory diseases.
To better understand the factors that influence the humoral immune response to vaccination against SARS-CoV-2 in patients with immune-mediated inflammatory diseases (IMIDs). Patients and controls from a large COVID-19 study, with (1) no previous history of COVID-19, (2) negative baseline anti-SARS-CoV-2 IgG test and (3) SARS-CoV-2 vaccination at least 10 days before serum collection were measured for anti-SARS-CoV-2 IgG. Demographic, disease-specific and vaccination-specific data were recorded. Vaccination responses from 84 patients with IMID and 182 controls were analysed. While all controls developed anti-SARS-CoV-2 IgG, five patients with IMID failed to develop a response (p=0.003). Moreover, 99.5% of controls but only 90.5% of patients with IMID developed neutralising antibody activity (p=0.0008). Overall responses were delayed and reduced in patients (mean (SD): 6.47 (3.14)) compared with controls (9.36 (1.85); p<0.001). Estimated marginal means (95% CI) adjusted for age, sex and time from first vaccination to sampling were 8.48 (8.12-8.85) for controls and 6.90 (6.45-7.35) for IMIDs. Significantly reduced vaccination responses pertained to untreated, conventionally and anticytokine treated patients with IMID. Immune responses against the SARS-CoV-2 are delayed and reduced in patients with IMID. This effect is based on the disease itself rather than concomitant treatment.


Differential scanning calorimetry of asparate transcarbamoylase and its isolate subunits.
The thermal denaturation of aspartate transcarbamoylas of Escherichia coli was investigated by differential scanning calorimetry. Isolated regulatory and catalytic subunits were heat denatured at 55 and 80 degrees C, respectively. In contrast, the intact enzyme was denatured in two steps. A small endotherm near 73 degrees C was assoicated with denaturation of the regulatory subunits and the major endotherm at 82 degrees C with denaturation of the catalytic subunits. Thus regulatory subunits are stabilized against heat denaturation by more than 17 degrees C when incorporated in the enzyme. Similar conclusions were obtained from measurements of the enthalpy of heat denaturation. Regulatory subunits yielded a much lower value of the enthalpy of denaturation, 1.91 cal/g, than that found for the catalytic subunit, 3.94 cal/g, or typical globular proteins (4 to 6 cal/g). When the regulatory subunits were incorporated into aspartate transcarbamoylase their enthalpy of denaturation was increased 125% (to 4.3 cal/g). The enthalpy of the catalytic subunits in the intact enzyme was increased 38% (enthalpy of denaturation of 5.43 cal/g). Stabilization of the isolated catalytic subunit as well as the intact enzyme was achieved by the addition of the bisubstrate analog N-(phosphonacetyl)-L-aspartate. Similarly the allosteric effectors, CTP and ATP, stabilized the isolated regulatory subunits or those subunits within the intact enzyme. However, the addition of the bisubstrate analog caused a decrease in the enthalpy of denaturation of the regulatory subunits within the enzyme. These results are consistent with other studies of the ligand-promoted conformational changes in the native enzyme.


Preoperative high-sensitivity C-reactive protein to lymphocyte ratio index plays a vital role in the prognosis of hepatocellular carcinoma after surgical resection.
At present, the predictive ability of the prognostic indicator of hepatocellular carcinoma (HCC) is still limited. This study aims to analyze the relationship between the preoperative high-sensitivity C-reactive protein to lymphocyte ratio (HCLR) and the clinicopathologic characteristics of HCC. A total of 229 HCC patients undergoing surgical resection were retrospectively analyzed. The majority of the patients (132/229) had tumors larger than 5 cm, and 45 out of 229 had more than one tumor focus. Receiver operating characteristic curve analysis was used to decide the cutoff value of HCLR. The overall survival (OS) and progression-free survival (PFS) rates were evaluated by adopting the Kaplan-Meier method. The cutoff value of HCLR for the best discrimination of HCC prognosis was 1.3 with a sensitivity of 75.5% and a specificity of 71.8%. The area under the receiver operating characteristic curve was 0.791 (95% CI, 0.731-0.840). Preoperative HCLR at a high level (>1.3) was positively correlated with large tumor size, TNM stage, microvascular invasion, and recurrence. The mean OS and PFS in patients with HCLR >1.3 were significantly shorter than in those with HCLR ≤1.3. Univariate and multivariate analyses revealed the HCLR was an independent predictor of OS and PFS. HCLR was an important independent predictor of dismal prognosis in HCC patients and can be used as a sensitive indicator for the dynamic monitoring of postoperative patients.


