Structure of adeno-associated virus serotype 8, a gene therapy vector.
Adeno-associated viruses (AAVs) are being developed as gene therapy vectors, and their efficacy could be improved by a detailed understanding of their viral capsid structures. AAV serotype 8 (AAV8) shows a significantly greater liver transduction efficiency than those of other serotypes, which has resulted in efforts to develop this virus as a gene therapy vector for hemophilia A and familial hypercholesterolemia. Pseudotyping studies show that the differential tissue tropism and transduction efficiencies exhibited by the AAVs result from differences in their capsid viral protein (VP) amino acids. Towards identifying the structural features underpinning these disparities, we report the crystal structure of the AAV8 viral capsid determined to 2.6-A resolution. The overall topology of its common overlapping VP is similar to that previously reported for the crystal structures of AAV2 and AAV4, with an eight-stranded beta-barrel and long loops between the beta-strands. The most significant structural differences between AAV8 and AAV2 (the best-characterized serotype) are located on the capsid surface at protrusions surrounding the two-, three-, and fivefold axes at residues reported to control transduction efficiency and antibody recognition for AAV2. In addition, a comparison of the AAV8 and AAV2 capsid surface amino acids showed a reduced distribution of basic charge for AAV8 at the mapped AAV2 heparin sulfate receptor binding region, consistent with an observed non-heparin-binding phenotype for AAV8. Thus, this AAV8 structure provides an additional platform for mutagenesis efforts to characterize AAV capsid regions responsible for differential cellular tropism, transduction, and antigenicity for these promising gene therapy vectors.


Standardizing in vitro diagnostics tasks in clinical trials: a call for action.
Translational research is defined as the process of applying ideas, insights and discoveries generated through basic scientific inquiry to treatment or prevention of human diseases. Although precise information is lacking, several lines of evidence attest that up to 95% early-phase studies may not translate into tangible outcomes for improving clinical management. Major theoretical hurdles exist in the translational process, but is it also undeniable that many studies may have failed for practical reasons, such as the use of inappropriate diagnostic testing for evaluating efficacy, effectiveness or safety of a given medical intervention, or poor quality in laboratory testing. This can generate biased test results and result in misconceptions during data interpretation, eventually leading to no clinical benefit, possible harm, and a waste of valuable resources. From a genuine economic perspective, it can be estimated that over 10 million euros of funding may be lost each year in clinical trials in the European Union due to preanalytical and analytical problems. These are mostly attributions to the heterogeneity of current guidelines and recommendations for the testing process, to the poor evidence base for basic pre-analytical, analytical and post-analytical requirements in clinical trials, and to the failure to thoughtfully integrate the perspectives of clinicians, patients, nurses and diagnostic companies in laboratory best practices. The most rational means for filling the gap between what we know and what we practice in clinical trials cannot discount the development of multidisciplinary teams including research scientists, clinicians, nurses, patients associations and representative of in vitro diagnostic (IVD) companies, who should actively interplay and collaborate with laboratory professionals to adapt and disseminate evidence-based recommendations about biospecimen collection and management into the research settings, from preclinical to phase III studies.


The presence of care homes and excess deaths during the COVID-19 pandemic: Evidence from Italy.
This paper explores the relationship between the spatial distribution of excess deaths and the presence of care home facilities during the first wave of the COVID-19 outbreak in Italy. Using registry-based mortality data for Lombardy, one of the areas most severely hit by the pandemic we show that the presence of a care home in a municipality is associated with significantly higher excess death rates in the population. This effect appears to be driven by excess mortality in the elderly population of 70 years old and older. Our results are robust to controlling for the number of residents in each care home, suggesting that the presence of such facilities may have acted as one of factors contributing to the diffusion of COVID-19 at the local level.


Evidence for involvement of the astrocytic benzodiazepine receptor in the mechanism of action of convulsant and anticonvulsant drugs.
The anticonvulsant drugs carbamazepine, phenobarbital, trimethadione, valproic acid and ethosuximide at pharmacologically relevant concentrations inhibit [3H]diazepam binding to astrocytes in primary cultures but have much less effect on a corresponding preparation of neurons. Phenytoin as well as pentobarbital (which is not used chronically as an anticonvulsant) are equipotent in the two cell types. The convulsants picrotoxinin and pentylenetetrazol, the convulsant benzodiazepine RO 5-3663 and the two convulsant barbiturates DMBB and CHEB similarly inhibit diazepam binding to astrocytes but have little effect on neurons. On the basis of these findings it is suggested that these convulsants and anticonvulsants owe at least part of their effect to an interaction with the astrocytic benzodiazepine receptor, perhaps by interference with a calcium channel.


Role of Inflammatory Risk Factors in the Pathogenesis of Streptococcus pneumoniae.
Streptococcus pneumoniae (Spn) is a colonizer of the human nasopharynx (NP), causing a variety of infections in humans including otitis media, pneumonia, sepsis, and meningitis. The NP is an immune permissive site which allows for the persistence of commensal bacteria. Acute or chronic respiratory airway inflammation constitutes a significant risk factor for the manifestation of Spn infections. The inflammatory conditions caused by an upper respiratory viral infection or respiratory conditions such as allergic asthma and chronic obstructive pulmonary disorders (COPDs) are implicated in the dysregulation of airway inflammation and tissue damage, which compromise the respiratory barrier integrity. These immune events promote bacterial outgrowth leading to Spn dissemination and invasion into the bloodstream. Therefore, suppression of inflammation and restoration of respiratory barrier integrity could contain Spn infections manifesting in the backdrop of an inflammatory disease condition. The gained knowledge could be harnessed in the design of novel therapeutic interventions to circumvent Spn bacterial infections.


Subcortical ischaemic changes in young hypertensive patients: frequency, effect on cognitive performance and relationship with markers of endothelial and haemostatic activation.
Information on subcortical ischaemic changes (SIC) in young hypertensive patients is scarce. We evaluated the frequency of SIC at magnetic resonance imaging (MRI), the possible effect on cognition of these patients, and the role of plasma markers known as indicators of endothelial and haemostatic activation. Inclusion criteria were age <or=54 years, hypertension for at least 2 years and absence of cerebrovascular disease or other conditions possibly related to SIC. Patients with SIC at MRI and two control groups (matched for age, sex and education) of hypertensive patients without SIC and non-hypertensive healthy subjects underwent an extensive neuropsychological examination and evaluation of plasma markers. Amongst the 200 patients evaluated, 50 (25%) showed SIC at MRI. Mean age was 48.4 +/- 4.8 years. Compared with both control groups, hypertensive patients with SIC performed significantly worse in general cognition, attention, memory and executive functions. Moreover, they showed significantly more often increased levels of all plasma markers compared with healthy controls, and of von Willebrand factor (vWF) compared with both control groups (P < 0.001). In young hypertensive patients SIC are frequent, related to a worse cognitive performance and endothelial dysfunction. Our findings suggest vWF as marker of end-organ damage, underscoring the relevance of treating hypertension at younger age.


Association of Protein Tyrosine Phosphatase Nonreceptor 22 (PTPN22) C1858T gene polymorphism with susceptibility to autoimmune thyroid diseases: a meta-analysis.
Results from studies on the association of PTPN22 C1858T polymorphism with AITD risk are conflicting, we thereby perform this meta-analysis to derive a more precise effect on this possible association. Two investigators independently searched the PubMed, Embase, Wanfang and CNKI (China National Knowledge Infrastructure) databases. A total of 11 studies with 3764 AITDs cases and 3328 controls were finally identified. Statistically significant association was observed between PTPN22 C1858T polymorphism and AITD risk based on all studies (TT vs. CC, OR=2.18, 95%CI=1.31˜3.62; TC vs. CC, OR=1.50, 95%CI=1.29˜1.73; TT/TC vs. CC, OR=1.41, 95%CI=1.12˜1.78; TT vs. TC/CC, OR=2.00, 95%CI=1.21˜3.33). The results of subgroup analysis showed that: (1) regarding ethnic diversity, the variant genotypes TT/TC of C1858T were associated with a significantly increased AITD risk in Caucasians (TT/TC vs. CC, OR=1.41, 95%CI=1.09˜1.83) (2) regarding different countries, the statistically significantly association was observed in UK (TC vs. CC, OR=1.64, 95%CI=1.36˜1.98; TT/TC vs. CC, OR=1.65, 95%CI=1.37˜1.98) and other countries (including South Tunisia, Russia, Polish, Japanese) (TT vs. CC, OR=3.65, 95%CI=1.43˜9.33; TT vs. TC/CC, OR=3.41, 95%CI=1.34˜8.65). (3) regarding the subtypes of AITDs, patients with Graves' disease (GD) had a significant higher degree of C1858T polymorphism (TT vs. CC, OR=2.35, 95%CI=1.36˜4.05; TC vs. CC, OR=1.46, 95%CI=1.12˜1.89; TT/TC vs. CC, OR=1.54, 95%CI=1.33˜1.80; TT vs. TC/CC, OR=2.16, 95%CI=1.25˜3.72), while no association was observed in patients with Hashimoto's thyroiditis (HT). No publication bias was observed. Our results demonstrated that PTPN22 C1858T polymorphism was associated with AITD risk, especially in Caucasians.


