Clinical characteristics of COVID-19 in children compared with adults in Shandong Province, China.
The COVID-19 outbreak spread in China and is a threat to the world. We reported on the epidemiological, clinical, laboratory, and radiological characteristics of children cases to help health workers better understand and provide timely diagnosis and treatment. Retrospectively, two research centers' case series of 67 consecutive hospitalized cases including 53 adult and 14 children cases with COVID-19 between 23 Jan 2020 and 15 Feb 2020 from Jinan and Rizhao were enrolled in this study. Epidemiological, clinical, laboratory, and radiological characteristics of children and adults were analyzed and compared. Most cases in children were mild (21.4%) and conventional cases (78.6%), with mild clinical signs and symptoms, and all cases were of family clusters. Fever (35.7%) and dry cough (21.4%) were described as clinical manifestations in children cases. Dry cough and phlegm were not the most common symptoms in children compared with adults (p = 0.03). In the early stages of the disease, lymphocyte counts did not significantly decline but neutrophils count did in children compared with adults (p = 0.02). There was a lower level of CRP (p = 0.00) in children compared with adults. There were 8 (57.1%) asymptomatic cases and 6 (42.9%) symptomatic cases among the 14 children cases. The age of asymptomatic patients was younger than that of symptomatic patients (p = 0.03). Even among asymptomatic patients, 5 (62.5%) cases had lung injuries including 3 (60%) cases with bilateral involvement, which was not different compared with that of symptomatic cases (p = 0.58, p = 0.74). The clinical symptoms of children are mild, there is substantial lung injury even among children, but that there is less clinical disease, perhaps because of a less pronounced inflammatory response, and that the occurrence of this pattern appears to inversely correlate with age.


Supramolecular charge transfer nanostructures.
Supramolecular organization of π-conjugated chromophores into well defined nanostructures has gained much attention due to their promising role as active components in organic electronics. Charge-transfer (CT) nanostructures, in which aromatic donor (D) and acceptor (A) molecules are alternately arranged, (mixed stack) have emerged recently as prospective candidates in this direction, because they provide inherent, uniform doping conducive for excellent conducting properties. The present perspective highlights the importance of charge transfer (CT) based non-covalent interactions, with emphasis on supramolecular design principles, for construction of various CT nano-architectures. The whole article is divided into three parts themed on the type of interactions used for obtaining CT assemblies. Through some of our recent results, we have attempted to highlight the latent potential of this nascent field. Furthermore, we have presented our perspectives on the major challenges in this field which is expected to broaden the scope of this subject.


The Moderating Effect of Religion on the Relationship Between Depression and Suicidal Ideation in the Elderly.
This article aimed to compare the level of suicidal ideation in the religiously affiliated and nonaffiliated groups and identify the moderating effect of religion variables on the relationship between depression and suicidal ideation. The sample in this study was 1180 residents who were older than 60 years and who resided in Gangwon Province, South Korea. We studied the cross-sectional relationships among religions and studied variables including organizational religious activity (ORA), non-ORA (NORA), intrinsic religiosity (IR), depression, well-being, and suicidal ideation. After controlling for sociodemographic variables, the depression, well-being, and suicidal ideation level in the religiously affiliated group were not significantly different from that of the religiously nonaffiliated group and the variables also were not significantly different between Christians and Buddhists. The effect of depression on suicidal ideation was significantly moderated by ORA and IR, and the effect showed different patterns by religion; ORA was a moderator only among the Buddhist group, and IR only moderated the relationships among the Christians.


Treatment of intracranial broad-neck aneurysms with a new self-expanding stent and coil embolization.
Endovascular treatment of broad-neck intracranial aneurysms with detachable coils requires special techniques. Placement of a stent over the aneurysm neck and secondary coil embolization prevents coil migration and allows attenuated packing of the coils. However, access for the stent-delivery system can be technically limited in tortuous anatomy. We present six cases of broad-neck aneurysms treated with a new self-expanding stent and coil embolization. Three aneurysms of the supraophthalmic internal carotid artery and three aneurysms of the basilar tip with extension to the origin of a posterior cerebral artery were treated. The stent was a new self-expanding stent with a 3F over-the-wire microcatheter delivery system. Coil embolization was performed with electrolytically detachable coils. Time-of-flight MR angiography was performed after treatment in five cases. Three other patients could not be treated with the stent because deployment was not possible after correct positioning of the delivery system. Access with the stent-delivery system was easy, and the aneurysm neck was covered sufficiently. After stent placement, total coil embolization was achieved in four and subtotal coil embolization was achieved in two. Parent arteries remained open, and no secondary coil migration was seen. On follow-up MR imaging, the stent was clearly visible and patency of the parent vessel and emerging branches was assessable. This new stent is a safe and efficient tool for the endovascular treatment of intracranial broad-neck aneurysms. Access to smaller vessels was easy, but the mechanism of deployment had to be improved. Follow-up MR imaging was sufficient.


Relation between number of apolipoprotein(a) kringle 4 repeats and mobility of isoforms in agarose gel: basis for a standardized isoform nomenclature.
The size of apolipoprotein(a) [apo(a)] varies from 187 to 648 kDa because of interallelic differences in the number of kringle 4-encoding sequences in the apo(a) gene. Plasma apo(a) isoform sizes were determined by a high-resolution sodium dodecyl sulfate-agarose gel electrophoretic method, followed by immunoblotting. The relation between the number of apo(a) kringle 4-encoding sequences in the apo(a) gene, as assessed by pulsed-field gel electrophoresis and genomic blotting, and the mobility of apo(a) isoforms in agarose gel was evaluated in 29 individuals who had 48 expressed apo(a) isoforms that contained between 12 and 41 kringle 4 repeats. The log of the kringle number was linearly related to the distance the isoform migrated on the agarose gel (r= 0.999). A nomenclature is proposed to designate apo(a) isoforms by the respective number of kringle 4 repeats.


Influence of dietary ginger (Zingiber officinales Rosc) on oxidative stress induced by malathion in rats.
Pesticide chemicals may induce oxidative stress leading to generation of free radicals and alterations in antioxidants or oxygen free radical (OFR) scavenging enzymes. Hence, the effect of subchronic malathion (O,O-dimethyl-S-1,2, bis ethoxy carbonyl ethyl phosphorodithioate) exposure was evaluated on lipid peroxidation, glutathione and related enzymes and OFR scavenging enzymes in albino rats. Administration of malathion (20 ppm) for 4 weeks increased the malondialdehyde (MDA) levels in serum, activities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) in erythrocytes and glutathione reductase (GR) and glutathione S-transferase (GST) in serum. However, it decreased the glutathione (GSH) level in whole blood. Concomitant dietary feeding of Zingiber officinales Rosc (ginger 1%, w/w) significantly attenuated malathion induced lipid peroxidation and oxidative stress in these rats. These results indicate the possible involvement of free radicals in organophosphate-induced toxicity and highlight the protective action of ginger, an indigenous medicinal plant product.


Intensive chemotherapy and bone marrow rescue for young children with newly diagnosed malignant brain tumors.
To evaluate a strategy that avoids radiotherapy in children less than 6 years of age with newly diagnosed malignant brain tumors, by administering myeloablative consolidation chemotherapy with autologous bone marrow reconstitution (ABMR) after maximal surgical resection and conventional induction chemotherapy. Between March 1991 and April 1995, 62 children (median age, 30 months) with newly diagnosed malignant brain tumors were enrolled onto this trial. Children received conventional induction chemotherapy with vincristine, cisplatin, cyclophosphamide, and etoposide, repeated every 3 weeks for five cycles. Children without disease progression on induction chemotherapy were offered consolidation with myeloablative chemotherapy that incorporated carboplatin, thiotepa, and etoposide followed by ABMR. Irradiation was used only for residual tumor at consolidation or for progressive/recurrent disease. Induction chemotherapy was well tolerated by most patients; however, progression was noted in 17 children (27%) and four (6%) died of treatment complications. Of 37 children who received consolidation chemotherapy with ABMR, 15 are free of disease progression (median post-ABMR without further treatment, >44 months). The remaining 22 all progressed within 15 months of ABMR; three of 37 (8%) died of treatment-related complications. The 3-year overall survival (OS) and event-free survival (EFS) rates from diagnosis for all children are 40% (95% confidence interval [CI], 28% to 52%) and 25% (95% CI, 13% to 37%), respectively. Radiotherapy was administered to 19 of 62 children: 17 for progressive disease (PD) and two for residual disease at the time of ABMR. A significant proportion of children with malignant brain tumors can avoid radiotherapy and prolonged maintenance chemotherapy yet still achieve durable remission with this brief intensive chemotherapy regimen.


Pharmacokinetic and pharmacodynamic study of NO-donating aspirin in F344 rats.
Nitric oxide-donating aspirin (NO-ASA) represents class of promising chemopreventive NO-NSAIDs. NO-ASA combines the beneficial effects of ASA and the gut-sparing effect of the NO moiety. There is, however, limited information on its pharmacokinetic and pharmacodynamic effects in vivo. Herein, experiments were designed to identify the optimal dose, the effective route of administration, and targeted markers in plasma and colonic tissues of male F344 rats. Seven weeks old male F344 rats were randomized into 9 groups (16/group) and fed the control diet. At eight weeks of age, groups 2-5 were each administered one of four different doses of NO-ASA by gavage (33, 66, 132 and 264 mg/kg) and each of groups 6-9 were fed diets containing NO-ASA (35, 700, 1,400 and 2,800 ppm) for two weeks. Rats were sacrificed 2 and 10 h after completion of the two weeks of treatment with NO-ASA and plasma and colonic mucosa were collected and analyzed for NO-ASA, its metabolites, and PGE2 and TXB2 levels. Our results indicate that NO-ASA is rapidly metabolized, predominantly to salicylic acid; no intact NO-ASA was detected in plasma. Compared to diet-fed NO-ASA, gavaging generated much higher salicylic acid levels over a wide range of doses and a relatively broad time period (10 h). Regardless of its route of administration, NO-ASA lowered the levels of PGE2 in colonic tissues and plasma, as well as TxB2 in plasma in a dose- and time-dependent manner. These findings may have practical utility for the administration of NO-ASA to humans.