Terahertz spectral domain computational analysis of hydration shell of proteins with increasingly complex tertiary structure.
Solvation dynamics of biomolecules and water in a hydration shell have been studied by different methods; however, a clear picture of this process is not yet established. Terahertz (THz) studies of molecular behavior in binary solutions present unique information on the picosecond motions of molecules. A complete mechanical interpretation of THz absorption spectra associated with solvated biomolecules remains a challenging task. The Gromacs molecular dynamics (MD) simulation package is used here to examine the spectral characteristics of water molecules in close proximity to biomolecules using vibrational density of states (VDOS). Systematic simulation of solvation dynamics of proteins of different size and tertiary structure are presented. The following have been selected for analysis. They range from less to more complex tertiary structure (corresponding to an increased number of secondary structure elements): TRP-cage13-20 peptide, TRP-cage, BPTI, and lysozyme. The initial study predicts that the depth of the hydration shell, determined by VDOS of water, extends to approximately 10 Å and does not depend on protein size. Furthermore the integral perturbation coefficient of the whole solvation layer is found to be increased for larger proteins due to a higher retardation rate of water molecules in their shells. Differences in solvation dynamics among the proteins considered originate primarily from the water molecules buried in the interior of the protein and not from the on-surface molecules.


Analysis of in-hospital deaths from myocardial infarction after coronary care unit discharge.
Clinical records of 48 patients who died suddenly and unexpectedly following coronary care unit discharge were analyzed. Twenty-five had myocardial infarction as sole cause of death and 23 had other contributing entitles. Patients with moderate to severe congestive heart failure had a higher total incidence of specific dysrhythmias in the coronary care unit compared to others. Large infarctions involving the anterior wall, especially in patients with moderate to severe heart failure in the coronary care unit, were negative prognostic factors. Serious dysrhythmias occurred with greater frequency in patients with moderate to severe congestive heart failure compared to others. Degree of congestive heart failure was not related to death among patients with atrioventricular block in the coronary care unit. Monitoring after the coronary care unit (Intermediate coronary care unit) may further reduce mortality.


Single cell impedance cytometry for identification and counting of CD4 T-cells in human blood using impedance labels.
Single cell microfluidic impedance cytometry has been used to identify cells at high speed, on the basis of their dielectric properties. However, there is no electrical analogue to a fluorescent label, meaning that it is not possible to identify subpopulations of cells. We demonstrate discrimination and enumeration of antigenically defined cell subpopulations using an alternating current (AC) impedance labeling method. Small antibody conjugated beads are mixed with cells and bind to the target population, changing the electrical properties of the target subset of cells. The principle of the technique is demonstrated by identifying and enumerating the CD4 T-lymphocyte subpopulation in human whole blood. The technique represents a simple method for detecting a subpopulation of cells within a heterogeneous mix. The impedance-based antibody identification method could form the basis of simple low-cost point of care diagnostic technologies.


Management of Glenoid Bone Loss in Shoulder Instability: Where We Are in 2023.
The management of glenoid bone loss in shoulder instability can be challenging. Although shoulder instability can often be managed with arthroscopic soft-tissue procedures alone, the extent of glenoid bone loss and bipolar bone defects may require bone augmentation procedures for restoration of stability. In this setting, patient evaluation, examination, treatment options, and surgical pearls are vital. Furthermore, a treatment algorithm is established to guide both indications and the technical application of procedures including Bankart repair with remplissage, Latarjet procedure, and glenoid bone graft options. The limitations, complications, and current research pertinent to each treatment assist in guiding treatment.