Access opening guide produced using a 3D printer (AOG-3DP) as an effective tool in difficult cases for dental students.
The aim of this study was to determine the effectiveness of using an access opening guide in teaching ideal access opening shape and preventing excessive tooth loss, with a focus on predoctoral dental students. Ninety teeth that were mounted in a box just below the level of the cementoenamel junction using tray resin were randomly divided into two study groups. An access opening guide produced using a 3D printer (AOG-3DP) was designed using cone-beam computed tomography (CBCT). The AOG-3DP was applied in the test groups, while no aid was used in the control group. Access preparations in both groups performed by predoctoral dental students were scanned using CBCT to detect overpreparation. The preparation time and access cavity volume were evaluated. The mean times required for achieving access opening were 327.2 and 97.4 s in the control and AOG-3DP groups, respectively, for premolars, and 547.4 and 104.5 s for molars. The mean volumes for premolars and molars differed from the ideal cavities by 38.1 and 72.2 mm3 , respectively, in the control group, and by -2.0 and -8.7 mm3 the AOG-3DP group. Using the AOG-3DP significantly reduced the access opening time for premolars and molars. However, there is a limitation in that CBCT DICOM images must be converted to stereolithographic .stl files in order to be printed via 3D technology. This requires additional preclinical treatment time for imaging and subsequent printing. It could be considered that this can be a useful method in difficult cases.


Analysis of reflectance and transmittance measurements on absorbing and scattering small samples using a modified integrating sphere setup.
The aim of the present paper is to analyze reflectance and transmittance measurements on small scattering and absorbing samples. The long term goal is to perform quantitative, spectroscopic in vivo measurements of pigments in small samples of plant material. Small samples such as small leaves constitute a special experimental challenge in cases in which the sample beam has a larger cross-sectional area than the sample. The experimental errors introduced when measuring reflectance and transmittance on small absorbing and scattering samples are investigated theoretically and experimentally by using a blue polyester sample as an appropriate test sample. The experiments are performed with either a mask or a lens setup combined with a mask inserted in the sample beam. In particular, the errors introduced in the reflectance measurements can be very large and larger than 100%. It is shown that any direct illumination of the mask must be avoided. To obtain more accurate values for the reflection coefficient it is necessary to combine the mask with a focusing lens system, adjust the mask and sample very carefully, and choose the ratio between the aperture of the mask and the beam area as large as possible. In the case of transmittance measurements, it is shown that the combination of a special sample fixture and a lens system gives rise to smaller errors compared to the errors introduced by the mask alone or the mask combined with a focusing lens system.


Management of common anxiety disorders.
Anxiety disorders affect 16 percent of the U.S. population. Family physicians treat 90 percent of patients presenting with one or more anxiety disorders. Common anxiety disorders include generalized anxiety disorder, panic disorder and social phobia. Differentiation among these disorders may be difficult, since symptoms and presentations are often similar. Underlying medical disorders and depressive illness may mimic or coexist with anxiety disorders. The chronic, remitting and relapsing nature of anxiety disorders requires the institution of a long-term plan of care. The integration of pharmacologic and psychotherapeutic interventions generally produces the greatest benefit to patients. Pharmacotherapeutic options frequently prescribed by family physicians include benzodiazepines, beta blockers, monoamine oxidase inhibitors, tricyclic antidepressants and azapirones. Useful psychotherapeutic models featuring brief interventions include supportive and cognitive approaches, and behavioral therapies, such as biofeedback, in vivo exposure and systematic desensitization.


Laryngeal chondrosarcoma as a rare cause of subglottic stenosis.
Laryngeal chondrosarcoma (CS) is a very rare entity. It is usually seen in 50-80-year olds. It is developed from cricoid cartilage largely. Patients have laryngeal CS complaint of respiratuvar distress, dysphonia, and dysphagia generally. A submucous mass is usually seen in physical examination with an intact mucosa. Distant metastasis is rare in CSs. Main treatment is surgical excision. An 82-year-old patient who has respiratuvar distress is presented in this paper and laryngeal CS is reviewed in the light of the literature.


Cost-effectiveness of intensive inpatient treatments for severely obese children and adolescents in the Netherlands; a randomized controlled trial (HELIOS).
Intensive combined lifestyle interventions are the recommended treatment for severely obese children and adolescents, but there is a lack of studies and their cost-effectiveness. The objective of this study is to compare the cost-effectiveness of two intensive one-year inpatient treatments and usual care for severely obese children and adolescents. Participants are 40 children aged 8-13 and 40 adolescents aged 13-18 with severe obesity (SDS-BMI ≥ 3.0 or SDS-BMI ≥ 2.3 with obesity related co-morbidity). They will be randomized into two groups that will receive a comprehensive treatment program of 12 months that focuses on nutrition, physical activity and behavior change of the participant and their parents. The two programs are the same in total duration (12 months), but differ in inpatient treatment duration. Group A will participate in a 6 month intensive inpatient treatment program during weekdays, followed by six monthly return visits of 2 days. Group B will participate in a 2 month intensive inpatient treatment program during weekdays, followed by biweekly return visits of 2 days during the next four months, followed by six monthly return visits of 2 days. Several different health care professionals are involved, such as pediatricians, dieticians, psychologists, social workers, nurses and physiotherapists. Results will also be compared to a control group that receives usual care. The primary outcome is SDS-BMI. Secondary outcomes include quality of life using the EQ-5D and cardiovascular risk factors. Data will be collected at baseline and after 6, 12 and 24 months. An economic evaluation will be conducted alongside this study. Healthcare consumption will be based on actual resource use, using prospective data collection during 2 years through cost diaries. Quality Adjusted Life Years (QALYs) will be calculated using the EQ-5D. This study will provide useful information on the effectiveness and cost-effectiveness of inpatient treatment in severely obese children and adolescents. Valuable information on long term effects, after 2 years, is also included. Netherlands Trial Register (NTR): NTR1678.


The Risk of Arterial Thrombosis in Patients With Chronic Myeloid Leukemia Treated With Second and Third Generation BCR-ABL Tyrosine Kinase Inhibitors May Be Explained by Their Impact on Endothelial Cells: An In-Vitro Study.
BCR-ABL tyrosine kinase inhibitors (TKIs) revolutionized the treatment of chronic myeloid leukemia, inducing deep molecular responses, largely improving patient survival and rendering treatment-free remission possible. However, three of the five BCR-ABL TKIs, dasatinib, nilotinib, and ponatinib, increase the risk of developing arterial thrombosis. Prior investigations reported that nilotinib and ponatinib affect the endothelium, but the mechanisms by which they exert their toxic effects are still unclear. The impact of dasatinib and bosutinib on endothelial cells has been poorly investigated. Here, we aimed to provide an in vitro homogenous evaluation of the effects of BCR-ABL TKIs on the endothelium, with a special focus on the type of cell death to elucidate the mechanisms responsible for the potential cytotoxic effects of BCR-ABL TKIs nilotinib and ponatinib on endothelial cells. We tested the five BCR-ABL TKIs at three concentrations on human umbilical venous endothelial cells (HUVECs). This study highlights the endothelial toxicity of ponatinib and provides insights about the mechanisms by which it affects endothelial cell viability. Ponatinib induced apoptosis and necrosis of HUVECs after 72 h. Dasatinib affected endothelial cells in vitro by inhibiting their proliferation and decreased wound closure as soon as 24 h of treatment and even at infra-therapeutic dose (0.005 µM). Comparatively, imatinib, nilotinib, and bosutinib had little impact on endothelial cells at therapeutic concentrations. They did not induce apoptosis nor necrosis, even after 72 h of treatment but they inhibited HUVEC proliferation. Overall, this study reports various effects of BCR-ABL TKIs on endothelial cells and suggests that ponatinib and dasatinib induce arterial thrombosis through endothelial dysfunction.


Equiatomic binary phases of Copper-Rare Earth Elements. An overview of monocuprides from first-principles calculations.
Equiatomic binary phases of copper with rare earth (RE) elements exhibit either primitive cubic ( P m 3 ‾ m ${Pm\bar 3m}$ ) or orthorhombic (Pnma) structures and in some cases both. By using density functional theory (DFT), we calculated the enthalpies of formation along the series of RE elements combined equimolarly with copper. For RE from Sc to Lu, the calculated enthalpies of formation fall in the range -49.8 kJ/mol for LuCu to -9.1 kJ/mol for the least thermodynamically stable CeCu. Except NdCu, all the other cubic or orthorhombic compounds exhibit lattice stability. Either forms of NdCu indicated lattice instability. Along the Sc-group, the hypothetical primitive cubic and orthorhombic forms of LuCu are found thermodynamically and mechanically stable. The overall trend of the formation enthalpies as a function of the Meyer Periodic Number is consistent with the energy trend of the 4 f-orbital filling as moving from Sc to Lu monocuprides. In addition, the calculated Gibbs free energies indicate that the thermodynamic stability is largely due to the entropic contributions. All standard DFT calculations were also repeated with DFT+U to better describe the correlation between the 5d-4f and 3d shells of RECu compounds. It has been found that DFT+U slightly affects the enthalpies of formation of RECu binaries. Moreover, DFT+U shifts up the f-band energies of RECu with light RE elements (such as La, Ce and Pr) and in contrast lowers them in the case of RECu with heavy RE elements from Nd to Lu.