Hepatitis C virus in American Indian/Alaskan Native and Aboriginal peoples of North America.
Liver diseases, such as hepatitis C virus (HCV) infection, are "broken spirit" diseases. The prevalence of HCV infection for American Indian/Alaskan Native (AI/AN) in the United States and Canadian Aboriginals varies; nonetheless, incidence rates of newly diagnosed HCV infection are typically higher relative to non-indigenous people. For AI/AN and Aboriginal peoples risk factors for the diagnosis of HCV infection can reflect that of the general population: predominately male, a history of injection drug use, in midlife years, with a connection with urban centers. However, the face of the indigenous HCV infected individual is becoming increasingly female and younger compared to non-indigenous counterparts. Epidemiology studies indicate that more effective clearance of acute HCV infection can occur for select Aboriginal populations, a phenomenon which may be linked to unique immune characteristics. For individuals progressing to chronic HCV infection treatment outcomes are comparable to other racial cohorts. Disease progression, however, is propelled by elevated rates of co-morbidities including type 2 diabetes and alcohol use, along with human immunodeficiency virus (HIV) co-infection relative to non-indigenous patients. Historical and personal trauma has a major role in the participation of high risk behaviors and associated diseases. Although emerging treatments provide hope, combating HCV-related morbidity and mortality will require interventions that address the etiology of broken spirit diseases.


[Immune response in rabbits to tumoral tissue extracts of human colon].
Carcinoembryonic antigen (CEA) was purified after perchloric acid extraction of glycoprotein from human normal and tumoral colon. Antibodies against those extracts as well as purified CEA were raised in rabbits. Sera obtained from animals immunized with tumoral extract in protracted schemes showed disperse behavior on polyacrylamide gel electrophoresis (PAGE) for proteins in the area with gamma, mobility which were markedly increased. In addition, a large increase of proteins with a mobility comparable to alpha 2 proteins was observed. The latter increase was not present in sera of rabbits immunized with normal colon extracts. Low titer antisera were obtained after immunization with either antigen as revealed by immunodiffusion. The relatively highest titers were seen against the glycoprotein fraction of tumor extracts which had previously been enriched by isoelectric focusing. Immunoelectrophoresis of tumor extracts against homologous antisera revealed bands with beta mobility due to the presence of CEA antibodies only in the sera of animals injected with tumor extracts. Antibody titers assayed by radioimmunoassay (RIA) revealed that the highest titers were obtained from tumor glycoprotein extracts was used as an immunogen. Measurements of CEA concentrations in serum of patients with low and high levels of CEA showed non significant differences by statistical analysis, when antisera obtained from different bleedings of the same animals were used. It is concluded that in order to establish a CEA RIA for clinical purposes it is necessary to purify up to the isoelectric focusing step the material to be labelled as tracer or used as standard. Antibody reagent may be obtained by immunizing schemes or protracted schemes using crude perchloric acid extracts of colon tumor.


Diameter-dependent bending modulus of individual multiwall boron nitride nanotubes.
The mechanical properties of individual multiwall boron nitride nanotubes (MWBNNTs) synthesized by a growth-vapor-trapping chemical vapor deposition method are investigated by a three-point bending technique via atomic force microscopy. Multiple locations on suspended tubes are probed in order to determine the boundary conditions of the supported tube ends. The bending moduli (EB) calculated for 20 tubes with diameters ranging from 18 to 58 nm confirm the exceptional mechanical properties of MWBNNTs, with an average EB of 760 ± 30 GPa. For the first time, the bending moduli of MWBNNTs are observed to increase with decreasing diameter, ranging from 100 ± 20 GPa to as high as 1800 ± 300 GPa. This diameter dependence is evaluated by Timoshenko beam theory. The Young's modulus and shear modulus were determined to be 1800 ± 300 and 7 ± 1 GPa, respectively, for a trimmed data set of 16 tubes. The low shear modulus of MWBNNTs is the reason for the detected diameter-dependent bending modulus and is likely due to the presence of interwall shearing between the crystalline and faceted helical nanotube structures of MWBNNTs.


A theoretical and experimental benchmark study of core-excited states in nitrogen.
The high resolution near edge X-ray absorption fine structure spectrum of nitrogen displays the vibrational structure of the core-excited states. This makes nitrogen well suited for assessing the accuracy of different electronic structure methods for core excitations. We report high resolution experimental measurements performed at the SOLEIL synchrotron facility. These are compared with theoretical spectra calculated using coupled cluster theory and algebraic diagrammatic construction theory. The coupled cluster singles and doubles with perturbative triples model known as CC3 is shown to accurately reproduce the experimental excitation energies as well as the spacing of the vibrational transitions. The computational results are also shown to be systematically improved within the coupled cluster hierarchy, with the coupled cluster singles, doubles, triples, and quadruples method faithfully reproducing the experimental vibrational structure.


Modification-Specific Proteomic Analysis Reveals Cysteine S-Nitrosylation Mediated the Effect of Preslaughter Transport Stress on Pork Quality Development.
This study aimed to explore the effects of preslaughter transport stress on protein S-nitrosylation levels and S-nitrosylated proteome in post-mortem pork longissimus thoracis (LT) muscle. Pigs (N= 16) were randomly divided into 3 h transport (high-stress group, HS) and 3 h transport followed by 3 h resting treatments (low-stress control group, LS). Results demonstrated that high transport stress levels induced nitric oxide (NO) overproduction by promoting NO synthase (NOS) activity and neuronal NOS (nNOS) expression, which thereby notably increased protein S-nitrosylation levels in post-mortem muscle (p < 0.05). Proteomic analysis indicated that 133 S-nitrosylation-modified cysteines belonging to 85 proteins were significantly differential, of which 101 cysteines of 63 proteins were higher in the HS group (p < 0.05). Differential proteins including cytoskeletal and calcium-handling proteins, glycolytic enzymes, and oxidoreductase were mainly involved in the regulation of muscle contraction and energy metabolism that might together mediate meat quality development. Overall, this study provided direct evidence for changes in S-nitrosylation levels and proteome in post-mortem muscle in response to preslaughter transport stress and revealed the potential impact of S-nitrosylated proteins on meat quality.


Species-specific and age-dependent bile acid composition: aspects on CYP8B and CYP4A subfamilies in bile acid biosynthesis.
The present review aims to give an overview of the cytochrome P450 8B (CYP8B) and cytochrome P450 4A (CYP4A) subfamilies in relation to biosynthesis of bile acids, in particular trihydroxy bile acids. Trihydroxy bile acids are basically required in most species and have an impact on cholesterol and lipid metabolism. The primary trihydroxy bile acid in most mammals is cholic acid. Some species produce other important trihydroxy bile acids, for example the adult pig which produce hyocholic acid instead of cholic acid. The position of the third hydroxyl group in cholic acid and hyocholic acid, 12alpha or 6alpha position, respectively, has a profound effect on the hydrophilic-hydrophobic property of the trihydroxy bile acids. The CYP8B subfamily is required for introduction of the 12alpha-hydroxyl group in cholic acid biosynthesis. The enzyme responsible for 6alpha-hydroxylation in hyocholic acid biosynthesis, however, varies among species. This review will discuss, in particular, porcine members of the CYP8B and CYP4A subfamilies because interesting findings regarding members of these subfamilies have recently been recognized in this species. CYP8B1 was for a long time believed to be absent in the pig but was recently found to be expressed in fetal pig liver. The enzyme catalyzing the 6alpha-hydroxylation in hyocholic acid biosynthesis in pig was found to be an atypical member of the CYP4A subfamily, denoted CYP4A21. The review presents bile acid biosynthesis in view of these findings and discusses physiochemical properties and developmental-dependent aspects related cholic acid and hyocholic acid biosynthesis.


Speaking the same language: treatment outcome definitions for multidrug-resistant tuberculosis.
Globally it is estimated that 273000 new cases of multidrug-resistant tuberculosis (MDR-TB, resistance to isoniazid and rifampicin) occurred in 2000. To address MDR-TB management in the context of the DOTS strategy, the World Health Organization and partners have been promoting an expanded treatment strategy called DOTS-Plus. However, standard definitions for MDR-TB patient registration and treatment outcomes do not exist. To propose a standardized set of case registration groups and treatment outcome definitions for MDR-TB and procedures for conducting cohort analyses under the DOTS-Plus strategy. Using published definitions for drug-susceptible TB as a guide, a 2-year-long series of meetings, conferences, and correspondence was undertaken to review published literature and country-specific program experience, and to develop international agreement. Definitions were designed for MDR-TB patient categorization, smear and culture conversion, and treatment outcomes (cure, treatment completion, death, default, failure, transfer out). Standards for conducting outcome analyses were developed to ensure comparability between programs. Optimal management strategies for MDR-TB have not been evaluated in controlled clinical trials. Standardized definitions and cohort analyses will facilitate assessment and comparison of program performance. These data will contribute to the evidence base to inform decision makers on approaches to MDR-TB control.


One nucleotide in a kappaB site can determine cofactor specificity for NF-kappaB dimers.
The transcription factor NF-kappaB regulates a wide variety of genes involved in multiple processes. Although the apparent consensus sequence of DNA binding sites for NF-kappaB (kappaB sites) is very broad, the sites active in any one gene show remarkable evolutionary stability. Using a lentivirus-based methodology for implantation of gene regulatory sequences we show that for genes with two kappaB sites, both are required for activity. Swapping sites between kappaB-dependent genes altered NF-kappaB dimer specificity of the promoters and revealed that two kappaB sites can function together as a module to regulate gene activation. Further, although the sequence of the kappaB site is important for determining kappaB family member specificity, rather than determining the ability of a particular dimer to bind effectively, the sequence affects which coactivators will form productive interactions with the bound NF-kappaB dimer. This suggests that binding sites may impart a specific configuration to bound transcription factors.


Disease modifying effects of N-butyryl glucosamine in a streptococcal cell wall induced arthritis model in rats.
To evaluate the effect of different doses of N-butyryl glucosamine (GlcNBu) on joint preservation and subchondral bone density and quality in a streptococcal cell wall (SCW) induced arthritis model in Lewis rats. Chronic arthritis was induced in 36 female Lewis rats by a single intraperitoneal injection of SCW antigen. The 4 groups studied were: (1) no arthritis, no drug treatment; (2) arthritis, no drug treatment; (3) arthritis, oral GlcNBu 20 mg/kg/day; and (4) arthritis, oral GlcNBu 200 mg/kg/day. Inflammation (ankle swelling) was quantified throughout the clinical course; bone mineral density (BMD) was measured by dual-energy x-ray absorptiometry on dissected distal femurs and proximal tibiae, in user defined regions of interest. Qualitative and quantitative 3-D bone architecture changes were determined using microcomputerized tomography on the left tibiae. Subchondral plate thickness and trabecular bone connectivity were studied on the proximal tibia epiphyses from the central coronal sections of each scanned tibia. GlcNBu inhibited inflammatory ankle swelling at both 20 and 200 mg/kg/day, the latter being statistically significant, with an average reduction of 33%. GlcNBu preserved or enhanced BMD and bone connectivity and prevented further bone loss at both the high and the low dose. Comparisons of the isosurfaces and the architectural measures in the different groups showed that GlcNBu effectively protected the joint surfaces from further erosion in this model of chronic inflammatory arthritis. For some of the bone measurements, increasing doses of GlcNBu showed increasing protective effects, while for other measurements, effects were maximal at the lower dose. These data indicate that GlcNBu provides antiinflammatory and antierosive effects by preserving BMD, joint integrity, and bone architecture in involved joints of the SCW model.