Intraocular pressure measurement precision with the Goldmann applanation, dynamic contour, and ocular response analyzer tonometers.
To examine the repeatability and reproducibility of intraocular pressure (IOP) measurements obtained with the Goldmann applanation tonometer (GAT), the Pascal dynamic contour tonometer (DCT; Swiss Microtechnology AG, Port, Switzerland), and the Reichert Ocular Response Analyzer (ORA; Reichert Ophthalmic Instruments, Buffalo, NY). A secondary objective was to assess agreement between the devices. Evaluation of technology. One hundred participants; a mixture of glaucoma suspects, patients, and control volunteers. The IOP measurements were obtained with the GAT, DCT, and ORA by 2 of 3 experienced clinicians. Keratometry (CC) measurements were made using the IOLMaster (Carl Zeiss Meditech, AG, Jena, Germany). Three ORA corneal compensated IOP (IOPcc) measurements were obtained before the instillation of anesthesia, after which 2 GAT IOP and 3 DCT IOP measurements were obtained in a randomized order. Central corneal thickness (CCT) was measured using an ultrasound pachymeter. The average ORA corneal response factor (CRF) and the average DCT ocular pulse amplitude (OPA) were determined. Intraobserver variability was calculated by the repeatability coefficient. Interobserver variability (measurement reproducibility) and device agreement were calculated by Bland-Altman analysis (mean difference [bias] and 95% limits of agreement [LoA]). The effect of corneal characteristics (CC, CCT, and CRF) on the IOP measurement differences between tonometers also was determined. Repeatability and reproducibility of the GAT, DCT, and ORA IOPcc and agreement between tonometers. The repeatability coefficients for GAT, DCT, and ORA were 2.2, 2.3, and 4.3 mmHg, respectively. The intraobserver variability of ORA measurements was shown to be significantly associated with OPA and to a lesser degree with the quality of ORA waveform scans. The interobserver bias (95% LoA) was -0.8 (+/-3.9) mmHg for GAT -0.2 (+/-2.8) mmHg for DCT and -0.3 (+/-3.9) mmHg for ORA IOPcc. On average, GAT under-read both DCT and ORA IOP measurements by approximately 2 mmHg. The IOP measurement differences were better predicted by CRF than CCT. The DCT shows excellent measurement precision, displaying the best repeatability and reproducibility of the 3 tonometers. Corneal stiffness, as defined using CRF, was associated significantly with agreement between devices. The IOP measurements with each device are not interchangeable. Proprietary or commercial disclosure may be found after the references.


[Notes on the hemostatic effect of the cryodestruction of bone tumors].
Cryodestruction is a comparatively new method in orthopedic oncology used for the treatment of bone tumors and not practised on a large scale in the clinic. The work elucidates peculiarities of the postoperative period observed in 112 patients with bone tumors after exposure to cryogenic procedures. The "hemostatic effect" following cryodestruction of tumors and tumoral injuries of bones is critically analyzed.


Antenatal magnesium sulfate and intestinal morbidities in preterm infants with extremely low gestational age.
Antenatal magnesium sulfate is widely used as a tocolytic, for maternal seizures, and for seizure prophylaxis in preeclampsia. Recent studies have suggested that antenatal magnesium sulfate use is associated with favorable neurodevelopmental outcomes in preterm infants. However, there are concerns regarding the effects of antenatal magnesium sulfate on neonates, especially regarding gastrointestinal morbidities. This study aims to explore the effects of antenatal magnesium sulfate on intestinal morbidities requiring surgery in preterm infants. This was a retrospective cohort study of 181 preterm infants who were born at less than 28 weeks of gestational age. Subjects were categorized as infants exposed to antenatal magnesium sulfate and those not exposed to antenatal magnesium sulfate. Antenatal magnesium sulfate was associated with a decreased risk of surgical conditions of the intestine (OR 0.393, 95% CI 0.170-0.905). The multivariate analysis showed that the duration of antenatal magnesium sulfate use was associated with surgical conditions of the intestine (adjusted OR 0.766, 95% CI 0.589-0.997). In the <26 weeks of gestational age subgroup, the use of antenatal magnesium sulfate was significantly associated with decreased intestinal morbidities requiring surgery (adjusted OR 0.234, 95% CI 0.060-0.922). Antenatal magnesium sulfate use appears to have a protective effect on intestinal morbidities requiring surgery in preterm infants in a duration-dependent manner. Association of antenatal magnesium sulfate use and decreased intestinal morbidities requiring surgery was more distinct in preterm infants <26 weeks of gestational age.


Synthesis and comparison of the meta-analyses evaluating the efficacy of memantine in moderate to severe stages of Alzheimer's disease.
The N-methyl-D-aspartate receptor antagonist, memantine, is licensed for the treatment of moderate to severe Alzheimer's disease (AD). Memantine is administered both as a monotherapy and as an add-on therapy in patients already receiving acetylcholinesterase inhibitors. Several meta-analyses have been published that examine the efficacy of memantine in the treatment of AD, based on clinical trial data. However, different disease severities and concomitant medication use in the trial populations means that synthesis of this data is challenging with numerous methodological decisions required. The main objectives of this study were to review the methodologies of different meta-analyses, assess the impact of specific methodological approaches on efficacy results, and to help interpret previous meta-analyses results concerning the efficacy of memantine in moderate to severe stages of AD. The methodologies of five meta-analyses were reviewed in terms of the included trials, combination of data, choice of outcome, and analysis methods. Results were extracted and compared in line with the methodological approach taken. The most robust results were observed on cognition, activities of daily living, and overall assessment, where memantine showed a consistent benefit over placebo. The benefit of memantine on behavioral symptoms was also demonstrated, but results were more heterogeneous. Variability could not be explained by baseline severity and concomitant treatment alone. It is stressed that interpretation of meta-analysis results must be considered within the context of the methodological approach. Overall, results from individual clinical trials and from meta-analyses demonstrate that memantine represents a valuable treatment option in AD.