The North American mitochondrial disease registry.
The North American Mitochondrial Disease Consortium (NAMDC) comprises a network of 17 clinical centers with a mission to conduct translational research on mitochondrial diseases. NAMDC is a part of the Rare Disease Clinical Research Network (RDCRN) and is funded by the National Institutes of Health. To foster its mission, NAMDC has implemented a comprehensive Mitochondrial Disease Clinical Registry (hereafter NAMDC Registry), collected biosamples deposited into the NAMDC Biorepository, defined phenotypes and genotypes of specific disorders, collected natural history data, identified outcome measures, characterized safety and long-term toxicity and efficacy of promising therapies, and trained young investigators interested in patient-oriented research in mitochondrial disease. Research conducted by NAMDC is built on the foundation of the Clinical Registry. Data within the registry are encrypted and maintained in a centralized database at Columbia University Medical Center. In addition to clinical data, NAMDC has established a mitochondrial disease biorepository, collecting DNA, plasma, cell, and tissue samples. Specimens are assigned coded identifiers in compliance with all relevant regulatory entities and with emerging NIH guidelines for biorepositories. NAMDC funds two pilot projects each year. Pilot grants are small grants typically supporting an early stage concept to obtain preliminary data. Pilot grants must enhance and address major issues in mitochondrial medicine and specific areas of need for the field and for the successful outcome of NAMDC. The grant selection process is facilitated by input from multiple stakeholders including patient organizations and the strategic leadership of NAMDC. To train new mitochondrial disease investigators, NAMDC has established a Fellowship Program which offers a unique training opportunity to senior postdoctoral clinical fellows. The fellowship includes a 6-month period of intensive training in clinical trial methodology through the Clinical Research Enhancement through Supplemental Training program and equivalent programs at the other sites, along with rotations up to 3 months each to two additional consortium sites where a rich and varied training experience is provided. Nine core educational sites participate in this training program, each offering a summer grant program in mitochondrial medicine funded by our NAMDC partner the United Mitochondrial Disease Foundation (www.umdf.org). All clinical research in NAMDC depends on the participation of mitochondrial disease patients. Since individual mitochondrial disorders are often extremely rare, major communication and recruitment efforts are required. Therefore, NAMDC has forged a very close partnership with the premier patient advocacy group for mitochondrial diseases in North America, the United Mitochondrial Disease Foundation (UMDF). The NAMDC Registry has confirmed the clinical and genetical heterogeneity of mitochondrial diseases due to primary mutations in mitochondrial DNA or nuclear DNA. During the 8 years of this NIH-U54 grant, this consortium, acting in close collaboration with a patient advocacy group, the UMDF, has effectively addressed these complex diseases. NAMDC has expanded a powerful patient registry with more than 1600 patients enrolled to date, a website for education and recruitment of patients (www.namdc.org), a NAMDC biorepository housed at the Mayo Clinic in Rochester, MN, and essential diagnostic guidelines for consensus research. In addition, eight clinical studies have been initiated and the NAMDC fellowship program has been actively training the next generation of mitochondrial disease clinical investigators, of which six have completed the program and remain actively involved in mitochondrial disease research. The NAMDC Patient Registry and Biorepository is actively facilitating mitochondrial disease research, and accelerating progress in the understanding and treatment of mitochondrial diseases.


Productivity losses due to influenza and influenza-like illness in Switzerland: results of the Swiss Sentinel Surveillance Network in a non-pandemic era.
The incidence of influenza and influenza-like illnesses in Switzerland is generally high. Although related direct medical costs can be substantial, especially if hospitalisations occur, several studies suggested that indirect costs due to the loss of productivity may represent an even higher economic burden. The aim of this study was to assess the costs arising from lost productivity due to influenza and influenza-like illnesses in Switzerland. Analyses were based on data collected in 2016 and 2017 by the Swiss Sentinel Surveillance Network of the Swiss Federal Office of Public Health (SFOPH). The available information covered details on the physicians collecting the data, patients' characteristics, symptoms, treatments, and inability to work (in terms of physician-recorded workdays lost for own sickness or caregiving). The cost of lost productivity, estimated using the human capital approach, was calculated as the number of workdays lost due to influenza-like illnesses multiplied by the mean salary for one working day. Salary differences across sex, age and region were considered. Extrapolation to the national level was performed by adjusting for the size of the Swiss population, the age and sex distribution, the regional distribution, the number of Sentinel general physician contacts and the specialisation of the physician. At the Swiss national level, the estimated total yearly number of cases of inability to work due to influenza and influenza-like illnesses was 101,287 in 2016 and 86,373 in 2017. In subgroups defined by year, gender, region and age class, numbers of cases per 100,000 inhabitants ranged from 12 to 2396. The total number of workdays lost in Switzerland, considering degree of employment and visit day, were estimated to be 324,118 in 2016 and 278,121 in 2017. The number of workdays lost was generally higher in men (53.7% of the total in 2016 and 55.6% of the total in 2017) than women. The estimated total costs due to inability to work, calculated using a human capital approach and including the caregiving costs, were CHF 115 million in 2016 and CHF 103 million in 2017, equivalent to CHF 1.4 million per 100,000 inhabitants. The costs of lost productivity due to influenza and influenza-like illnesses in Switzerland are substantial and may vary considerably between different years, regions and age classes. As the present analyses could not consider all causes of lost productivity (e.g., short-term inability to work not requiring a physician consultation, hospitalisations, early retirement, premature death), the total indirect costs due to influenza or influenza-like illnesses can be expected to be higher than the presented estimates.


The failure of infarction and/or nephrectomy in stage IV renal cell cancer to influence survival or metastatic regression.
The success of cancer therapy depends on the destruction of all viable cancer cells in the primary site, as well as in metastatic areas. Surgery alone can do little for the patient whose tumor has produced distant involvement except in those situations where surgical excision, radiotherapy, chemotherapy, or immunotherapy can be relied on to eradicate metastatic disease. Because of the paucity of systemic therapy for renal cell carcinoma, an aggressive surgical approach to the primary tumor is justifiable when all metastatic lesions can be excised or otherwise definitively treated and in experimental protocols in which adjuvant therapy of possible benefit can be combined with palliative nephrectomy. There is no evidence, however, in reported studies to suggest that routine palliative nephrectomy in patients who will not be offered adjuvant systemic therapy or radiation is beneficial. Such practice is also associated with a higher incidence of complications and mortality than is expected for resection of localized renal cell carcinoma. For these reasons, it is reasonable to recommend adjunctive nephrectomy only in certain selected instances, which include (1) the control of a patient's current symptoms related to the primary disease, for example, flank pain, hematuria, fever and toxicity, anemia, erythrocytosis, and hypercalcemia; (2) nephrectomy with the excision of a solitary metastasis; and (3) the patient who is willing to undergo experimental therapy, part of which involves removal of the primary tumor.


Ethics and drug resistance.
This paper reviews the dynamics behind, and ethical issues associated with, the phenomenon of drug resistance. Drug resistance is an important ethical issue partly because of the severe consequences likely to result from the increase in drug resistant pathogens if more is not done to control them. Drug resistance is also an ethical issue because, rather than being a mere quirk of nature, the problem is largely a product of drug distribution. Drug resistance results from the over-consumption of antibiotics by the wealthy; and it, ironically, results from the under-consumption of antibiotics, usually by the poor or otherwise marginalized. In both kinds of cases the phenomenon of drug resistance illustrates why health (care)--at least in the context of infectious disease--should be treated as a (global) public good. The point is that drug resistance involves 'externalities' affecting third parties. When one patient develops a resistant strain of disease because of her over- or under-consumption of medication, this more dangerous malady poses increased risk to others. The propriety of free-market distribution of goods subject to externalities is famously dubious--given that the 'efficiency' rationale behind markets assumes an absence of externalities. Market failure in the context of drug resistance is partly revealed by the fact that no new classes of antibiotics have been developed since 1970. I conclude by arguing that the case of drug resistance reveals additional reasons--to those traditionally appealed to by bioethicists--for treating health care as something special when making policy decisions about its distribution.