Hormone sensitivity of the R3327-G rat prostate adenocarcinoma: growth rate, DNA content, and hormone receptors.
The growth of the R3327-G rat prostatic adenocarcinoma was significantly reduced when implanted in orchiectomized male rats (ORCH tumors). Tumors grown in intact animals (control tumors) had a doubling time of 7.4 days as compared to 9.2 days in ORCH tumors. A computer-based analysis of flow cytometric DNA histograms also detected significant differences between control and ORCH tumors. ORCH tumors were found to have 25% fewer cells with hyperdiploid DNA than control tumors (p less than 0.01). This androgen sensitivity in growth rate and the proportion of hyperdiploid cells were further reflected in the binding of [3H]methyltrienolone ([3H]-R1881) to cytoplasmic (cytosol) and nuclear tumor extracts. ORCH tumor cytosols had a [3H]R1881 binding capacity which was 70% lower than controls (6071 fmol/g tumor tissue). Nuclear [3H]R1881 binding in ORCH tumors was undetectable in seven of eight samples while in control tumors, binding was detectable in five of six preparations. Sucrose density gradient analysis showed that cytosolic [3H]R1881 receptors sedimented at 8.1 S in low salt and 4.6 to 3.3S in high salt. Nuclear [3H]R1881 receptors in high salt sedimented at 4.1 to 3.3S. Competition experiments using [3H]R1881 showed that [3H]-R1881 receptors were primarily androgenic, although some displacement by estradiol did occur. In contrast, [3H]estradiol binding was found to be highly specific. The binding capacity of [3H]estradiol in ORCH tumor cytosols was 30% higher than controls (962 fmol/g tumor issue), while binding to ORCH and control nuclear extracts was similar. These data suggest that the inhibition of androgen-sensitive R3327-G tumor cells was related to the concentration of androgen receptors and that this in turn was expressed as a reduction in the proportion of hyperdiploid cells.


Mitophagy-promoting agents and their ability to promote healthy-aging.
The removal of damaged mitochondrial components through a process called mitochondrial autophagy (mitophagy) is essential for the proper function of the mitochondrial network. Hence, mitophagy is vital for the health of all aerobic animals, including humans. Unfortunately, mitophagy declines with age. Many age-associated diseases, including Alzheimer's and Parkinson's, are characterized by the accumulation of damaged mitochondria and oxidative damage. Therefore, activating the mitophagy process with small molecules is an emerging strategy for treating multiple aging diseases. Recent studies have identified natural and synthetic compounds that promote mitophagy and lifespan. This article aims to summarize the existing knowledge about these substances. For readers' convenience, the knowledge is presented in a table that indicates the chemical data of each substance and its effect on lifespan. The impact on healthspan and the molecular mechanism is reported if known. The article explores the potential of utilizing a combination of mitophagy-inducing drugs within a therapeutic framework and addresses the associated challenges of this strategy. Finally, we discuss the process that balances mitophagy, i.e. mitochondrial biogenesis. In this process, new mitochondrial components are generated to replace the ones cleared by mitophagy. Furthermore, some mitophagy-inducing substances activate biogenesis (e.g. resveratrol and metformin). Finally, we discuss the possibility of combining mitophagy and biogenesis enhancers for future treatment. In conclusion, this article provides an up-to-date source of information about natural and synthetic substances that activate mitophagy and, hopefully, stimulates new hypotheses and studies that promote healthy human aging worldwide.


Stress analysis in a pedicle screw fixation system with flexible rods in the lumbar spine.
Breakage of screws has been one of the most common complications in spinal fixation systems. However, no studies have examined the breakage risk of pedicle screw fixation systems that use flexible rods, even though flexible rods are currently being used for dynamic stabilization. In this study, the risk of breakage of screws for the rods with various flexibilities in pedicle screw fixation systems is investigated by calculating the von Mises stress as a breakage risk factor using finite element analysis. Three-dimensional finite element models of the lumbar spine with posterior one-level spinal fixations at L4-L5 using four types of rod (a straight rod, a 4 mm spring rod, a 3 mm spring rod, and a 2 mm spring rod) were developed. The von Mises stresses in both the pedicle screws and the rods were analysed under flexion, extension, lateral bending, and torsion moments of 10 Nm with a follower load of 400 N. The maximum von Mises stress, which was concentrated on the neck region of the pedicle screw, decreased as the flexibility of the rod increased. However, the ratio of the maximum stress in the rod to the yield stress increased substantially when a highly flexible rod was used. Thus, the level of rod flexibility should be considered carefully when using flexible rods for dynamic stabilization because the intersegmental motion facilitated by the flexible rod results in rod breakage.


Plasma alpha-protease inhibitors in Norwegian Landrace and Czech Landrace pigs.
The studies on alpha-protease inhibitors systems, controlled by four tightly linked loci, were performed within 159 families of Norwegian Landrace (NL) and 40 families of Czech Landrace (CL) pigs. Significant differences in allele and haplotype frequencies between the two breeds were shown. The SE-F and SSsS haplotypes (Pi1, Po1A, Po1B, Pi2 loci) appeared to be the most frequent haplotypes in NL and CL breeds respectively. This system of blood plasma proteins can be very useful for studying the relationship between breeds.


Associations of hospital volume and hospital competition with short-term, middle-term and long-term patient outcomes after breast cancer surgery: a retrospective population-based study.
For oncological care, there is a clear tendency towards centralisation and collaboration aimed at improving patient outcomes. However, in market-based healthcare systems, this trend is related to the potential trade-off between hospital volume and hospital competition. We analyse the association between hospital volume, competition from neighbouring hospitals and outcomes for patients who underwent surgery for invasive breast cancer (IBC). Surgical margins, 90 days re-excision, overall survival. In this population-based study, we use data from the Netherlands Cancer Registry. Our study sample consists of 136 958 patients who underwent surgery for IBC between 2004 and 2014 in the Netherlands. Our findings show that treatment types as well as patient and tumour characteristics explain most of the variation in all outcomes. After adjusting for confounding variables and intrahospital correlation in multivariate logistic regressions, hospital volume and competition from neighbouring hospitals did not show significant associations with surgical margins and re-excision rates. For patients who underwent surgery in hospitals annually performing 250 surgeries or more, multilevel Cox proportional hazard models show that survival was somewhat higher (HR 0.94). Survival in hospitals with four or more (potential) competitors within 30 km was slightly higher (HR 0.97). However, this effect did not hold after changing this proxy for hospital competition. Based on the selection of patient outcomes, hospital volume and regional competition appear to play only a limited role in the explanation of variation in IBC outcomes across Dutch hospitals. Further research into hospital variation for high-volume tumours like the one studied here is recommended to (i) use consistently measured quality indicators that better reflect multidisciplinary clinical practice and patient and provider decision-making, (ii) include more sophisticated measures for hospital competition and (iii) assess the entire process of care within the hospital, as well as care provided by other providers in cancer networks.


Impact of intermittent preventive treatment in pregnancy with azithromycin-containing regimens on maternal nasopharyngeal carriage and antibiotic sensitivity of Streptococcus pneumoniae, Haemophilus influenzae, and Staphylococcus aureus: a cross-sectional survey at delivery.
Sulfadoxine-pyrimethamine (SP) plus azithromycin (AZ) (SPAZ) has the potential for intermittent preventive treatment of malaria in pregnancy (IPTp), but its use could increase circulation of antibiotic-resistant bacteria associated with severe pediatric infections. We evaluated the effect of monthly SPAZ-IPTp compared to a single course of SP plus chloroquine (SPCQ) on maternal nasopharyngeal carriage and antibiotic susceptibility of Streptococcus pneumoniae, Haemophilus influenzae, and Staphylococcus aureus at delivery among 854 women participating in a randomized controlled trial in Papua New Guinea. Serotyping was performed, and antibiotic susceptibility was evaluated by disk diffusion and Etest. Potential risk factors for carriage were examined. Nasopharyngeal carriage at delivery of S. pneumoniae (SPAZ, 7.2% [30/418], versus SPCQ, 19.3% [84/436]; P<0.001) and H. influenzae (2.9% [12/418] versus 6.0% [26/436], P=0.028), but not S. aureus, was significantly reduced among women who had received SPAZ-IPTp. The number of macrolide-resistant pneumococcal isolates was small but increased in the SPAZ group (13.3% [4/30], versus SPCQ, 2.2% [2/91]; P=0.033). The proportions of isolates with serotypes covered by the 13-valent pneumococcal conjugate vaccine were similar (SPAZ, 10.3% [3/29], versus SPCQ, 17.6% [16/91]; P=0.352). Although macrolide-resistant isolates were rare, they were more commonly detected in women who had received SPAZ-IPTp, despite the significant reduction of maternal carriage of S. pneumoniae and H. influenzae observed in this group. Future studies on SPAZ-IPTp should evaluate carriage and persistence of macrolide-resistant S. pneumoniae and other pathogenic bacteria in both mothers and infants and assess the clinical significance of their circulation.


Plant glutamine synthetase complements a glnA mutation in Escherichia coli.
A glutamine synthetase gene from alfalfa (Medicago sativa) has been expressed in Escherichia coli after fusion of bacterial transcription and translation signals to a complete alfalfa glutamine synthetase coding sequence. Synthesis of the alfalfa glutamine synthetase enzyme in Escherichia coli was demonstrated by functional genetic complementation of a glutamine synthetase-deficient mutant and by immunoblotting analysis. These results should facilitate protein engineering and structure-function analysis of the plant enzyme.