Review of patient-reported outcome instruments measuring health-related quality of life and satisfaction in patients with type 2 diabetes treated with oral therapy.
Treatments and their mode of administration may represent a burden for patients and can therefore impact their health-related quality of life (HRQL) or treatment/health satisfaction. Patients with type 2 diabetes mellitus (T2DM) can be treated with oral hypoglycemic agents (OHAs), injectable medications (such as insulin), or a combination of agents. This review aimed to identify patient-reported outcome (PRO) instruments measuring HRQL and/or satisfaction that could differentiate between oral medications based on medication related attributes such as efficacy, tolerability, weight loss, dosing frequency and pill burden. Medline, Embase, PsycINFO, Cochrane Library and the Patient-Reported Outcome and Quality of Life Questionnaires (PROQOLID) biomedical databases were searched to identify instruments and document their development methodology, content and psychometric properties (i.e. validity, reliability), responsiveness and ability to detect changes between treatments. Nineteen instruments were retained based on their potential to differentiate between OHAs. Ten instruments assessed HRQL, amongst which the Audit of Diabetes Dependent Quality of Life, Diabetes 39, Diabetes Health Profile and Impact of Weight on Quality of Life displayed good psychometric properties in T2DM populations and comprehensive HRQL content. Nine instruments assessed satisfaction. Both the Oral Hypoglycemic Agent Questionnaire (OHAQ) and Diabetes Medication Satisfaction (DiabMedSat) Questionnaire have highly relevant content regarding drug attributes. The OHAQ is specific to oral treatment and the DiabMedSat includes HRQL items. The Diabetes Treatment Satisfaction Questionnaire is a standard instrument that is extensively used and provides conclusive results in studies of patients with T2DM. Very few of the existing PRO instruments are specific to OHAs. Despite satisfaction instruments being recommended to differentiate between OHAs in studies of T2DM based on medication attributes, we find that none of the existing instruments appear to be useful in detecting differences between treatments, therefore limiting their use in clinical and observational research.


Radiation therapy quality indicators for invasive breast cancer.
Radiation therapy (RT) for breast cancer has evolved considerably over the past two decades. A concise list of optimal care indexes is lacking. The purpose of this project was to generate a suite of quality of care indicators for breast cancer RT. A modified Delphi approach was used including a comprehensive literature and guideline review (1995-2015), an initial review of potential quality indicators (QIs) by a steering committee, a survey of Canadian Radiation Oncologists, and a face-to-face consensus development meeting with breast cancer experts to develop a list of breast RT quality indicators. The literature review identified 163 potential QIs, which was reduced to 73 by the steering committee. After all rounds of the Delphi process the final suite included 33 QIs. Of these, 28 (85%) received at least 80% acceptance from the Radiation Oncologists who participated in the final online survey. A suite of measureable RT quality indicators to be considered during management of invasive breast cancer was developed. These indicators could be used to assess the quality and consistency of breast cancer RT practices.


Cellular localization and functional expression of P-glycoprotein in rat astrocyte cultures.
We investigated the cellular/subcellular localization and functional expression of P-glycoprotein, an ATP-dependent membrane-associated efflux transporter, in astrocytes, a brain parenchyma compartment that is poorly characterized for the expression of membrane drug transporters. Analyses were carried out on primary cultures of astrocytes isolated from the cerebral cortex of neonatal Wistar rats and CTX TNA2, an immortalized rat astrocyte cell line. Both cell cultures display morphological features typical of type I astrocytes. RT-PCR analysis revealed mdr1a and mdr1b mRNA in primary cultures of astrocytes and in CTX TNA2 cells. Western blot analysis using the P-glycoprotein monoclonal C219 antibody detected a single band of appropriate size in both cell systems. Immunocytochemical analysis using the monoclonal antibodies C219 and MRK16 labeled P-glycoprotein along the plasma membrane, caveolae, coated vesicles and nuclear envelope. Immunoprecipitation studies using the caveolin-1 polyclonal H-97 antibody demonstrated that P-glycoprotein is physically associated with caveolin-1 in both cell culture systems. The accumulation of [(3)H]digoxin (an established P-glycoprotein substrate) by the astrocyte cultures was significantly enhanced in the presence of standard P-glycoprotein inhibitors and an ATP depleting agent. These results demonstrate the cellular/subcellular location and functional expression of P-glycoprotein in rat astrocytes and suggest that this glial compartment may play an important role in the regulation of drug transport in the CNS.