Hybrid echo and x-ray image guidance for cardiac catheterization procedures by using a robotic arm: a feasibility study.
We present a feasibility study on hybrid echocardiography (echo) and x-ray image guidance for cardiac catheterization procedures. A self-tracked, remotely operated robotic arm with haptic feedback was developed that attached to a standard x-ray table. This was used to safely manipulate a three-dimensional (3D) trans-thoracic echo probe during simultaneous x-ray fluoroscopy and echo acquisitions. By a combination of calibration and tracking of the echo and x-ray systems, it was possible to register the 3D echo images with the 2D x-ray images. Visualization of the combined data was achieved by either overlaying triangulated surfaces extracted from segmented echo data onto the x-ray images or by overlaying volume rendered 3D echo data. Furthermore, in order to overcome the limited field of view of the echo probe, it was possible to create extended field of view (EFOV) 3D echo images by co-registering multiple tracked echo data to generate larger roadmaps for procedure guidance. The registration method was validated using a cross-wire phantom and showed a 2D target registration error of 3.5 mm. The clinical feasibility of the method was demonstrated during two clinical cases for patients undergoing cardiac pacing studies. The EFOV technique was demonstrated using two healthy volunteers.


Sugarcane Aphid (Hemiptera: Aphididae): Host Range and Sorghum Resistance Including Cross-Resistance From Greenbug Sources.
The graminous host range and sources of sorghum [Sorghum bicolor (L.) Moench.] plant resistance, including cross-resistance from greenbug, Schizaphis graminum (Rondani), were studied for the newly emerging sugarcane aphid, Melanaphis sacchari (Zehntner), in greenhouse no-choice experiments and field evaluations. The sugarcane aphid could not survive on field corn, Zea mays (L.), Teff grass, Eragrostis tef (Zucc.), proso millet, Panicum miliaceum L., barley, Hordeum vulgare L., and rye, Secale cereale L. Only sorghum genotypes served as hosts including Johnsongrass, Sorghum halepense (L.), a highly suitable noncrop host that generates high numbers of sugarcane aphid and maintains moderate phenotypic injury. The greenbug-resistant parental line RTx2783 that is resistant to greenbug biotypes C and E was resistant to sugarcane aphid in both greenhouse and field tests, while PI 55607 greenbug resistant to biotypes B, C, and E was highly susceptible. PI 55610 that is greenbug resistant to biotypes B, C, and E maintained moderate resistance to the sugarcane aphid, while greenbug-resistant PI 264453 was highly susceptible to sugarcane aphid. Two lines and two hybrids from the Texas A&M breeding program B11070, B11070, AB11055-WF1-CS1/RTx436, and AB11055-WF1-CS1/RTx437 were highly resistant to sugarcane aphid, as were parental types SC110, SC170, and South African lines Ent62/SADC, (Macia/TAM428)-LL9, (SV1*Sima/IS23250)-LG15. Tam428, a parental line that previously showed moderate resistance in South Africa and India, also showed moderate resistance in these evaluations. Overall, 9 of 20 parental sorghum entries tested for phenotypic damage in the field resulted in good resistance to the sugarcane aphid and should be utilized in breeding programs that develop agronomically acceptable sorghums for the southern regions of the United States.


Pathophysiological roles of thrombospondin-4 in disease development.
Thrombospondin-4 (TSP-4) belongs to the extracellular matrix glycoprotein family of thrombospondins (TSPs). The multidomain, pentameric structure of TSP-4 allows its interactions with numerous extracellular matrix components, proteins and signaling molecules that enable its modulation to various physiological and pathological processes. Characterization of TSP-4 expression under development and pathogenesis of disorders has yielded important insights into mechanisms underlying the unique role of TSP-4 in mediating various processes including cell-cell, cell-extracellular matrix interactions, cell migration, proliferation, tissue remodeling, angiogenesis, and synaptogenesis. Maladaptation of these processes in response to pathological insults and stress can accelerate the development of disorders including skeletal dysplasia, osteoporosis, degenerative joint disease, cardiovascular diseases, tumor progression/metastasis and neurological disorders. Overall, the diverse functions of TSP-4 suggest that it may be a potential marker or therapeutic target for prognosis, diagnosis, and treatment of various pathological conditions upon further investigations. This review article highlights recent findings on the role of TSP-4 in both physiological and pathological conditions with a focus on what sets it apart from other TSPs.


Magnetic separation-based blood purification: a promising new approach for the removal of disease-causing compounds?
Recent studies report promising results regarding extracorporeal magnetic separation-based blood purification for the rapid and selective removal of disease-causing compounds from whole blood. High molecular weight compounds, bacteria and cells can be eliminated from blood within minutes, hence offering novel treatment strategies for the management of intoxications and blood stream infections. However, risks associated with incomplete particle separation and the biological consequences of particles entering circulation remain largely unclear. This article discusses the promising future of magnetic separation-based purification while keeping important safety considerations in mind.


Orthodontic bonding and debonding induces structural changes but does not alter the mechanical properties of enamel.
The purpose of the study is to investigate the effect of the bonding procedure on the mechanical properties of human enamel. A total of 20 extracted human premolars were included in this study, with the half of each tooth acting as its own internal control. Embedded and horizontally cut specimens were prepared, and two bucco-orally zones were separated. The first enamel zone of each tooth remained untreated. The opposing zone was subjected to simulated bonding and debonding, including etching with 37% phosphoric acid, bonding with primer and flowable composite resin, and subsequent removal of the composite with an adhesive removal bur. The properties tested were (a) elemental composition by energy-dispersive X-ray analysis, (b) mechanical properties of specimens by instrumented indentation testing (Martens hardness, elastic modulus, and elastic index), (c) enamel morphology by low-vacuum scanning electron microscopy, and (d) molecular composition by Raman microspectroscopy. Statistical analysis was performed by one-way mixed-effects analysis of variance at a = 0.05. No significant differences could be found in the mechanical properties (Martens hardness, elastic modulus, and elastic index) and elemental composition of intact and treated enamel, with the possible exception of Si traces, which were found only in the latter. Raman analysis revealed no differences between the two surface states while shallow grooves and parallel lines were found on the surface of treated enamel by SEM analysis. Under the limitations of the conditions of the study, there were no mechanical properties' alterations on enamel subjected to orthodontic bonding.


[Ochratoxin A in foods for human consumption: review].
Ochratoxin A is a neurotoxic, immunosuppressive, genotoxic, carcinogenic and teratogenic mycotoxins present in human food, mainly cereals and cereals products, alcoholic beverages and mill products (coffee, cocoa). The levels of Ochratoxin A in food are closely related with the production and conservation conditions. This review aims to assess the presence of OTA in different food groups, and to update the knowledge about its toxicity, mechanism of action, methods of analysis used for detection and quantification, and different aspects about regulations. References and publications related to the mechanism of action, toxicity, analysis and regulations about OTA in foods were searched and selected based on inclusion criteria. MEDLINE/PubMed, Scielo, Science Direct, Ebscohost were used as databases. The presence of OTA keeps on being observed in different food groups. The detected OTA levels are below those permitted by limits set by the regulations However, inadequate agrotechnological production practices and improper storage of foods remain as critical control points to avoid the toxic hazards resulting from human exposure to this toxin. It's recommended to promote the correct use of agrotechnological practices for raw materials and processed products to reduce the concentration of OTA in foods and to avoid the toxicity resulting from the consumption of OTA contaminated foods.


Viral pulmonary infections in thoracic and cardiovascular surgery.
Viral respiratory infections are uncommon causes of pulmonary infiltrates in immunocompetent patients who undergo cardiothoracic surgery. In winter months, however, influenza can be acquired in the community preoperatively or in the hospital setting. The recognition of influenza cases is essential to prevent nosocomial transmission. Respiratory syncytial virus is also an important pulmonary pathogen in pediatric patients who undergo cardiothoracic surgery and may produce serious disease in children with underlying pulmonary or congenital heart disease. Viral infections of the respiratory tract are important causes of morbidity and mortality in heart and lung transplant recipients, especially cytomegalovirus (CMV). Other herpes viruses such as varicella zoster virus and herpes simplex virus may also occasionally involve the lung. Epstein-Barr virus has been incriminated in the pathogenesis of post-transplant lymphoproliferative disease, an uncommon but severe complication of transplantation. Except for Epstein-Barr virus, effective therapy exists for CMV and the other herpes viruses. Prophylaxis with ganciclovir is effective in preventing serious CMV infections in seropositive heart transplant recipients. However, better strategies are needed to prevent primary CMV infection in these patients.


Prevalence of Salmonella in marketed Penaeus monodon shrimps in North Western Province, Sri Lanka.
The examination of a total of 180 samples from both captured and cultured shrimps from Sri Lanka for the presence of Salmonella revealed an overall prevalence of 12.8%. The prevalence of Salmonella in captured shrimps and cultured shrimps was 14.4% and 11.1% respectively, but thedifference was not statistically significant (p = 0.66). The serovar most frequently isolated was S. Newport (47.8% of the isolates), followed by S. Weltevreden (8.7%).