Natural pharmacopoeia used in traditional Toba medicine for the treatment of parasitosis and skin disorders (Central Chaco, Argentina).
To assess the knowledge and use of natural pharmacopoeia for the treatment of parasitosis and skin disorders, as well as for the control of their etiological agents or vectors, of a Toba community in Central Chaco, Argentina. Information was obtained by open, extensive and recurrent interviews and semi-structured surveys. Plant and animal pharmacopoeia was documented by collecting material in field assays carried out in the company of informers. The list of applications with the greatest consensus of uses, the list of species with most medicinal applications and the list of species with the highest reputation (according to the level of fidelity) for the aforementioned disorders were obtained using quantitative methods. A total of 178 medicinal uses were documented corresponding to 87 species (72 plant and 15 animal species) belonging to 51 different families (39 plant and 12 animal families). The most represented families according to the number of species were Solanaceae (7 species), Asteraceae (6 species) and Fabaceae (5 species) for plants, and Bovidae (3 species) for animals. Although the list of medicinal species includes some symbolical applications, others are supported by phytochemical information. In other cases the applications coincide with other pharmacopoeias of the Gran Chaco region indicating the presence of an active exchange of knowledge through interethnic contacts.


Influence of CeO2 and ZnO nanoparticles on cucumber physiological markers and bioaccumulation of Ce and Zn: a life cycle study.
With the dramatic increase in nanotechnologies, it has become increasingly likely that food crops will be exposed to excess engineered nanoparticles (NPs). In this study, cucumber plants were grown to full maturity in soil amended with either CeO2 or ZnO NPs at concentrations of 0, 400, and 800 mg/kg. Chlorophyll and gas exchange were monitored, and physiological markers were recorded. Results showed that, at the concentrations tested, neither CeO2 nor ZnO NPs impacted cucumber plant growth, gas exchange, and chlorophyll content. However, at 800 mg/kg treatment, CeO2 NPs reduced the yield by 31.6% compared to the control (p ≤ 0.07). ICP-MS results showed that the high concentration treatments resulted in the bioaccumulation of Ce and Zn in the fruit (1.27 mg of Ce and 110 mg Zn per kg dry weight). μ-XRF images exhibited Ce in the leaf vein vasculature, suggesting that Ce moves between tissues with water flow during transpiration. To the authors' knowledge, this is the first holistic study focusing on the impacts of CeO2 and ZnO NPs in the life cycle of cucumber plants.


Kinetic and stereochemical characterization of hamster liver 3 alpha-hydroxysteroid dehydrogenase and 3 alpha(17 beta)-hydroxysteroid dehydrogenase.
The kinetic mechanism of NADP(+)-dependent 3 alpha-hydroxysteroid dehydrogenase and NAD(+)-dependent 3 alpha(17 beta)-hydroxysteroid dehydrogenase, purified from hamster liver cytosol, was studied in both directions. For 3 alpha-hydroxysteroid dehydrogenase, the initial velocity and product inhibition studies indicated that the enzyme reaction sequence is ordered with NADP+ binding to the free enzyme and NADPH being the last product to be released. Inhibition patterns by Cibacron blue and hexestrol, and binding studies of coenzyme and substrate are also consistent with an ordered bi bi mechanism. For 3 alpha(17 beta)-hydroxysteroid dehydrogenase, the steady-state kinetic measurements and substrate binding studies suggest a random binding pattern of the substrates and an ordered release of product; NADH is released last. However, the two enzymes transferred the pro-R-hydrogen atom of NAD(P)H to the carbonyl substrate.


Dysfunctional connections between the nucleus and the actin and microtubule networks in laminopathic models.
Laminopathies encompass a wide array of human diseases associated to scattered mutations along LMNA, a single gene encoding A-type lamins. How such genetic alterations translate to cellular defects and generate such diverse disease phenotypes remains enigmatic. Recent work has identified nuclear envelope proteins--emerin and the linker of the nucleoskeleton and cytoskeleton (LINC) complex--which connect the nuclear lamina to the cytoskeleton. Here we quantitatively examine the composition of the nuclear envelope, as well as the architecture and functions of the cytoskeleton in cells derived from two laminopathic mouse models, including Hutchinson-Gilford progeria syndrome (Lmna(L530P/L530P)) and Emery-Dreifuss muscular dystrophy (Lmna(-/-)). Cells derived from the overtly aphenotypical model of X-linked Emery-Dreifuss muscular dystrophy (Emd(-/y)) were also included. We find that the centrosome is detached from the nucleus, preventing centrosome polarization in cells under flow--defects that are mediated by the loss of emerin from the nuclear envelope. Moreover, while basal actin and focal adhesion structure are mildly affected, RhoA activation, cell-substratum adhesion, and cytoplasmic elasticity are greatly lowered, exclusively in laminopathic models in which the LINC complex is disrupted. These results indicate a new function for emerin in cell polarization and suggest that laminopathies are not directly associated with cells' inability to polarize, but rather with cytoplasmic softening and weakened adhesion mediated by the disruption of the LINC complex across the nuclear envelope.


Socioeconomic status, physical fitness, self-concept, attitude toward physical education, and academic achievement of children.
The goal was to analyze the physical fitness, self-concept, attitudes toward physical education, and academic achievement of Turkish elementary school children by socioeconomic status. 198 (101 boys, 97 girls) students from Grades 7 and 8 completed the Children's Attitude Inventory towards Physical Education, the Piers-Harris Children's Self-concept Scale, and Eurofit Physical Fitness Test Battery. Significant differences were found between the groups of Low and High socioeconomic status (SES) in terms of physical fitness and academic achievement. While the Low SES group had higher mean scores on physical fitness, mean academic achievements of the High SES group were higher. Mean differences in height, self-concept, and children's attitudes toward physical education by socioeconomic status were not statistically significant. Particular attention should be paid to physical fitness in children of high socioeconomic status and the academic achievement of children with low socioeconomic status.


Poly(ADP-ribose) polymerase in base excision repair: always engaged, but not essential for DNA damage processing.
Poly(ADP-ribose) polymerase (PARP-1) is an abundant nuclear protein with a high affinity for single- and double-strand DNA breaks. Its binding to strand breaks promotes catalysis of the covalent modification of nuclear proteins with poly(ADP-ribose) synthesised from NAD(+). PARP-1-knockout cells are extremely sensitive to alkylating agents, suggesting the involvement of PARP-1 in base excision repair; however, its role remains unclear. We investigated the dependence of base excision repair pathways on PARP-1 and NAD(+) using whole cell extracts derived from normal and PARP-1 deficient mouse cells and DNA substrates containing abasic sites. In normal extracts the rate of repair was highly dependent on NAD(+). We found that in the absence of NAD(+) repair was slowed down 4-6-fold after incision of the abasic site. We also established that in extracts from PARP-1 deficient mouse cells, repair of both regular and reduced abasic sites was increased with respect to normal extracts and was NAD(+)-independent, suggesting that in both short- and long-patch BER PARP-1 slows down, rather than stimulates, the repair reaction. Our data support the proposal that PARP-1 does not play a major role in catalysis of DNA damage processing via either base excision repair pathway.


Improving Attitudes to Volunteering Among Older Adults: A Randomized Trial Approach.
Promoting engagement in formal volunteering represents a potential means of facilitating healthy aging. Given reluctance to participate in volunteering has been partially attributed to negative perceptions of various aspects of this activity, this study assessed whether trialing volunteering can improve perceptions among older people. Using a parallel-group design, Australians aged 60+ years (n = 445) were randomly assigned to one of two conditions, one in which they were encouraged to trial volunteering and one in which they were asked to continue their usual activities. Perceptions and attitudes among those in the volunteering condition became significantly more favorable over 6 months relative to those in the control condition, with this change predicted by several aspects of the volunteering experience (e.g., acquisition of skills, increased social connectedness). Providing access to roles that cater to the learning and social needs of older adults appears to be important for improving attitudes toward engaging in volunteer work.


Creation and assessment of a clinical predictive model for candidaemia in patients with candiduria.
Candidaemia is the most common clinical presentation of invasive candidiasis and is a major cause of morbidity and mortality. Candiduria is a predictor for candidaemia; however, patient characteristics that are associated with concurrent candidaemia in the setting of candiduria are unclear. Identifying these characteristics could aid in the early detection of systemic disease. We performed a retrospective cohort analysis of hospitalised patients with candiduria at our institution over a 13-year period. Our evaluation of patient characteristics included demographics, comorbidities, medications, procedures, devices, vital signs and laboratory values. We developed a multivariable logistic model to identify factors associated with candidaemia in patients with candiduria. We identified 4240 patients with candiduria, 263 (6.2%) of whom had candidaemia. Predictors for increased risk of candidaemia with candiduria included hospitalisations > 12 days, central venous catheter, parenteral nutrition, haematological and gynaecological malignancy, and receipt of β-lactam/β-lactamase inhibitors. Vital signs and laboratory values associated with candidaemia included elevated heart rate, temperature and creatinine, along with neutropenia and neutrophilia. Factors that demonstrated a decreased risk of candidaemia included diabetes mellitus, gastrostomy and urinary catheter with antibiotic use. The c-statistic was 0.741 (95% CI, 0.710-0.772). We identified a set of clinical characteristics that can predict the presence of candidaemia with candiduria.


Removal of nutrients from septic tank effluent with baffle subsurface-flow constructed wetlands.
Three new baffle flow constructed wetlands (CWs), namely the baffle horizontal flow CW (Z1), baffle vertical flow CW (Z2) and baffle hybrid flow CW (Z3), along with one traditional horizontal subsurface flow CW (Z4) were designed to test the removal efficiency of nitrogen (N) and phosphorus (P) from the septic tank effluent under varying hydraulic retention times (HRTs). Results showed that the optimal HRT was two days for maximal removal of N and P from the septic tank effluent among the four CWs. At this HRT, the Z1, Z2, Z3 and Z4 CWs removed, respectively, 49.93, 58.50, 46.01 and 44.44% of TN as well as 87.82, 93.23, 95.97 and 91.30% of TP. Our study further revealed that the Z3 CW was the best design for overall removal of N and P from the septic tank effluent due to its hybrid flow directions with better oxygen supply inside the CW system.