Major adverse limb events and major adverse cardiac events after contemporary lower extremity bypass and infrainguinal endovascular intervention in patients with claudication.
Major adverse limb events (MALEs) and major adverse cardiovascular events (MACEs) at 30 days provide standardized metrics for comparison and have been adopted by the Society for Vascular Surgery's objective performance goals for critical limb ischemia. However, MALEs and MACEs have not been widely adopted within the claudication population, and the comparative outcomes after lower extremity bypass (LEB) and infrainguinal endovascular intervention (IEI) remain unclear. The purpose of this study was to compare MALEs and MACEs after LEB and IEI in a contemporary national cohort and to determine predictors of MALEs and MACEs after revascularization for claudication. A national data set of LEB and IEI performed for claudication was obtained using National Surgical Quality Improvement Program vascular targeted Participant Use Data Files from 2011 to 2014. Patients were stratified by LEB vs IEI and compared by appropriate univariate analysis. The primary outcomes were MALE (defined as untreated loss of patency, reintervention on the index arterial segment, or amputation of the index limb) and MACE (defined as stroke, myocardial infarction, or death). Multivariable logistic regression was used to identify predictors of MALEs and MACEs. A total of 3925 infrainguinal revascularization procedures (2155 LEB and 1770 IEI) were performed for claudication. There was no difference in 30-day MALEs between LEB and IEI (4.0% vs 3.2%; P = .17). On multivariable logistic regression, predictors of 30-day MALEs included tibial revascularization (odds ratio [OR], 2.2; P < .0001) and prior LEB on the same arterial segment (OR, 1.8; P = .004). LEB had significantly higher 30-day MACEs (2.0% vs 1.0%; P = .01) but similar mortality (0.5% vs 0.4%; P = .6). Predictors of MACEs included LEB vs IEI (OR, 2.1; P = .01), chronic obstructive pulmonary disease (OR, 2.2; P = .01), dialysis dependence (OR, 4.4; P = .003), and diabetes (OR, 1.9; P = .02). In this large national cohort, LEB and IEI for claudication are associated with similar 30-day MALEs. Tibial revascularization and revascularization after prior failed bypass predict MALEs in claudicants and should therefore be undertaken with caution. LEB was associated with more 30-day MACEs but comparable 30-day mortality compared with IEI. Patients with end-stage renal disease, chronic obstructive pulmonary disease, and diabetes are at high risk for MACEs. The risk of 30-day MACEs after LEB should be weighed against the longer term outcomes of LEB vs IEI and conservative management, particularly in these higher risk patients. This analysis helps define contemporary 30-day outcomes after infrainguinal revascularization performed for claudication and serves as a baseline with which the short-term outcomes of future treatments can be compared.


Sinosporangium fuscum sp. nov., isolated from soil.
A novel actinomycete, A-T 8343T was isolated from a moist evergreen forest soil sample collected in the Trat Province, Thailand. Based on 16S rRNA gene sequence analysis, strain A-T 8343T belonged to the genus Sinosporangium and was closely related to Sinosporangium siamense A-T 1946T (98.81 %) and Sinosporangium album 6014T (98.54 %). The DNA-DNA relatedness values were 21.8-27 % with S. siamense A-T 1946T and 31.1-31.9 % with S. album 6014T, which were significantly below 70 %. The result differentiated A-T 8343T from the closest species. The organism developed spherical sporangia containing non-motile spores on aerial mycelia. The cell-wall peptidoglycan contained meso-diaminopimelic acid. The whole-cell sugars contained rhamnose, ribose, madurose and glucose. The predominant menaquinones were MK-9(H2) and MK-9(H4). The diagnostic phospholipids were phosphatidylmethylethanolamine, phosphatidylethanolamine, hydroxyl-phosphatidylethanolamine, diphosphatidylglycerol, lyso-phosphatidylethanolamine, N-acetylglucosamine-containing phospholipids, phosphatidylglycerol, phosphatidylinositol, phosphatidylinositol-mannosides, aminophosphoglycolipid and one unknown phospholipid. The major cellular fatty acids were saturated C16 : 0, iso C16 : 0, unsaturated C16 : 1 and C18 : 1. Following an evaluation of phenotypic, chemotaxonomic and genotypic characteristics, the new isolate is proposed as a representative novel species of the genus Sinosporangium to be named Sinosporangiumfuscum sp. nov. The type strain is A-T 8343T ( = BCC 52770T = NBRC 109516T).