Lessons From the First Decade of the Native American Summer Research Internship at the University of Utah.
American Indian/Alaska Native (AI/AN) populations are facing multiple health crises, including limited access to care, high rates of chronic disease, and early mortality that is far worse than other underrepresented minorities in the United States. According to the Association of American Indian Physicians, AI/AN people represent 2.0% of the U.S. population but only 0.2% of medical students and 0.1% of full-time faculty at MD-granting institutions. Increasing the number of AI/AN clinicians and scientists is one strategy to improve health outcomes in the AI/AN population and address these crises. In 2010, the University of Utah partnered with research, cultural, and professional mentors to create a 10-week summer Native American Research Internship (NARI) program for AI/AN college students across the United States who are interested in pursuing biomedical careers. NARI attracts and supports AI/AN students by offering mentored summer research internships in an innovative, culturally aware framework that adapts to observed challenges to optimize educational experiences and support biomedical career aspirations. During the first decade of the NARI program, 128 students from 22 U.S. states, representing 46 tribal nations and 57 colleges and universities, participated. Of those 128 students, 113 (88%) have completed a bachelor's degree and the remaining 15 (12%) are currently working toward a bachelor's degree. No NARI student has dropped out of college. Twenty-six (20%) NARI alumni have matriculated to medical school and 30 (23%) to graduate school. Eight (6%) participants have completed medical school, and 3 (2%) are pursuing a PhD in science. An additional 36 (28%) have gained employment in biomedical research fields. The NARI program has increased the participation of AI/AN students in medicine and the biomedical sciences. The innovative, culturally aware, and adaptive framework is a model for other programs for AI/AN students and students in other underrepresented communities.


Opposite polarity of virus budding and of viral envelope glycoprotein distribution in epithelial cells derived from different tissues.
We compared the surface envelope glycoprotein distribution and the budding polarity of four RNA viruses in Fischer rat thyroid (FRT) cells and in CaCo-2 cells derived from a human colon carcinoma. Whereas both FRT and CaCo-2 cells sort similarly influenza hemagglutinin and vesicular stomatitis virus (VSV) G protein, respectively, to apical and basolateral membrane domains, they differ in their handling of two togaviruses, Sindbis and Semliki Forest virus (SFV). By conventional EM Sindbis virus and SFV were shown to bud apically in FRT cells and basolaterally in CaCo-2 cells. Consistent with this finding, the distribution of the p62/E2 envelope glycoprotein of SFV, assayed by immunoelectronmicroscopy and by domain-selective surface biotinylation was predominantly apical on FRT cells and basolateral on CaCo-2 cells. We conclude that a given virus and its envelope glycoprotein can be delivered to opposite membrane domains in epithelial cells derived from different tissues. The tissue specificity in the polarity of virus budding and viral envelope glycoprotein distribution indicate that the sorting machinery varies considerably between different epithelial cell types.


A new irradiation method with a neutron filter for silicon neutron transmutation doping at the Japan research reactor no. 3 (JRR-3).
We studied a new silicon irradiation holder with a neutron filter designed to make the vertical neutron flux profile uniform. Since an irradiation holder has to be made of a low activation material, we applied aluminum blended with B4C as the holder material. Irradiation methods to achieve uniform flux with a filter are discussed using Monte-Carlo calculation code MVP. Validation of the use of the MVP code for the holder's analyses is also discussed via characteristic experiments.


Antibiotic-induced disruption of the microbiome exacerbates chemotherapy-induced diarrhoea and can be mitigated with autologous faecal microbiota transplantation.
Chemotherapy is well documented to disrupt the gut microbiome, leading to poor treatment outcomes and a heightened risk of adverse toxicity. Although strong associations exist between its composition and gastrointestinal toxicity, its causal contribution remains unclear. Our inability to move beyond association has limited the development and implementation of microbial-based therapeutics in chemotherapy adjuncts with no clear rationale of how and when to deliver them. Here, we investigate the impact of augmenting the gut microbiome on gastrointestinal toxicity caused by the chemotherapeutic agent, methotrexate (MTX). Faecal microbiome transplantation (FMT) delivered after MTX had no appreciable impact on gastrointestinal toxicity. In contrast, disruption of the microbiome with antibiotics administered before chemotherapy exacerbated gastrointestinal toxicity, impairing mucosal recovery (P < 0.0001) whilst increasing diarrhoea severity (P = 0.0007) and treatment-related mortality (P = 0.0045). Importantly, these detrimental effects were reversed when the microbiome was restored using autologous FMT (P = 0.03), a phenomenon dictated by the uptake and subsequent expansion of Muribaculaceae. These are the first data to show that clinically impactful symptoms of gastrointestinal toxicity are dictated by the microbiome and provide a clear rationale for how and when to target the microbiome to mitigate the acute and chronic complications caused by disruption of the gastrointestinal microenvironment. Translation of this new knowledge should focus on stabilising and strengthening the gut microbiome before chemotherapy and developing new microbial approaches to accelerate recovery of the mucosa. By controlling the depth and duration of mucosal injury, secondary consequences of gastrointestinal toxicity may be avoided.


Supramolecular multicomponent self-assembly of shape-adaptive nanoprisms: wrapping up C(60) with three porphyrin units.
Self-assembly of a C(3v) symmetric trisphenanthroline and linear bisterpyridines in the presence of Cu(+) did not furnish the expected supramolecular nanoprisms in quantitative yield. With an accurately sized tripyridine as a stabilizing template, the nanoprism formed exclusively. Furthermore, an adaptive constriction of the nanoprism was seen with C(60) as template: as a result of the smaller size of C(60) the nanoframework wrapped up around the guest like an accordion-type host system.


Comprehensive tobacco marketing restrictions: promotion, packaging, price and place.
Evidence of the causal role of marketing in the tobacco epidemic and the advent of the WHO Framework Convention on Tobacco Control have inspired more than half the countries in the world to ban some forms of tobacco marketing. This paper briefly describes the ways in which cigarette marketing is restricted and the tobacco industry's efforts to subvert restrictions. It reviews what is known about the impact of marketing regulations on smoking by adults and adolescents. It also addresses what little is known about the impact of marketing bans in relation to concurrent population-level interventions, such as price controls, anti-tobacco media campaigns and smoke-free laws. Point of sale is the least regulated channel and research is needed to address the immediate and long-term consequences of policies to ban retail advertising and pack displays. Comprehensive marketing restrictions require a global ban on all forms of promotion, elimination of packaging and price as marketing tools, and limitations on the quantity, type and location of tobacco retailers.


A post-thyroidectomy convulsion: an unusual presentation of chronic hypoparathyroidism.
A 59-year-old woman with previously undiagnosed hypoparathyroidism presented with a tonic-clonic seizure 38 years after thyroidectomy. This case is unusual because of the initial presentation, but also unique because it is the longest latency period between surgery and presentation in recent literature.


The association between HIV media campaigns and number of patients coming forward for HIV antibody testing.
To assess the relationship between national and local media campaigns with respect to the number of patients requesting HIV antibody tests as a surrogate marker of the effectiveness of different campaign strategies. Analysis by month of the numbers of HIV tests performed in the regional genitourinary (GUM) clinic for Lothian over a 5 year period and in the whole of Lothian Region, Scotland over a 3 year period. Changes in testing rates were monitored with respect to media campaigns over the same time period. Television based media campaigns produced the greatest increase in testing rates (average 46% increase over 2 months) compared with newspapers and poster campaigns (average 6% increase over 2 months). Regional HIV testing rates correlated significantly with GUM clinic testing rates. No increase in positive HIV tests was seen following media campaigns. Using HIV testing rates as a surrogate marker, television based media campaigns appear to be the most effective way of increasing awareness of HIV. The effect of media campaigns is short-lived indicating a need for constant reminder of the dangers of HIV infection. The increase in HIV testing occurs largely in the "worried well" with few additional HIV positive patients being identified.


Longer latency of sensory response to intravenous odor injection predicts olfactory neural disorder.
A near loss of smell may result from conductive and/or neural olfactory disorders. However, an olfactory test to selectively detect neural disorders has not been established. We investigated whether onset latency of sensory response to intravenous odor injection can detect neural disorders in humans and mice. We showed that longer preoperative onset latency of odor recognition to intravenous odor in patients with chronic rhinosinusitis predicted worse recovery of olfactory symptoms following sinus surgery. The onset latency of the olfactory sensory neuron (OSN) response to intravenous odor using synaptopHluorin signals from OSN axon terminals was delayed in mice with reduced numbers of OSNs (neural disorder) but not with increased mucus or blocked orthonasal pathways (conductive disorders). Moreover, the increase in onset latency correlated with the decrease in mature OSN numbers. Longer onset latency to intravenous odor injection is a useful biomarker for presence and severity of olfactory disorders with neural etiology.