Scalable and interpretable alternative to chart review for phenotype evaluation using standardized structured data from electronic health records.
Chart review as the current gold standard for phenotype evaluation cannot support observational research on electronic health records and claims data sources at scale. We aimed to evaluate the ability of structured data to support efficient and interpretable phenotype evaluation as an alternative to chart review. We developed Knowledge-Enhanced Electronic Profile Review (KEEPER) as a phenotype evaluation tool that extracts patient's structured data elements relevant to a phenotype and presents them in a standardized fashion following clinical reasoning principles. We evaluated its performance (interrater agreement, intermethod agreement, accuracy, and review time) compared to manual chart review for 4 conditions using randomized 2-period, 2-sequence crossover design. Case ascertainment with KEEPER was twice as fast compared to manual chart review. 88.1% of the patients were classified concordantly using charts and KEEPER, but agreement varied depending on the condition. Missing data and differences in interpretation accounted for most of the discrepancies. Pairs of clinicians agreed in case ascertainment in 91.2% of the cases when using KEEPER compared to 76.3% when using charts. Patient classification aligned with the gold standard in 88.1% and 86.9% of the cases respectively. Structured data can be used for efficient and interpretable phenotype evaluation if they are limited to relevant subset and organized according to the clinical reasoning principles. A system that implements these principles can achieve noninferior performance compared to chart review at a fraction of time.


Development of β-amino alcohol derivatives that inhibit Toll-like receptor 4 mediated inflammatory response as potential antiseptics.
Toll-like receptor 4 (TLR4) induced proinflammatory signaling has been directly implicated in severe sepsis and represents an attractive therapeutic target. Herein, we report our investigations into the structure-activity relationship and preliminary drug metabolism/pharmacokinetics study of β-amino alcohol derivatives that inhibit the TLR4 signaling pathway. Lead compounds were identified from in vitro cellular examination with micromolar potency for their inhibitory effects on TLR4 signaling and subsequently assessed for their ability to suppress the TLR4-induced inflammatory response in an ex vivo whole blood model. In addition, the toxicology, specificity, solubility, brain-blood barrier permeability, and drug metabolism of several compounds were evaluated. Although further optimizations are needed, our findings lay the groundwork for the future drug development of this class of small molecule agents for the treatment of severe sepsis.


Presidential address. The role of neuronal golgi apparatus in a centripetal membrane vesicular traffic.
The adsorptive endocytosis of conjugates of the marker enzyme horseradish peroxidase (HRP) with lectins and cholera toxin was studied in cultured neurons, neuroblastoma cells, and, in vivo, in the rat, by electron microscopic cytochemical (HRP), quantitative autoradiographic, morphometric, and biochemical techniques. The uptake of ricin-HRP by cultured neuroblastoma cells is 100 to 200 times greater than free HRP; furthermore, ricin does not stimulate the fluid phase endocytosis of HRP. Conjugates of wheat germ agglutinin and cholera toxin with HRP are 10 to 40 times more sensitive than free HRP in tracing retrograde connections in the rat central and peripheral nervous system. Conjugates of various ligands with HRP undergo endocytosis into the cisternae of the Golgi apparatus (or Golgi-Endoplasmic-Reticulum-Lysosome-GERL) and in residual bodies of cultured neurons and in vivo, while free HRP is found only in residual bodies. We conclude that: 1) various ligands with affinities to plasma membrane moieties are more sensitive, and probably more reliable, markers of "membrane" flow than free HRP, and 2) the pathway involved in the adsorptive endocytosis of ligands is different from the pathway of fluid phase uptake of HRP. These findings are consistent with the view that, in addition to its established role in the centrifugal traffic of various moieties, the neuronal Golgi apparatus is also involved in a centripetal vesicular membrane traffic. We spectulate that the neuronal Golgi apparatus, and probably the Golgi apparatus of other cells, is at the "crossroads" of a vesicular membrane traffic, and may thus exert significant controls on biologic membrane equilibria.


Tolerability of extended-release quetiapine fumarate compared with immediate-release quetiapine fumarate in older patients with Alzheimer's disease with symptoms of psychosis and/or agitation: a randomised, double-blind, parallel-group study.
The objective of this study was to assess the safety and tolerability of extended-release quetiapine fumarate (quetiapine XR) compared with quetiapine immediate-release (quetiapine IR) in older patients with Alzheimer's disease with symptoms of psychosis and/or agitation. This was a 6-week, double-blind, double-dummy, randomised study. Of the 109 patients screened, 100 were randomised to receive quetiapine XR (n = 68) or quetiapine IR (n = 32), at doses of 50 and 25 mg/day, respectively. Treatment was escalated to 100 mg/day by Day 4. At Day 8, a flexible-dose (50-300 mg/day) period began when dose adjustment was made at the investigator's discretion. The primary variable was incidence and type of adverse events (AEs). Secondary variables included efficacy and other safety assessments. Mean daily doses were 143.6 and 142.0 mg in the quetiapine XR and quetiapine IR groups, respectively. Ninety patients completed the study; only one withdrew (in the quetiapine XR group) because of an AE. Laboratory evaluations identified severe neutropaenia (one patient), mild neutropaenia (three patients) and eosinophilia (five patients); however, these were not reported, as AEs and confounding factors, such as patient age, concomitant illness and medication, made it difficult to determine any relationship to quetiapine treatment. Numerical improvements from baseline were seen across both treatment groups in Neuropsychiatric Inventory frequency × severity total, Neuropsychiatric Inventory-Nursing Home version, Cohen-Mansfield Agitation Inventory, Clinical Global Impression-Severity of Illness and Clinical Global Impression-Improvement scores. Quetiapine XR dosed up to 300 mg/day was generally well tolerated, with a similar profile to that of quetiapine IR.


Can an Internet-based health risk assessment highlight problems of heart disease risk factor awareness? A cross-sectional analysis.
Health risk assessments are becoming more popular as a tool to conveniently and effectively reach community-dwelling adults who may be at risk for serious chronic conditions such as coronary heart disease (CHD). The use of such instruments to improve adults' risk factor awareness and concordance with clinically measured risk factor values could be an opportunity to advance public health knowledge and build effective interventions. The objective of this study was to determine if an Internet-based health risk assessment can highlight important aspects of agreement between respondents' self-reported and clinically measured CHD risk factors for community-dwelling adults who may be at risk for CHD. Data from an Internet-based cardiovascular health risk assessment (Heart Aware) administered to community-dwelling adults at 127 clinical sites were analyzed. Respondents were recruited through individual hospital marketing campaigns, such as media advertising and print media, found throughout inpatient and outpatient facilities. CHD risk factors from the Framingham Heart Study were examined. Weighted kappa statistics were calculated to measure interrater agreement between respondents' self-reported and clinically measured CHD risk factors. Weighted kappa statistics were then calculated for each sample by strata of overall 10-year CHD risk. Three samples were drawn based on strategies for treating missing data: a listwise deleted sample, a pairwise deleted sample, and a multiple imputation (MI) sample. The MI sample (n=16,879) was most appropriate for addressing missing data. No CHD risk factor had better than marginal interrater agreement (κ>.60). High-density lipoprotein cholesterol (HDL-C) exhibited suboptimal interrater agreement that deteriorated (eg, κ<.30) as overall CHD risk increased. Conversely, low-density lipoprotein cholesterol (LDL-C) interrater agreement improved (eg, up to κ=.25) as overall CHD risk increased. Overall CHD risk of the sample was lower than comparative population-based CHD risk (ie, no more than 15% risk of CHD for the sample vs up to a 30% chance of CHD for the population). Interventions are needed to improve knowledge of CHD risk factors. Specific interventions should address perceptions of HDL-C and LCL-C. Internet-based health risk assessments such as Heart Aware may contribute to public health surveillance, but they must address selection bias of Internet-based recruitment methods.


High-resolution electric power load data of an industrial park with multiple types of buildings in China.
Considering the growing demand for electricity in industrial parks, understanding their electric power load patterns is critical for improving energy efficiency and ensuring the rational utilization of energy resources. However, the detailed electric power load data of various buildings in industrial parks are rarely available and accessible, which hinders the related studies. In this context, we present the electric power load data of 6 years (from January 1, 2016 to December 31, 2021) for various types of buildings in an industrial park in Suzhou, China. The data are obtained from smart meters and have various time resolutions (i.e., 5 minutes, 30 minutes, and 1 hour). This work describes the data collection, processing process, and different imputation methods. The high-resolution electric power load data can be used for various research tasks, including load prediction, load pattern recognition, anomaly detection, and demand response strategy development.


Routine 4D Cardiac CT to Identify Concomitant Transthyretin Amyloid Cardiomyopathy in Older Adults with Severe Aortic Stenosis.
Background Transthyretin amyloid cardiomyopathy (ATTR-CM) often coexists with severe aortic stenosis (AS). Although strain analysis from cardiac MRI and echocardiography was demonstrated to predict coexisting ATTR-CM, comparable data from four-dimensional (4D) cardiac CT are lacking despite wide availability. Purpose To evaluate the diagnostic performance of 4D cardiac CT-derived parameters in identifying ATTR-CM in older adults considered for transcatheter aortic valve implantation (TAVI). Materials and Methods This prospective single-center screening study for ATTR-CM included consecutive patients with severe AS considered for TAVI who underwent 4D cardiac CT between August 2019 and August 2021 approximately 1 day before technetium 99m (99mTc) 3,3-diphosphono-1,2-propanodicarboxylic-acid (DPD) scintigraphy. The diagnostic performance of CT-based left ventricular (LV), right ventricular, and left atrial dimensions, ejection fraction (EF), and myocardial strain were evaluated against 99mTc-DPD scintigraphy as the reference standard to identify ATTR-CM. Predictors and an unweighted cardiac CT score were validated with internal bootstrapping. The assignment of variables to the score was based on cutoff values achieving the highest Youden index J. Results Among 263 participants (mean age, 83 years ± 4.6 [SD]; 149 male and 114 female participants), 99mTc-DPD scintigraphy (Perugini grade 2 or 3) confirmed coexisting ATTR-CM in 27 (10.3%). CT-derived LV mass index, LV and LA global longitudinal strain (GLS), and relative apical longitudinal strain each predicted the presence of ATTR-CM with an area under the curve (AUC) of at least 0.70. Implementing these parameters with cutoff values of 81 g/m2 or higher, -14.9% or higher, less than 11.5%, and 1.7 or higher in the CT score, respectively, yielded high diagnostic performance (AUC = 0.89; 95% CI: 0.81, 0.94; P < .001) robust to internal bootstrapping validation (AUC = 0.88; 95% CI: 0.82, 0.94). If two criteria were fulfilled, the sensitivity and specificity in the detection of ATTR-CM were 96.3% (95% CI: 81.0, 99.9) and 58.9% (95% CI: 52.3, 65.2), respectively. Conclusion When compared against 99mTc-DPD scintigraphy as the reference standard, routine 4D cardiac CT in older adults considered for TAVI provided high diagnostic performance in the detection of concomitant ATTR-CM by assessing LV and left atrial GLS, relative apical longitudinal strain, and LV mass index. ClinicalTrials.gov registration no.: NCT04061213 © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Tavakoli and Onder in this issue.