Context-dependent repetition effects on recognition memory.
One widely acknowledged way to improve our memory performance is to repeatedly study the to be learned material. One aspect that has received little attention in past research regards the context sensitivity of this repetition effect, that is whether the item is repeated within the same or within different contexts. The predictions of a neuro-computational model (O'Reilly & Norman, 2002) were tested in an experiment requiring participants to study visual objects either once or three times. Crucially, for half of the repeated objects the study context (encoding task, background color and screen position) remained the same (within context repetition) while for the other half the contextual features changed across repetitions (across context repetition). In addition to behavioral measures, event-related potentials (ERP) were recorded that provide complementary information on the underlying neural mechanisms during recognition. Consistent with dual-process models behavioral estimates (remember/know-procedure) demonstrate differential effects of context on memory performance, namely that recognition judgements were more dependent on familiarity when repetition occurs across contexts. In accordance with these behavioral results ERPs showed a larger early frontal old/new effect for across context repetitions as compared to within context repetitions and single presentations, i.e. an increase in familiarity following repetition across study contexts. In contrast, the late parietal old/new effect, indexing recollection did not differ between both repetition conditions. These results suggest that repetition differentially affects familiarity depending on whether it occurs within the same context or across different contexts.


[Human walk in spacesuit as a self-oscillating process].
A series of 40 biomechanic and physiological tests of semi-rigid and flexible spacesuits as possible candidates for Moon explorations purposes were conducted with involvement of 20 volunteered subjects. Ability to walk in the spacesuits with the internal positive pressure of 0.4 kg/cm2 in the normal gravity was assessed simultaneously with energy expenditure for moving over preset distances. Also, mating of the leg movements with the spacesuit shell was investigated The longest distance test elicited the fact of acquisition of stable motor skills in the unusual circumstances. The acquired motor skills bring about restructuring of step kinematics and make equal knee flexures during leg transfer and stepping on platform (matching the angular movement of the spacesuit knee joint) to an accuracy of tenths of degree. This phenomenon is used by the authors as the ground for proposing a reasoned optimization of the walk pattern in spacesuits as a self-oscillating process.


Cerebrospinal fluid drainage options for posthemorrhagic hydrocephalus in premature neonates.
The literature describes various cerebrospinal fluid (CSF) drainage techniques to alleviate posthemorrhagic hydrocephalus in preterm newborns; however, consensus has not been reached. The scope of this study was describing a case series of premature neonates with posthemorrhagic hydrocephalus and assessing the outcomes of different approaches used for CSF diversion. A consecutive review of the medical records of neonates with posthemorrhagic hydrocephalus treated with CSF drainage was conducted. Forty premature neonates were included. Serial lumbar puncture, ventriculosubgaleal shunt, and ventriculoperitoneal shunt were the treatments of choice in 25%, 37.5% and 37.5% of the cases, respectively. Cerebrospinal fluid diversion should be tailored to each case with preference given to temporary CSF drainage in neonates with lower age and lower birth-weight, while the permanent ventriculoperitoneal shunt should be considered in healthier, higher birth-weight neonates born closer to term.


Molecular cytogenetic characterization of a small, familial supernumerary ring chromosome 7 associated with mental retardation and an abnormal phenotype.
A family is described in which a mother and two of her children were mosaic for a small supernumerary ring chromosome. As the origin of the ring chromosome could not be determined by routine cytogenetic studies, fluorescent in situ hybridization was performed, which indicated that the ring chromosome was derived from the pericentromeric region of chromosome 7. Further characterization with a YAC-probe showed the involvement of the proximal q-arm of chromosome 7. Both sibs had speech difficulties and were mildly mentally retarded whereas the mother's intelligence was at the lower end of the normal range. They all had an unusual face, characterized by a flat profile, short forehead, downslant of the palpebral fissures, high and broad nasal bridge, simply formed ears, and prognathia. This is the second report of a small supernumerary ring chromosome derived from the pericentromeric region of chromosome 7, and the described clinical phenotype differs from that delineated in the previous report.


Children's time production for concurrent nontemporal motor tasks.
An internal clock model has often been used to explain disruptions in timing production that occur when temporal and nontemporal tasks are performed simultaneously. In this study, participants' ability to walk 8 m in 8 sec. while executing various secondary concurrent nontemporal tasks was assessed for 16 children enrolled in sports at school. Children participated in six trials under five randomized task conditions involving different coordinative and cognitive workloads. The duration of timing production increased as the attention requirements or cognitive demands placed upon the completion of the task increased. However, participants also showed learning of timing over the six trials. Significant differences were found between the timing task and the concurrent nontemporal tasks depending on the difficulty and cognitive load of the secondary tasks. Results are discussed using attention models of time estimation and production.