Restless legs syndrome in multiple sclerosis.
Multiple sclerosis (MS) is a demyelinating neurodegenerative inflammatory autoimmune disease. Restless legs syndrome (RLS) is characterized as a strong urge to move the legs to stop abnormal sensations there. In this study, we aimed to investigate whether or not the increased RLS frequency seen in MS could be associated with depression and fatigue. The study involved 98 patients with definite MS and 129 healthy volunteers. The Beck Depression Inventory and Fatigue Severity Scale were used to assess all participants. The patients and the healthy volunteers were examined for RLS according to the criteria of the International Restless Legs Syndrome Study Group. When the factors related to RLS in MS were evaluated, there were significant relationships found among age, type of MS, pyramidal symptoms, intestinal and bladder symptoms, number of lesions in MR, depression, and fatigue. Risk factors for RLS were also seen more frequently in the MS group than in the healthy volunteers. RLS was seen 2.55 times more frequently in patients with MS than in the control group. This was due to the existence of numerous factors rather than a single factor - including depression and fatigue.


Can we respond mindfully to distressing voices? A systematic review of evidence for engagement, acceptability, effectiveness and mechanisms of change for mindfulness-based interventions for people distressed by hearing voices.
Adapted mindfulness-based interventions (MBIs) could be of benefit for people distressed by hearing voices. This paper presents a systematic review of studies exploring this possibility and we ask five questions: (1) Is trait mindfulness associated with reduced distress and disturbance in relation to hearing voices? (2) Are MBIs feasible for people distressed by hearing voices? (3) Are MBIs acceptable and safe for people distressed by hearing voices? (4) Are MBIs effective at reducing distress and disturbance in people distressed by hearing voices? (5) If effective, what are the mechanisms of change through which MBIs for distressing voices work? Fifteen studies were identified through a systematic search (n = 479). In relation to the five review questions: (1) data from cross-sectional studies showed an association between trait mindfulness and distress and disturbance in relation to hearing voices; (2) evidence from qualitative studies suggested that people distressed by hearing voices could engage meaningfully in mindfulness practice; (3) MBIs were seen as acceptable and safe; (4) there were no adequately powered RCTs allowing conclusions about effectiveness to be drawn; and (5) it was not possible to draw on robust empirical data to comment on potential mechanisms of change although findings from the qualitative studies identified three potential change processes; (i) reorientation of attention; (ii) decentring; and (iii) acceptance of voices. This review provided evidence that MBIs are engaging, acceptable, and safe. Evidence for effectiveness in reducing distress and disturbance is lacking however. We call for funding for adequately powered RCTs that will allow questions of effectiveness, maintenance of effects, mechanisms of change and moderators of outcome to be definitively addressed.


Effects of Early-Life Adversity on Hippocampal Structures and Associated HPA Axis Functions.
Early-life adversity (ELA) is one of the major risk factors for serious mental and physical health risks later in life. ELA has been associated with dysfunctional neurodevelopment, especially in brain structures such as the hippocampus, and with dysfunction of the stress system, including the hypothalamic-pituitary-adrenal (HPA) axis. Children who have experienced ELA are also more likely to suffer from mental health disorders such as depression later in life. The exact interplay of aberrant neurodevelopment and HPA axis dysfunction as risks for psychopathology is not yet clear. We investigated volume differences in the bilateral hippocampus and in stress-sensitive hippocampal subfields, behavior problems, and diurnal cortisol activity in 24 children who had experienced documented ELA (including out-of-home placement) in a circumscribed duration of adversity only in their first 3 years of life in comparison to data on 25 control children raised by their biological parents. Hippocampal volumes and stress-sensitive hippocampal subfields (Cornu ammonis [CA]1, CA3, and the granule-cell layer of the dentate gyrus [GCL-DG]) were significantly smaller in children who had experienced ELA, taking psychiatric diagnoses and dimensional psychopathological symptoms into account. ELA moderated the relationship between left hippocampal volume and cortisol: in the control group, hippocampal volumes were not related to diurnal cortisol, while in ELA children, a positive linear relationship between left hippocampal volume and diurnal cortisol was present. Our findings show that ELA is associated with altered development of the hippocampus, and an altered relationship between hippocampal volume and HPA axis activity in youth in care, even after they have lived in stable and caring foster family environments for years. Altered hippocampal development after ELA could thus be associated with a risk phenotype for the development of psychiatric disorders later in life.


[Kinematics of Stair Ascent in Children and Adolescents with Autism Spectrum Disorder].
We analyzed kinematics of stair ascent and descent in autistic children and adolescents in comparison with age-matched healthy children and adolescents. Eight healthy adolescents, 6 autistic adolescents, 7 healthy children and 6 autistic children participated in the study. We found that autistic subjects of both groups showed significantly more fluctuations of hip joint angular velocity than age-matched control subjects while preparing for stair ascent. During preparation for stair descent these velocity fluctuations appeared mainly in autistic adolescents, moreover, autistic children exhibited less velocity fluctuations than children in control group while preparing for stair descent. The kinematics of the movement itself demonstrated significantly less hip abduction in both autistic children and adolescents than in age-matched controls during stair ascent, and less ankle joint plantar extension in autistic adolescents than in healthy adolescents during stair descent. We suppose that age-related changes in kinematics of leg motion during stair ascent and descent in autistic patients indicate aggravated motor coordination in autistic adolescents as compared with both healthy adolescents and autistic children.


Gold manno-glyconanoparticles: multivalent systems to block HIV-1 gp120 binding to the lectin DC-SIGN.
The HIV envelope glycoprotein gp120 takes advantage of the high-mannose clusters on its surface to target the C-type lectin dendritic cell-specific intracellular adhesion molecule-3-grabbing non-integrin (DC-SIGN) on dendritic cells. Mimicking the cluster presentation of oligomannosides on the virus surface is a strategy for designing carbohydrate-based antiviral agents. Bio-inspired by the cluster presentation of gp120, we have designed and prepared a small library of multivalent water-soluble gold glyconanoparticles (manno-GNPs) presenting truncated (oligo)mannosides of the high-mannose undecasaccharide Man(9)GlcNAc(2) and have tested them as inhibitors of DC-SIGN binding to gp120. These glyconanoparticles are ligands for DC-SIGN, which also interacts in the early steps of infection with a large number of pathogens through specific recognition of associated glycans. (Oligo)mannosides endowed with different spacers ending in thiol groups, which enable attachment of the glycoconjugates to the gold surface, have been prepared. manno-GNPs with different spacers and variable density of mannose (oligo)saccharides have been obtained and characterized. Surface plasmon resonance (SPR) experiments with selected manno-GNPs have been performed to study their inhibition potency towards DC-SIGN binding to gp120. The tested manno-GNPs completely inhibit the binding from the micro- to the nanomolar range, while the corresponding monovalent mannosides require millimolar concentrations. manno-GNPs containing the disaccharide Manalpha1-2Manalpha are the best inhibitors, showing more than 20 000-fold increased activity (100 % inhibition at 115 nM) compared to the corresponding monomeric disaccharide (100 % inhibition at 2.2 mM). Furthermore, increasing the density of dimannoside on the gold platform from 50 to 100 % does not improve the level of inhibition.


Chondroitin-4-O-sulfatase from Bacteroides thetaiotaomicron: exploration of the substrate specificity.
Bacterial sulfatases can be good tools to increase the molecular diversity of glycosaminoglycan synthetic fragments. A chondroitin 4-O-sulfatase from the human commensal bacterium Bacteroides thetaiotaomicron has recently been identified and expressed. In order to use this enzyme for synthetic purposes, the minimal structure required for its activity has been determined. For that, four 4-O-sulfated monosaccharides and one 4-O-sulfated disaccharide have been synthesized and used as substrates with the sulfatase. The minimum structure was shown to be a disaccharide but in contrast to the natural substrate, which must have a 4,5-insaturation, the enzyme accepts as substrate, a disaccharide with a saturated glucuronic acid at the non-reducing end and even a glucopyranosyl moiety without the carboxylic acid functionality.


Deficiency in p53 is required for doxorubicin induced transcriptional activation of NF-кB target genes in human breast cancer.
NF-кB has been linked to doxorubicin resistance in breast cancer patients. NF-кB nuclear translocation and DNA binding in doxorubicin treated-breast cancer cells have been extensively examined; however its functional relevance at transcriptional level on NF-кB-dependent genes and the biological consequences are unclear. We studied NF-кB-dependent gene expression induced by doxorubicin in breast cancer cells and fresh human cancer specimens with different genetic backgrounds focusing on their p53 status. NF-кB-dependent signature of doxorubicin was identified by gene expression microarrays in breast cancer cells treated with doxorubicin and the IKKβ-inhibitor MLN120B, and confirmed ex vivo in human cancer samples. The association with p53 was functionally validated. Finally, NF-кB activation and p53 status was determined in a cohort of breast cancer patients treated with adjuvant doxorubicin-based chemotherapy. Doxorubicin treatment in the p53-mutated MDA-MB-231 cells resulted in NF-кB driven-gene transcription signature. Modulation of genes related with invasion, metastasis and chemoresistance (ICAM-1, CXCL1, TNFAIP3, IL8) were confirmed in additional doxorubicin-treated cell lines and fresh primary human breast tumors. In both systems, p53-deficient background correlated with the activation of the NF-кB-dependent signature. Furthermore, restoration of p53WT in the mutant p53 MDA-MB-231 cells impaired NF-кB driven transcription induced by doxorubicin. Moreover, a p53 deficient background and nuclear NF-кB/p65 in breast cancer patients correlated with reduced disease free-survival. This study supports that p53 deficiency is necessary for a doxorubicin driven NF-кB-response that limits doxorubicin cytotoxicity in breast cancer and is linked to an aggressive clinical behavior.