Practical and Statistical Considerations for the Long Term Follow-Up of Gene Therapy Trial Participants.
Study sponsors and market authorization holders are required by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) to enroll patients administered a gene therapy product, whether in a trial setting or post-licensure, in a long term follow-up safety study to continue the safety assessments of their product. These follow-up studies range between 5 and 15 years after dosing. This unprecedented duration of engagement with patients and caregivers raises logistical challenges that will require innovation and collaboration across sponsors and regulators. In this paper we delineate some of the key considerations for designing long term follow-up protocols in the gene therapy setting, with an eye toward platform and master protocol approaches, and offer guidance for innovative operational and statistical methods that can help assess the safety profile and durability of response for these novel therapeutics.


Functional Validation of Candidate Genes Detected by Genomic Feature Models.
Understanding the genetic underpinnings of complex traits requires knowledge of the genetic variants that contribute to phenotypic variability. Reliable statistical approaches are needed to obtain such knowledge. In genome-wide association studies, variants are tested for association with trait variability to pinpoint loci that contribute to the quantitative trait. Because stringent genome-wide significance thresholds are applied to control the false positive rate, many true causal variants can remain undetected. To ameliorate this problem, many alternative approaches have been developed, such as genomic feature models (GFM). The GFM approach tests for association of set of genomic markers, and predicts genomic values from genomic data utilizing prior biological knowledge. We investigated to what degree the findings from GFM have biological relevance. We used the Drosophila Genetic Reference Panel to investigate locomotor activity, and applied genomic feature prediction models to identify gene ontology (GO) categories predictive of this phenotype. Next, we applied the covariance association test to partition the genomic variance of the predictive GO terms to the genes within these terms. We then functionally assessed whether the identified candidate genes affected locomotor activity by reducing gene expression using RNA interference. In five of the seven candidate genes tested, reduced gene expression altered the phenotype. The ranking of genes within the predictive GO term was highly correlated with the magnitude of the phenotypic consequence of gene knockdown. This study provides evidence for five new candidate genes for locomotor activity, and provides support for the reliability of the GFM approach.


Arterial calcifications in beta-thalassemia.
The purpose of this study was to define the incidence of arterial calcifications in patients with beta-thalassemia. Beta-thalassemia patients have been shown to present a high prevalence of angioid streaks and skin lesions characteristic of pseudoxanthoma elasticum (PXE). Given the fact that vascular involvement in the form of arterial calcifications is also a common manifestation of PXE, the authors investigated radiographically the presence of arterial calcifications in beta-thalassemia patients. They studied 40 patients with beta-thalassemia over 30 years of age. Forty healthy, age- and sex-matched subjects were chosen as a control group. Radiographs of the tibias were performed in order to disclose arterial calcifications. The occurrence of PXE skin lesions and of angioid streaks (AS) was also investigated. Arterial calcifications were detected in the posterior tibial artery in 22 (55%) beta-thalassemia patients and in six (15%) controls (P < 0.01 for the comparison). PXE skin lesions and AS were found in eight (20%) and 21 (52%) patients respectively. A total of 34 patients (85%) had at least one of the three lesions, namely, arterial calcifications, angioid streaks, and/or PXE-like skin lesions. Stepwise logistic regression analysis did not reveal prognostic value in independent variables such as transfusions, chelation therapy, pseudoxanthoma elasticum skin lesions and/or angioid streaks, diabetes, hemoglobin, serum ferritin, and uric acid. It was concluded that arterial calcifications are common in older beta-thalassemia patients. This finding could be a manifestation of an acquired PXE syndrome associated with beta-thalassemia, and consequently, vascular events complicating PXE should be expected in these patients.


Decreased p110alpha catalytic activity accompanies increased myocyte apoptosis and cardiac hypertrophy in leptin deficient ob/ob mice.
Disruption of leptin signaling has been associated with both obesity and heart failure. We recently demonstrated that leptin deficiency in ob/ob mice and leptin insensitivity in db/db mice leads to increased myocyte apoptosis and left ventricular (LV) hypertrophy. We showed that LV mass, while similar among young ob/ob, db/db, and wild type (WT) mice, is significantly higher in old ob/ob and db/db versus WT. Ob/ob and db/db mice developed markedly increased rates of myocyte apoptosis by TUNEL and activated caspase-3 levels. An intriguing candidate for the study of obesity-associated cardiac hypertrophy and apoptosis is PI3K, which functions to not only regulate cell size but also maintain cell integrity through protection from apoptosis. Here we further show that ob/ob mice have decreased catalytic activity of phosphoinositide 3-kinase (PI3K) (p110alpha) which is reversed with leptin treatment. Leptin repletion in ob/ob mice also reduced both myocyte apoptosis and LV hypertrophy to WT levels. We have therefore concluded that normal leptin signaling is necessary to prevent age-related myocyte apoptosis and LV hypertrophy and that PI3K is a critical component of the leptin signaling axis. The decrease in p110alpha catalytic activity could explain the development of increased myocyte apoptosis and cardiac hypertrophy in these obese mouse models.


Genome-wide analysis of histone modifiers in tomato: gaining an insight into their developmental roles.
Histone post-translational modifications (HPTMs) including acetylation and methylation have been recognized as playing a crucial role in epigenetic regulation of plant growth and development. Although Solanum lycopersicum is a dicot model plant as well as an important crop, systematic analysis and expression profiling of histone modifier genes (HMs) in tomato are sketchy. Based on recently released tomato whole-genome sequences, we identified in silico 32 histone acetyltransferases (HATs), 15 histone deacetylases (HDACs), 52 histone methytransferases (HMTs) and 26 histone demethylases (HDMs), and compared them with those detected in Arabidopsis (Arabidopsis thaliana), maize (Zea mays) and rice (Oryza sativa) orthologs. Comprehensive analysis of the protein domain architecture and phylogeny revealed the presence of non-canonical motifs and new domain combinations, thereby suggesting for HATs the existence of a new family in plants. Due to species-specific diversification during evolutionary history tomato has fewer HMs than Arabidopsis. The transcription profiles of HMs within tomato organs revealed a broad functional role for some HMs and a more specific activity for others, suggesting key HM regulators in tomato development. Finally, we explored S. pennellii introgression lines (ILs) and integrated the map position of HMs, their expression profiles and the phenotype of ILs. We thereby proved that the strategy was useful to identify HM candidates involved in carotenoid biosynthesis in tomato fruits. In this study, we reveal the structure, phylogeny and spatial expression of members belonging to the classical families of HMs in tomato. We provide a framework for gene discovery and functional investigation of HMs in other Solanaceae species.


Initial preparation: anti-infective therapy.
The primary aim of anti-infective therapy is to eliminate or reduce the subgingival plaque and to arrest tissue breakdown associated with chronic or progressive periodontitis. Four to six weeks following anti-infective therapy, initial healing is usually complete, and the clinical status should be re-evaluated. After assessing the reduction in probing depths, bleeding on probing and clinical attachment levels, the clinician must decide whether the anti-infective therapy has arrested the disease. If it is determined that maximum healing has occurred, the initial phase of therapy is complete, and the patient is placed into the maintenance program. In sites that remain > or = 6 mm following anti-infective therapy, surgical debridement may be indicated to increase visualization of the roots for deposit removal because the evidence points to better calculus removal in an open versus closed environment. During surgical root preparation, fine diamonds or finishing burs produce the smoothest root surface followed by manual and power-driven scalers. Endoscopic cameras that enable the clinician to see subgingival calculus without benefit of surgical access may prove to be a valuable diagnostic tool for sites that do not respond to therapy. Diamond-coated ultrasonic inserts are available from some manufacturers and have been shown to be efficient and effective in surgical root preparation. New designs and finer grits may enable clinicians to use these instruments in nonsurgical applications in the future. Finally, new evidence from one group in Belgium has shown that significantly more attachment gain and probing depth reduction is achieved when scaling and root planing is done in one or two visits within 24 hours compared with the traditional method of scaling quadrant by quadrant over four visits. These preliminary results need to be confirmed by others but hold a great deal of promise for improving the outcomes from nonsurgical root preparation in the future.


Dynamical stability of body center cubic iron at the Earth's core conditions.
Here, using self-consistent ab initio lattice dynamical calculations that go beyond the quasiharmonic approximation, we show that the high-pressure high-temperature bcc-Fe phase is dynamically stable. In this treatment the temperature-dependent phonon spectra are derived by exciting all the lattice vibrations, in which the phonon-phonon interactions are considered. The high-pressure and high-temperature bcc-Fe phase shows standard bcc-type phonon dispersion curves except for the transverse branch, which is overdamped along the high symmetry direction Gamma-N, at temperatures below 4,500 K. When lowering the temperature down to a critical value T(C), the lattice instability of the bcc structure is reached. The pressure dependence of this critical temperature is studied at conditions relevant for the Earth's core.


Brain size predicts bees' tolerance to urban environments.
The rapid conversion of natural habitats to anthropogenic landscapes is threatening insect pollinators worldwide, raising concern regarding the negative consequences on their fundamental role as plant pollinators. However, not all pollinators are negatively affected by habitat conversion, as certain species find appropriate resources in anthropogenic landscapes to persist and proliferate. The reason why some species tolerate anthropogenic environments while most find them inhospitable remains poorly understood. The cognitive buffer hypothesis, widely supported in vertebrates but untested in insects, offers a potential explanation. This theory suggests that species with larger brains have enhanced behavioural plasticity, enabling them to confront and adapt to novel challenges. To investigate this hypothesis in insects, we measured brain size for 89 bee species, and evaluated their association with the degree of habitat occupancy. Our analyses revealed that bee species mainly found in urban habitats had larger brains relative to their body size than those that tend to occur in forested or agricultural habitats. Additionally, urban bees exhibited larger body sizes and, consequently, larger absolute brain sizes. Our results provide the first empirical support for the cognitive buffer hypothesis in invertebrates, suggesting that a large brain in bees could confer behavioural advantages to tolerate urban environments.