Ranking Medical Terms to Support Expansion of Lay Language Resources for Patient Comprehension of Electronic Health Record Notes: Adapted Distant Supervision Approach.
Medical terms are a major obstacle for patients to comprehend their electronic health record (EHR) notes. Clinical natural language processing (NLP) systems that link EHR terms to lay terms or definitions allow patients to easily access helpful information when reading through their EHR notes, and have shown to improve patient EHR comprehension. However, high-quality lay language resources for EHR terms are very limited in the public domain. Because expanding and curating such a resource is a costly process, it is beneficial and even necessary to identify terms important for patient EHR comprehension first. We aimed to develop an NLP system, called adapted distant supervision (ADS), to rank candidate terms mined from EHR corpora. We will give EHR terms ranked as high by ADS a higher priority for lay language annotation-that is, creating lay definitions for these terms. Adapted distant supervision uses distant supervision from consumer health vocabulary and transfer learning to adapt itself to solve the problem of ranking EHR terms in the target domain. We investigated 2 state-of-the-art transfer learning algorithms (ie, feature space augmentation and supervised distant supervision) and designed 5 types of learning features, including distributed word representations learned from large EHR data for ADS. For evaluating ADS, we asked domain experts to annotate 6038 candidate terms as important or nonimportant for EHR comprehension. We then randomly divided these data into the target-domain training data (1000 examples) and the evaluation data (5038 examples). We compared ADS with 2 strong baselines, including standard supervised learning, on the evaluation data. The ADS system using feature space augmentation achieved the best average precision, 0.850, on the evaluation set when using 1000 target-domain training examples. The ADS system using supervised distant supervision achieved the best average precision, 0.819, on the evaluation set when using only 100 target-domain training examples. The 2 ADS systems both performed significantly better than the baseline systems (P<.001 for all measures and all conditions). Using a rich set of learning features contributed to ADS's performance substantially. ADS can effectively rank terms mined from EHRs. Transfer learning improved ADS's performance even with a small number of target-domain training examples. EHR terms prioritized by ADS were used to expand a lay language resource that supports patient EHR comprehension. The top 10,000 EHR terms ranked by ADS are available upon request.


Impact of plasma lipids and time on memory performance in healthy elderly without dementia.
To examine the association of plasma lipid levels to changes in cognitive function in elderly subjects without dementia. The authors examined changes in performance in tests of memory, visuospatial/cognitive, and language abilities in 1,147 elderly individuals without dementia or cognitive impairment at baseline followed for 7 years using generalized estimating equations. Performance in all cognitive domains declined significantly over time, while there was no association between levels of any plasma lipid or lipid lowering treatment and memory, cognitive/visuospatial, or language performance at any interval. Higher age at baseline was related to lower scores in all three domains at each interval, while higher education and white ethnicity were associated with higher scores in all domains. Analyses relating plasma lipids to performance in color trails tests using proportional hazards regression showed no association. In subsequent analyses excluding subjects with incident dementia, memory performance declined over time, while cognitive/visuospatial and language performance did not. Higher plasma high density lipoprotein and total cholesterol were associated with higher scores in language performance at baseline; this domain declined faster among individuals with higher total cholesterol, but this result was not significant after taking multiple comparisons into account. Plasma triglycerides, low density lipoprotein, or treatment with lipid lowering agents were not associated with changes in cognitive performance. Plasma lipid levels or treatment with lipid lowering agents in the elderly were not associated with changes in cognitive function.


Predictive Validity of Radiographic Trabecular Bone Texture in Knee Osteoarthritis: The Osteoarthritis Research Society International/Foundation for the National Institutes of Health Osteoarthritis Biomarkers Consortium.
To evaluate radiographic subchondral trabecular bone texture (TBT) as a predictor of clinically relevant osteoarthritis (OA) progression (combination of symptom and structural worsening). The Foundation for the National Institutes of Health (FNIH) OA Biomarkers Consortium undertook a study of progressive knee OA cases (n = 194 knees with both radiographic and pain progression over 24-48 months) and comparators (n = 406 OA knees not meeting the case definition). TBT parameters were extracted from a medial subchondral tibial region of interest by fractal signature analysis of radiographs using validated semiautomated software. Baseline TBT and time-integrated values over 12 and 24 months were evaluated for association with case status and separately with radiographic and pain progression status, adjusted for age, sex, body mass index, race, baseline Kellgren/Lawrence grade, baseline joint space width, Western Ontario and McMaster Universities Osteoarthritis Index pain score, and pain medication use. C statistics were generated from receiver operating characteristic curves. Relative to comparators, cases were characterized by thinner vertical and thicker horizontal trabeculae. The summed composite of 3 TBT parameters at baseline and over 12 and 24 months best predicted case status (odds ratios 1.24-1.43). The C statistic for predicting case status using the TBT composite score (0.633-0.649) was improved modestly but statistically significantly over the use of covariates alone (0.608). One TBT parameter, reflecting thickened horizontal trabeculae in cases, at baseline and over 12 and 24 months, predicted risk of any progression (radiographic and/or pain progression). Although associations are modest, TBT could be an attractive means of enriching OA trials for progressors since it can be generated from screening knee radiographs already standard in knee OA clinical trials.