Near-infrared light-responsive nanomaterials for cancer theranostics.
Early diagnosis and effective cancer therapy are required, to properly treat cancer, which causes more than 8.2 million deaths in a year worldwide. Among various cancer treatments, nanoparticle-based cancer therapies and molecular imaging techniques have been widely exploited over the past decades to overcome current drawbacks of existing cancer treatments. In particular, gold nanoparticles (AuNPs), carbon nanotubes (CNTs), graphene oxide (GO), and upconversion nanocrystals (UNCs) have attracted tremendous attention from researchers due to their near-infrared (NIR) light-responsive behaviors. These nanomaterials are considered new multifunctional platforms for cancer theranostics. They would enable on-demand control of drug release or molecular imaging in response to a remote trigger by NIR light exposure. This approach allows the patient or physician to adjust therapy precisely to a target site, thus greatly improving the efficacy of cancer treatments, while reducing undesirable side effects. In this review, we have summarized the advantages of NIR light-responsive nanomaterials for in vivo cancer treatments, which includes NIR triggered photothermal therapy (PTT) and photodynamic therapy (PDT). Furthermore, recent developments, perspectives, and new challenges of NIR light-responsive nanomaterials are discussed for cancer theranostic applications.


Potentially fatal new trend in performance enhancement: a cautionary note on nitrite.
Considerable interest has been shown by athletes and scientists in the potential for nitric oxide and associated vasodilators to enhance performance. This study aims to explore potential misuse of vasodilators by the athletes, and to highlight the growing concern over these agents. Retrospective analyses of anonymous inquiries recorded in the Drug Information Database (DID) between January 2006 and June 2008 (inclusive). In this 30-month period, the DID recorded 198,023 inquiries, of which 118,724 were UK Licensed Pharmaceutical products with a further 79,299 inquiries made for substance not found in the database. Phosphodiesterase type 5 (PDE-5) inhibitors, dominated by Viagra(R), ranked 16th among the substance groups. The proportion of the inquiries made regarding PDE-5 inhibitors, especially in comparison to antibiotics, painkillers or alcohol, appears to be above the level that would normally be expected from medical need. No significant change in the months leading up to the Beijing Olympics was observed. On the contrary, the Nitric/Nitrate group showed a notable increase between 2006-2007 and 2008, suggesting a potential increase in interest in using nitric oxide among athletes. With patents recently filed for the use of agents containing sodium nitrite/nitrate to enhance blood flow for performance enhancement in sport, coupled with anecdotal evidence from internet athlete forums and media, there is a concern that athletes may endanger their health by using vasodilators to enhance athletic performance. PDE-5 inhibitors or chemicals in the nitrate/nitrate group are currently not prohibited or tested for by the doping control agencies but some are highly dangerous to health and can lead to cardiovascular collapse, coma and death. Its promotion among athletes as a performance enhancing supplement is ethically and medically questionable.


Stereotactic irradiation therapy. Physical and dosimetric problems.
In stereotactic irradiation by external beams there are many problems involved with dosimetry of small fields, three-dimensional representation of dose distribution, radiobiological involvement of tissue response to total dose and fractionation. Dosimetric problems arise by critical dimension of dosimetric chambers and by difficulties of films calibration. The amount of data required for a correct three-dimensional simulation of isodose curves, tumor and anatomical structures require a very speed computer system, sophisticated computer graphic techniques and calculation algorithm. By use the linear quadratic model of cell survival, maps of combined dose and biological effect (isoeffect curves) are also obtained.


The frequency and duration of Salmonella-macrophage adhesion events determines infection efficiency.
Salmonella enterica causes a range of important diseases in humans and a in a variety of animal species. The ability of bacteria to adhere to, invade and survive within host cells plays an important role in the pathogenesis of Salmonella infections. In systemic salmonellosis, macrophages constitute a niche for the proliferation of bacteria within the host organism. Salmonella enterica serovar Typhimurium is flagellated and the frequency with which this bacterium collides with a cell is important for infection efficiency. We investigated how bacterial motility affects infection efficiency, using a combination of population-level macrophage infection experiments and direct imaging of single-cell infection events, comparing wild-type and motility mutants. Non-motile and aflagellate bacterial strains, in contrast to wild-type bacteria, collide less frequently with macrophages, are in contact with the cell for less time and infect less frequently. Run-biased Salmonella also collide less frequently with macrophages but maintain contact with macrophages for a longer period of time than wild-type strains and infect the cells more readily. Our results suggest that uptake of S. Typhimurium by macrophages is dependent upon the duration of contact time of the bacterium with the cell, in addition to the frequency with which the bacteria collide with the cell.


The paired basic amino acid-cleaving enzyme 4 (PACE4) is involved in the maturation of insulin receptor isoform B: an opportunity to reduce the specific insulin receptor-dependent effects of insulin-like growth factor 2 (IGF2).
Gaining the full activity of the insulin receptor (IR) requires the proteolytic cleavage of its proform by intra-Golgi furin-like activity. In mammalian cells, IR is expressed as two isoforms (IRB and IRA) that are responsible for insulin action. However, only IRA transmits the growth-promoting and mitogenic effects of insulin-like growth factor 2. Here we demonstrate that the two IR isoforms are similarly cleaved by furin, but when this furin-dependent maturation is inefficient, IR proforms move to the cell surface where the proprotein convertase PACE4 selectively supports IRB maturation. Therefore, in situations of impaired furin activity, the proteolytic maturation of IRB is greater than that of IRA, and accordingly, the amount of phosphorylated IRB is also greater than that of IRA. We highlight the ability of a particular proprotein convertase inhibitor to effectively reduce the maturation of IRA and its associated mitogenic signaling without altering the signals emanating from IRB. In conclusion, the selective PACE4-dependent maturation of IRB occurs when furin activity is reduced; accordingly, the pharmacological inhibition of furin reduces IRA maturation and its mitogenic potential without altering the insulin effects.


Lengthening With Monolateral External Fixation Versus Magnetically Motorized Intramedullary Nail in Congenital Femoral Deficiency.
Limb lengthening for congenital femoral deficiency (CFD) with or without fibular hemimelia can be performed with both external and internal devices. The purpose of this study is to compare clinical outcomes of femoral lengthening utilizing monolateral external fixation versus a magnetically motorized intramedullary nail in patients with CFD with or without fibular hemimelia. This retrospective review included 62 patients with femoral lengthening, 32 patients had monolateral external fixation (group A), 30 patients had internal lengthening nail (group B). Mean age in years was 9.4±3.8 and 15.4±4.9 for groups A and B, respectively. Mean follow-up in years was 4.47±2.7 and 1.86±0.7 years for groups A and B, respectively. Mean lengthening achieved was 5.6±1.7 and 4.8±1.4 cm for group A and group B, respectively (P=0.052). Mean distraction index was 0.7±0.2 mm/d for group A and 0.7±0.2 mm/d for the group B (P=0.99). Mean consolidation index for group A was 29.3±12.7 and 34.8±11.2 d/cm for group B (P=0.08). Mean arc of motion before surgery and at final follow-up were similar between groups (P=0.35). Group A had significantly less range of motion at the end of distraction (P=0.0007) and at consolidation (P<0.0001). Both groups had similar rates of obstacles and complications. A significant difference between groups was found in the total problems (P<0.001) specifically with pin site/superficial infection (P<0.0001). The intramedullary nail had superior range of motion during the lengthening phase and at consolidation and an overall lower problem complication rate, while maintaining similar distraction and healing indices to monolateral external fixation. Internal lengthening nails represent a significant advance in technology for CFD lengthening. Level IV-therapeutic.


Prevalence and clinical implications of interactive toxicity beliefs regarding mixing alcohol and antiretroviral therapies among people living with HIV/AIDS.
Alcohol use is a barrier to medication adherence. Beyond the cognitive effects of intoxication, people living with HIV/AIDS who believe that alcohol should not be mixed with their medications may temporarily stop taking medications when drinking. To examine the effects of alcohol-treatment beliefs on HIV treatment adherence. People living with HIV/AIDS who were receiving treatment (n = 145) were recruited from community and clinical services during the period between January 2006 and May 2008 to complete measures of substance use and alcohol-antiretroviral (ARV) interactive toxicity beliefs (e.g., alcohol breaks down HIV medications so they will not work). Medication adherence was monitored using unannounced telephone-based pill counts. Forty percent of participants were currently using alcohol and nearly one in four drinkers reported stopping their medications when drinking. Beliefs that mixing alcohol and medications is toxic were common among drinkers and nondrinkers, with most beliefs endorsed more frequently by non-drinkers. Hierarchical regression analysis showed that stopping ARVs when drinking was associated with treatment nonadherence over and above quantity/frequency of alcohol use and problem drinking. Beliefs that alcohol and ARVs should not be mixed and that treatments should be interrupted when drinking are common among people living with HIV/AIDS. Clinicians should educate patients about the necessity of continuing to take ARV medications without interruption even if they are drinking alcohol.