Enteric disease surveillance under the AFHSC-GEIS: current efforts, landscape analysis and vision forward.
The mission of the Armed Forces Health Surveillance Center, Division of Global Emerging Infections Surveillance and Response System (AFHSC-GEIS) is to support global public health and to counter infectious disease threats to the United States Armed Forces, including newly identified agents or those increasing in incidence. Enteric diseases are a growing threat to U.S. forces, which must be ready to deploy to austere environments where the risk of exposure to enteropathogens may be significant and where routine prevention efforts may be impractical. In this report, the authors review the recent activities of AFHSC-GEIS partner laboratories in regards to enteric disease surveillance, prevention and response. Each partner identified recent accomplishments, including support for regional networks. AFHSC/GEIS partners also completed a Strengths, Weaknesses, Opportunities and Threats (SWOT) survey as part of a landscape analysis of global enteric surveillance efforts. The current strengths of this network include excellent laboratory infrastructure, equipment and personnel that provide the opportunity for high-quality epidemiological studies and test platforms for point-of-care diagnostics. Weaknesses include inconsistent guidance and a splintered reporting system that hampers the comparison of data across regions or longitudinally. The newly chartered Enterics Surveillance Steering Committee (ESSC) is intended to provide clear mission guidance, a structured project review process, and central data management and analysis in support of rationally directed enteric disease surveillance efforts.


Increased EFG- and PDGFalpha-receptor signaling by mutant FGF-receptor 2 contributes to osteoblast dysfunction in Apert craniosynostosis.
Dysregulations of osteoblast function induced by gain-of-function genetic mutations in fibroblast growth factor receptors (FGFRs) cause premature fusion of cranial sutures in syndromic craniosynostosis. The pathogenic signaling mechanisms induced by FGFR genetic mutations in human craniosynostosis remain largely unknown. In this study, we have used microarray analysis to investigate the signaling pathways that are activated by FGFR2 mutations in Apert craniosynostosis. Transcriptomic analysis revealed that EGFR and PDGFRalpha expression is abnormally increased in human Apert calvaria osteoblasts compared with wild-type cells. Quantitative RT-PCR and western blot analyses in Apert osteoblasts and immunohistochemical analysis of Apert sutures confirmed the increased EGFR and PDGFRalpha expression in vitro and in vivo. We demonstrate that pharmacological inhibition of EGFR and PDGFR reduces the pathological upregulation of phenotypic osteoblast genes and in vitro matrix mineralization in Apert osteoblasts. Investigation of the underlying molecular mechanisms revealed that activated FGFR2 enhances EGFR and PDGFRalpha mRNA expression via activation of PKCalpha-dependent AP-1 transcriptional activity. We also show that the increased EGFR protein expression in Apert osteoblasts results in part from a post-transcriptional mechanism involving increased Sprouty2-Cbl interaction, leading to Cbl sequestration and reduced EGFR ubiquitination. These data reveal novel molecular crosstalks between activated FGFR2, EGFR and PDGFRalpha that functionally contribute to the osteoblastic dysfunction in Apert craniosynostosis, which may provide a molecular basis for novel therapeutic approaches in this severe skeletal disorder.


LAST (local anesthetic systemic toxicity) but not least: systemic lidocaine toxicity during cardiac intervention.
Lidocaine is the most common medication used for local anesthesia in cardiac procedures. Sometimes, a higher dose of lidocaine is used to improve the patient's comfort, especially in device implantation or complex interventional procedures requiring several sheath insertions for access. We describe a patient with idiopathic cardiomyopathy who underwent implantable cardioverter defibrillator implantation for primary prevention and developed local anesthetic systemic toxicity (LAST) associated with lidocaine use. Multiple susceptible factors leading to lidocaine toxicity found in this case are common in patients with advanced heart failure. This case emphasizes the importance of dose adjustment of local anesthetic agents in individual patients, especially those with advanced heart failure who undergo cardiovascular procedures. The risk factors, preventive measures, and therapeutic approaches to manage this type of complication are discussed in detail.


Health-seeking behaviour for childhood malaria: household dynamics in rural Senegal.
Research on health care behaviour in sub-Saharan Africa usually considers the mother as the reference in the household when a child is sick. The study of health care management within the family is a key issue for understanding therapeutic rationales. This study was conducted in the region of Fatick in Senegal among 902 children with malaria-related fever. The data were taken from a retrospective quantitative survey conducted in all compounds of the DSS (Demographic Surveillance Site) of Niakhar. The results show that child care-taking is fundamentally a collective process: in 70.9% of out-of-home resorts, the treatment decision was collective. The health care process of 68.1% of morbid episodes involved several individuals. The involvement of the mother, the father and other relatives in the collective management of health care followed different logics. Each care-giver had a specific and complementary function depending on gender norms, intergenerational relations and characteristics of the family unit. Family management of illness aims at optimizing financial and human resources given the economic, logistical and social constraints on health care. Nevertheless, collective management also favoured home-based care, prevented good treatment compliance and delayed the resort to health facilities. These results suggest that health education campaigns should focus on an early involvement of fathers in health care-giving and also on the strengthening of the autonomy of mothers. Mothers' empowerment should give women more autonomy in their child's treatment choice. Lastly, there is a need to develop community health facilities and establish shared funding at the community level.


Autistic disorder versus other pervasive developmental disorders in young children: same or different?
Eighteen preschool children diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders Third Edition Revised (DSM III-R) as having Pervasive Developmental Disorder-Not Otherwise Specified (PDD-NOS) were compared to 176 children with DSM III-R Autistic Disorder (AD), and to 311 non-autistic children with developmental language disorders (DLD) (N = 201) or low IQ (N = 110). All children were partitioned into "high" and "low" cognitive subgroups at a nonverbal IQ of 80. Within cognitive subgroups, the 18 PDD-NOS children did not differ significantly from either the DLD or the AD children in verbal and adaptive skills and obtained scores intermediate between those of these groups. The PDD-NOS did not differ from the AD children in maladaptive behaviors. Both the PDD-NOS and AD children had many more of these behaviors than the non-autistic comparison groups. Children in the "high" and "low" cognitive subgroups of AD, but not of PDD-NOS, differed substantially on most measures, with the children with lower cognitive scores significantly more impaired on all measures. Similarity of PDD-NOS children to AD children in maladaptive behaviors and an intermediate position between autistic and non-autistic groups on virtually all measures explains the difficulty clinicians encounter in classifying children with PDD and raises questions about the specificity of these diagnostic subtypes of the autistic spectrum.


Houttuynia cordata thunb. alleviates inflammatory bowel disease by modulating intestinal microenvironment: a research review.
Inflammatory bowel disease (IBD) is a complex group of chronic intestinal diseases, the cause of which has not yet been clarified, but it is widely believed that the disorder of the intestinal microenvironment and its related functional changes are key factors in the development of the disease. Houttuynia cordata thunb. is a traditional plant with abundant resources and long history of utilization in China, which has attracted widespread attention in recent years due to its potential in the treatment of IBD. However, its development and utilization are limited owing to the aristolochic acid alkaloids contained in it. Therefore, based on the relationship between the intestinal microenvironment and IBD, this article summarizes the potential mechanisms by which the main active ingredients of Houttuynia cordata thunb., such as volatile oils, polysaccharides, and flavonoids, and related traditional Chinese medicine preparations, such as Xiezhuo Jiedu Formula, alleviate IBD by regulating the intestinal microenvironment. At the same time, combined with current reports, the medicinal and edible safety of Houttuynia cordata thunb. is explained for providing ideas for further research and development of Houttuynia chordate thunb. in IBD disease, more treatment options for IBD patients, and more insights into the therapeutic potential of plants with homology of medicine and food in intestinal diseases, and even more diseases.


Adjuvant 17-hydroxyprogesterone caproate in women withultrasound-indicated cerclage: a systematic review and meta-analysis.
Objective: To assess the additional benefits of 17-hydroxyprogesterone caproate (17-OHPC) therapy in preventing recurrent spontaneous preterm birth in women with an ultrasound-indicated cerclage.Methods: Electronic databases (Medline, Scopus, ClinicalTrials.gov, PROSPERO, Embase, Scielo, and the Cochrane Central Register of Controlled Trials) were searched for studies published before September 2018. Keywords included "preterm birth", "ultrasound-indicated cerclage", "pregnancy" and "17-hydroxyprogesterone caproate". Studies comparing ultrasound-indicated cerclage alone to cerclage plus 17-OHPC were included. The primary outcome measure was preterm birth at <35 weeks of gestation. Secondary outcome measures include preterm birth <24 weeks, <28 weeks, <32 weeks and <37 weeks of gestation, necrotizing enterocolitis (NEC), fetal birth weight, and intraventricular hemorrhage (grades III and IV). Meta-analysis was performed using the random effects model of DerSimonian and Laird. Risk of bias and quality assessment was performed using the risk of bias in nonrandomized studies of interventions (ROBINS-I).Results: Four studies met inclusion criteria and were included in the final analysis. Of the 396 women who received ultrasound-indicated cerclage, 142 (35.9%) received adjuvant 17-OHPC. The primary outcome, preterm birth <35 weeks of gestation, was present in three studies and 332/396 singleton pregnancies. Though there was a trend towards a reduced risk of preterm birth, the summary estimate of effect was not statistically significant when comparing cerclage alone to cerclage plus 17-OHPC at <35 weeks (relative risk (RR) 0.95, 95% CI 0.77-1.17). Similarly, we found no differences in preterm birth at <24 weeks (RR 0.30, 95% CI 0.06-1.60), <28 weeks (RR 0.57, 95% CI 0.13-2.53), and <32 weeks (RR 0.99, 95% CI 0.44-2.27) when comparing cerclage alone to cerclage plus 17-OHPC. There were no differences in fetal birth weight, intraventricular hemorrhage and necrotizing enterocolitis comparing cerclage alone to cerclage plus 17-OHPC.Conclusion: Intramuscular 17-OHPC in combination with ultrasound-indicated cerclage in women with prior preterm birth had no additional effect in reducing spontaneous recurrent preterm birth or improving perinatal outcomes.