Dosing patterns in Europe: Efficacy and safety of risperidone long-acting injectable in doses of 25, 37.5 and 50 mg.
Objective. To assess the dose prescription patterns for risperidone long-acting injectable (RLAI) in patients with schizophrenia who participated in the 6-month, open-label Switch to Risperidone Microspheres (StoRMi) trial. Methods. Clinically stable patients requiring a change in medication were converted to RLAI prescribed using clinically-appropriate doses, as determined by treating clinicians. RLAI 25 mg was recommended as the starting dose, although higher initiation doses were permitted if deemed necessary. RLAI was administered intramuscularly every 2 weeks, with dosage adjustments permitted, and continued for a total of 6 months. Efficacy outcomes included Positive and Negative Syndrome Scale (PANSS) and Clinical Global Impression-Severity (CGI-S). Treatment-emergent adverse events (AEs) were monitored. Results. A total of 1,849 patients were included. Modal dose was 25 mg for 52.9% of patients. At baseline, patients treated with lower RLAI doses were more likely to be female, have shorter disease duration, milder symptoms, and be using less polypharmacy. The strongest predictors that a patient would remain on 25 mg RLAI were baseline PANSS hallucinatory behaviour item score (odds ratio [OR]=0.78), baseline CGI-S score (OR=0.69), female gender (OR=1.56), and country of residence (P<0.001 for all). Efficacy measures improved in all dose groups, with the greatest improvement seen in patients treated with lower doses. AEs were more common in patients treated with 50 mg RLAI (68 vs. 57% with lower doses; P<0.0001), although most AEs were mild to moderate in severity. Conclusion. In this study, 25 mg RLAI was the most commonly prescribed dose. RLAI was effective and well tolerated over the full range of doses.


Stress-Induced Hyperglycemia, but Not Diabetic Hyperglycemia, Is Associated with Higher Mortality in Patients with Isolated Moderate and Severe Traumatic Brain Injury: Analysis of a Propensity Score-Matched Population.
Background: Admission hyperglycemia is associated with higher morbidity and mortality in patients with traumatic brain injury (TBI). Stress-induced hyperglycemia (SIH), a form of hyperglycemia induced by the stress response, is associated with increased patient mortality following TBI. However, admission hyperglycemia occurs not only in SIH but also in patients with diabetic hyperglycemia (DH). Current information regarding whether trauma patients with SIH represent a distinct group with differential outcomes compared to those with DH remains limited. Methods: Serum glucose concentration ≥200 mg/dL upon arrival at the emergency department was defined as hyperglycemia. Presence of diabetes mellitus (DM) was determined by patient history and/or admission glycated hemoglobin (HbA1c) level ≥6.5%. In the present study, the patient cohort included those with moderate and severe TBI, as defined by an Abbreviated Injury Scale (AIS) score ≥3 points in the head, and excluded those who had additional AIS scores ≥3 points in any other region of the body. A total of 1798 adult patients with isolated moderate to severe TBI were allocated into four groups: SIH (n = 140), DH (n = 187), diabetic normoglycemia (DN, n = 186), and non-diabetic normoglycemia (NDN, n = 1285). Detailed patient information was retrieved from the Trauma Registry System at a level I trauma center between 1 January 2009, and 31 December 2015. Unpaired Student's t- and Mann-Whitney U-tests were used to analyze normally and non-normally distributed continuous data, respectively. Categorical data were compared using the Pearson chi-square or two-sided Fisher's exact tests. Matched patient populations were allocated in a 1:1 ratio according to propensity scores calculated by NCSS software. Logistic regression was used to evaluate the effect of SIH and DH on the adjusted mortality outcome. Results: In patients with isolated moderate to severe TBI, the presence of SIH and DH led to 9.1-fold and 2.3-fold higher odds of mortality, respectively, than patients with NDN. After adjusting for confounding factors, including sex and age, pre-existing co-morbidities, existence of different kinds of intracerebral hemorrhage, and injury severity, patients with SIH still had 6.6-fold higher odds of mortality than those with NDN; however, DH did not present significantly higher adjusted mortality odds. SIH and DH presented different effects on outcomes after TBI. The results also suggested that the pathophysiological effect associated with SIH was different from that of DH. Conclusions: This study demonstrated that patients with SIH and DH had significantly higher mortality than patients with NDN. However, the adjusted mortality was significantly higher only in the selected propensity score-matched patients with SIH and not in those with DH.