Treatment of breast abscesses with US-guided percutaneous needle drainage without indwelling catheter placement.
To assess ultrasonographically (US) guided needle aspiration of breast abscesses as an alternative to surgical incision and drainage or indwelling catheter placement. The authors reviewed hospital records from 1995 to 1997 for patients undergoing US-guided aspiration of breast abscesses. Two radiologists reviewed the US, mammographic, and US-guided aspiration studies for the size, appearance, and drainage of abscesses. The medical records were reviewed for follow-up data. Thirteen patients aged 15-69 years underwent US-guided percutaneous aspiration of 13 breast abscesses. All patients presented with a palpable mass, nine of which were retroareolar. At US, four abscesses were oval, nine (including three with septa) were irregularly shaped, and five had a thick rind. Of seven abscesses 2.4 cm or smaller, two were almost completely drained and five were completely aspirated. All seven abscesses resolved without surgery. Of six women with incompletely aspirated abscesses larger than 2.4 cm (one 3 cm, four 4 cm, one 7 cm), five required surgical referral; one of these cases was referred after repeat aspiration had been performed. Percutaneous aspiration of breast abscesses can enable diagnosis of abscesses and be used to treat small abscesses if they are completely drained. Partial drainage of abscesses larger than 3 cm may be palliative, but incision and drainage still may be necessary for definitive treatment.


Intradermal transgenic expression of granulocyte-macrophage colony-stimulating factor induces neutrophilia, epidermal hyperplasia, Langerhans' cell/macrophage accumulation, and dermal fibrosis.
Granulocyte-macrophage colony-stimulating factor (GM-CSF), a pleiotropic cytokine, is up-regulated in a number of chronic skin inflammatory diseases, particularly atopic dermatitis. However, its role in these conditions remains largely unclear. To explore its function, we have established a rat intradermal transgene model by using a replication-deficient adenoviral vector expressing GM-CSF. Intradermal GM-CSF gene transfer led to a prolonged compartmentalized expression of transgene protein in the dermis. This expression induced an unexpectedly wide spectrum of pathologies in both epidermis and dermis, including neutrophilia, epidermal hyperplasia (acanthosis), an increased number of epidermal Langerhans' cells, accumulation of MHC II-positive macrophages, as well as mild eosinophilia in the dermis at earlier stages and upper dermal fibrosis at later stages. These findings thus identify GM-CSF as a potent multifunctional cytokine at skin site that is capable of evolving numerous inflammatory processes ranging from the early acute neutrophilia to later chronic fibrotic responses, and also suggest the important role of this cytokine in the development and perpetuation of pathologic changes in chronic skin inflammatory conditions including chronic atopic dermatitis. In addition, our study presents a novel model of adult normal animals that is useful for identifying and studying key cytokines involved in inflammatory skin diseases.


Klf5 Mediates Odontoblastic Differentiation through Regulating Dentin-Specific Extracellular Matrix Gene Expression during Mouse Tooth Development.
Klf5, a member of the Krüppel-like transcription factor family, has essential roles during embryonic development, cell proliferation, differentiation, migration and apoptosis. This study was to define molecular mechanism of Klf5 during the odontoblastic differentiation. The expression of Klf5, odontoblast-differentiation markers, Dspp and Dmp1 was co-localized in odontoblastic cells at different stages of mouse tooth development and mouse dental papilla mesenchymal cells. Klf5 was able to promote odontoblastic differentiation and enhance mineral formation of mouse dental papilla mesenchymal cells. Furthermore, overexpression of Klf5 could up-regulate Dspp and Dmp1 gene expressions in mouse dental papilla mesenchymal cells. In silico analysis identified that several putative Klf5 binding sites in the promoter and first intron of Dmp1 and Dspp genes that are homologous across species lines. Electrophoretic mobility shift assay and chromatin immunoprecipitation analysis indicated that Klf5 bound to these motifs in vitro and in intact cells. The responsible regions of Dmp1 gene were located in the promoter region while effect of Klf5 on Dspp activity was in the first intron of Dspp gene. Our results identify Klf5 as an activator of Dmp1 and Dspp gene transcriptions by different mechanisms and demonstrate that Klf5 plays a pivotal role in odontoblast differentiation.


Smoking in chronic hemodialysis patients: prevalence and cardiovascular morbidity
Smoking is common in chronic hemodialysis patients who are characterized by a high cardiovascular risk. This is a multicenter cross-sectional study over a period of 4 months, from July 2021 to October 2021, in the Agadir province. Among the 245 patients interviewed, 9,4% were current smokers and 16,7% were former smokers. Compared to non-smoking patients, former and current smokers were predominantly male, had more comorbidities, higher diastolic blood pressure, higher mean ultrafiltration rate and more antihypertensive treatments. In multivariate analysis, active smoking was significantly associated with the presence of cardiovascular disease. Smoking is an important and modifiable cardiovascular risk factor in chronic hemodialysis patients.


Does Specification Matter? Experiments with Simple Multiregional Probabilistic Population Projections.
Population projection models that introduce uncertainty are a growing subset of projection models in general. In this paper, we focus on the importance of decisions made with regard to the model specifications adopted. We compare the forecasts and prediction intervals associated with four simple regional population projection models: an overall growth rate model, a component model with net migration, a component model with in-migration and out-migration rates, and a multiregional model with destination-specific out-migration rates. Vector autoregressive models are used to forecast future rates of growth, birth, death, net migration, in-migration and out-migration, and destination-specific out-migration for the North, Midlands and South regions in England. They are also used to forecast different international migration measures. The base data represent a time series of annual data provided by the Office for National Statistics from 1976 to 2008. The results illustrate how both the forecasted subpopulation totals and the corresponding prediction intervals differ for the multiregional model in comparison to other simpler models, as well as for different assumptions about international migration. The paper ends end with a discussion of our results and possible directions for future research.


Review: Genetics and the Classification of Arthritis in Adults and Children.
Current classification of primary inflammatory arthritis begins from the assumption that adults and children are different. No form of juvenile idiopathic arthritis bears the same name as an adult arthritis, a nomenclature gap with implications for both clinical care and research. Recent genetic data have raised questions regarding this adult/pediatric divide, revealing instead broad patterns that span the age spectrum. Combining these genetic patterns with demographic and clinical data, we propose that inflammatory arthritis can be segregated into 4 main clusters, largely irrespective of pediatric or adult onset: seropositive, seronegative (likely including a distinct group that usually begins in early childhood), spondyloarthritis, and systemic. Each of these broad clusters is internally heterogeneous, highlighting the need for further study to resolve etiologically discrete entities. Eliminating divisions based on arbitrary age cutoffs will enhance opportunities for collaboration between adult and pediatric rheumatologists, thereby helping to promote the understanding and treatment of arthritis.


Forensic scientists' conclusions: how readable are they for non-scientist report-users?
Scientists have an ethical responsibility to assist non-scientists to understand their findings and expert opinions before they are used as decision-aids within the criminal justice system. The communication of scientific expert opinion to non-scientist audiences (e.g., police, lawyers, and judges) through expert reports is an important but under-researched issue. Readability statistics were used to assess 111 conclusions from a proficiency test in forensic glass analysis. The conclusions were written using an average of 23 words per sentence, and approximately half of the conclusions were expressed using the active voice. At an average Flesch-Kincaid Grade level of university undergraduate (Grade 13), and Flesch Reading Ease score of difficult (42), the conclusions were written at a level suitable for people with some tertiary education in science, suggesting that the intended non-scientist readers would find them difficult to read. To further analyse the readability of conclusions, descriptive features of text were used: text structure; sentence structure; vocabulary; elaboration; and coherence and unity. Descriptive analysis supported the finding that texts were written at a level difficult for non-scientists to read. Specific aspects of conclusions that may pose difficulties for non-scientists were located. Suggestions are included to assist scientists to write conclusions with increased readability for non-scientist readers, while retaining scientific integrity. In the next stage of research, the readability of expert reports in their entirety is to be explored.


Successful treatment of acquired hemophilia A associated with immune thrombocytopenia and joint hemarthrosis: A case report and literature review.
Acquired hemophilia A (AHA) is a rare bleeding disease caused by autoantibodies against factor VIII (FVIII). Spontaneous bleeding symptoms usually affect the skin, musco, muscle, and internal organs, while joint hemarthrosis in AHA is an extremely rare manifestation. AHA may have an autoimmune cause and is often associated with autoimmune disease, but no demonstrable platelet impairment was found in AHA patients. We report a patient with AHA complicated with a right shoulder joint hemarthrosis and immune thrombocytopenia. The patient was treated with fresh frozen plasma (FFP) and human prothrombin complex concentrate (hPCC) to control the active bleeding. Simultaneously this patient firstly accepted cyclophosphamide combined with prednisone to eradicate the inhibitor, while the treatment effect of cyclophosphamide combined with prednisone was not satisfactory. At last, she was successfully treated through the use of an anti-CD20 monoclonal antibody. AHA is an autoimmune disease and can co-exist with immune cytopenia besides connective tissue disease (CTD). Joint hemarthrosis is not specific to congenital hemophilia and mainly related to the extent of prolonged aPTT and weight loading of joint in AHA. When the first-line therapy of cyclophosphamide combined with prednisone is not enough to eradicate the inhibitor, especially for a higher inhibitor titer, anti-CD20 monoclonal antibody could play an important role.


Nicotine reverses hypofrontality in animal models of addiction and schizophrenia.
The prefrontal cortex (PFC) underlies higher cognitive processes that are modulated by nicotinic acetylcholine receptor (nAChR) activation by cholinergic inputs. PFC spontaneous default activity is altered in neuropsychiatric disorders, including schizophrenia-a disorder that can be accompanied by heavy smoking. Recently, genome-wide association studies (GWAS) identified single-nucleotide polymorphisms (SNPs) in the human CHRNA5 gene, encoding the α5 nAChR subunit, that increase the risks for both smoking and schizophrenia. Mice with altered nAChR gene function exhibit PFC-dependent behavioral deficits, but it is unknown how the corresponding human polymorphisms alter the cellular and circuit mechanisms underlying behavior. Here we show that mice expressing a human α5 SNP exhibit neurocognitive behavioral deficits in social interaction and sensorimotor gating tasks. Two-photon calcium imaging in awake mouse models showed that nicotine can differentially influence PFC pyramidal cell activity by nAChR modulation of layer II/III hierarchical inhibitory circuits. In α5-SNP-expressing and α5-knockout mice, lower activity of vasoactive intestinal polypeptide (VIP) interneurons resulted in an increased somatostatin (SOM) interneuron inhibitory drive over layer II/III pyramidal neurons. The decreased activity observed in α5-SNP-expressing mice resembles the hypofrontality observed in patients with psychiatric disorders, including schizophrenia and addiction. Chronic nicotine administration reversed this hypofrontality, suggesting that administration of nicotine may represent a therapeutic strategy for the treatment of schizophrenia, and a physiological basis for the tendency of patients with schizophrenia to self-medicate by smoking.