Immunocytochemical evidence for centrosomal phosphoproteins in mitotic sea urchin eggs.
The change in distribution of centrosomal phosphoproteins was examined in sea urchin eggs from fertilization to the first cleavage by immunofluorescence staining with the anti-phosphoprotein antibodies, MPM-1 and MPM-2. The antibodies reacted with female pronuclei in unfertilized eggs as well as centriolar complexes located at the base of sperm flagella. After insemination, male and female pronuclei fused together to form a zygotic nucleus which was visualized by staining of fertilized eggs with the antiphosphoprotein antibodies. No major change in staining pattern was detected in extracted whole eggs until mitosis. As the fertilized eggs approached mitosis, however, the antigens started to redistribute from nuclei to the perinuclear position where the mitotic centrosomes were located. Detailed immunofluorescence observation of isolated spindles revealed that the phosphoantigens were retained in isolated structures. A major 225 kd polypeptide was recognized by the antibodies, suggesting that the 225 kd protein is a phosphocomponent of centrosomes. The area recognized by the antibody in mitotic poles enlarged with the progress of mitosis, suggesting that the antigens were apparently localized in the centrosphere. Centrospheres prepared from isolated spindles by salt extraction strongly reacted with the antibodies. One or two bright dots, which may represent centrioles, were visible in the isolated centrosphere. At the end of mitosis, the antigens again appeared in the newly formed daughter nuclei. Centriole-containing cytasters and centriole-free monasters were parthenogenetically induced in unfertilized eggs (Kuriyama and Borisy, (1983) J. Cell Sci. 61: 175-189). The antibodies stained centers of both the asters whether they contained centrioles or not, indicating that the antibodies recognizes the components of the pericentriolar material.


Serotonin Injections Induce Metamorphosis in Larvae of the Gastropod Mollusc Ilyanassa obsoleta.
Bath-applied serotonin (5-HT) induces competent larvae of the marine snail Ilyanassa obsoleta to metamorphose. Previously, the mode of action of 5-HT, whether as an external ligand or as an internal neurotransmitter, was unknown. Larvae were injected with 10-4 M 5-HT and other pharmacological agents to provide evidence that serotonergic neurons are necessary for metamorphosis in Ilyanassa larvae and that serotonin functions as a neurotransmitter or neuromodulator during this process. About 50% of 5-HT-injected animals metamorphose within 48 hours. Fluoxetine, a 5-HT reuptake inhibitor, and alpha-methyl-5-hydroxytryptamine (αm5HT), a 5-HT agonist, were also effective inducers of metamorphosis. Gramine (3-[dimethylaminomethyl]indole), a 5-HT antagonist, inhibited the inductive activity of 5-HT, while the amino acid gammaaminobutyric acid (GABA) resulted in rates of morphological restructuring similar to those of controls. Collectively, the results of our experiments support the idea that serotonergic neurons are active during larval metamorphosis of Ilyanassa and that 5-HT does not induce metamorphosis by binding to epidermal chemoreceptors.


Assessment and management of agitation in the elderly.
The management of agitated behavior in the elderly represents one of the major challenges in geriatric medicine. Inappropriate verbal, vocal, or motor activity often results in problem behavior that burdens caregivers or nursing home staff. A careful differential diagnostic approach to agitated behavior is imperative to avoid misdiagnosis. The misuse of psychoactive drugs often begins with an unclear idea of the underlying pathophysiology. Treatment should be combined with an explicit establishment of therapeutic goals and a precise understanding of the pharmacological profiles of commonly used drugs.


Pregnancy wantedness and adverse pregnancy outcomes: differences by race and Medicaid status.
The relationship between pregnancy wantedness and adverse pregnancy outcomes was studied using data from 2,828 mothers who participated in the Missouri Maternal and Infant Health Survey. The wantedness of a pregnancy was measured using traditional classifications of mistimed and unwanted, as well as additional measures gauging how the woman felt about the pregnancy while she was pregnant. Fifty-eight percent of the very low birth weight infants and 59% of the moderately low birth weight infants resulted from unintended pregnancies, as did 62% of the normal-birth-weight infants. Logistic regression showed that mothers of very low birth weight infants were significantly more likely than those who had a normal-weight baby to report that they had felt unhappy about the pregnancy (odds ratio of 1.53). Very low birth weight was also associated with early denial of the pregnancy (1.54). Odds ratios associating these two unwantedness categories with low-birth-weight babies were higher among Medicaid recipients than among women not receiving Medicaid. Associations between very low birth weight and the denial variable were also significant among white women when very low birth weight outcomes were compared with normal outcomes, but there was no significant association among black women. There were no significant associations between low birth weight and the traditional unwantedness variables.


Recommendations in pre-registrations and internal review board proposals promote formal power analyses but do not increase sample size.
In this preregistered study, we investigated whether the statistical power of a study is higher when researchers are asked to make a formal power analysis before collecting data. We compared the sample size descriptions from two sources: (i) a sample of pre-registrations created according to the guidelines for the Center for Open Science Preregistration Challenge (PCRs) and a sample of institutional review board (IRB) proposals from Tilburg School of Behavior and Social Sciences, which both include a recommendation to do a formal power analysis, and (ii) a sample of pre-registrations created according to the guidelines for Open Science Framework Standard Pre-Data Collection Registrations (SPRs) in which no guidance on sample size planning is given. We found that PCRs and IRBs (72%) more often included sample size decisions based on power analyses than the SPRs (45%). However, this did not result in larger planned sample sizes. The determined sample size of the PCRs and IRB proposals (Md = 90.50) was not higher than the determined sample size of the SPRs (Md = 126.00; W = 3389.5, p = 0.936). Typically, power analyses in the registrations were conducted with G*power, assuming a medium effect size, α = .05 and a power of .80. Only 20% of the power analyses contained enough information to fully reproduce the results and only 62% of these power analyses pertained to the main hypothesis test in the pre-registration. Therefore, we see ample room for improvements in the quality of the registrations and we offer several recommendations to do so.


Association of HO-1 and BRCA1 Is Critical for the Maintenance of Cellular Homeostasis in Prostate Cancer.
Prostate cancer is the second leading cause of cancer-related death in men worldwide. Many factors that participate in the development of prostate cancer promote imbalance in the redox state of the cell. Accumulation of reactive oxygen species causes injury to cell structures, ultimately leading to cancer development. The antioxidant enzyme heme oxygenase 1 (HMOX1/HO-1) is responsible for the maintenance of the cellular homeostasis, playing a critical role in the oxidative stress and the regulation of prostate cancer development and progression. In the present study, the transcriptional regulation of HO-1 was investigated in prostate cancer. Interestingly, the tumor suppressor BRCA1 binds to the HO-1 promoter and modulates HO-1, inducing its protein levels through both the increment of its promoter activity and the induction of its transcriptional activation. In addition, in vitro and in vivo analyses show that BRCA1 also controls HO-1-negative targets: MMP9, uPA, and Cyclin D1. HO-1 transcriptional regulation is also modulated by oxidative and genotoxic agents. Induction of DNA damage by mitoxantrone and etoposide repressed HO-1 transcription, whereas hydrogen peroxide and doxorubicin induced its expression. Xenograft studies showed that HO-1 regulation by doxorubicin also occurs in vivo. Immunofluorescence analysis revealed that BRCA1 overexpression and/or doxorubicin exposure induced the cytoplasmic retention of HO-1. Finally, the transcription factor NRF2 cooperates with BRCA1 protein to activate HO-1 promoter activity. In summary, these results show that the activation of BRCA1-NRF2/HO-1 axis defines a new mechanism for the maintenance of the cellular homeostasis in prostate cancer. Oxidative and genotoxic stress converge on HO-1 transcriptional activity through the combined actions of BRCA1 and NRF2.


Combined Endosonographic Mediastinal Lymph Node Staging in Positron Emission Tomography and Computed Tomography Node-Negative Non-Small-Cell Lung Cancer in High-Risk Patients.
Positron emission tomography (PET) with computed tomography (CT) is routinely utilized to investigate lymph node (LN) metastases in non-small-cell lung cancer. However, it is less sensitive in normal-sized LNs. This study was performed in order to define the prevalence of mediastinal LN metastases discovered on combined endosonography by endobronchial ultrasound (EBUS) and endoscopic ultrasound (EUS) fine needle aspiration in patients with a radiologically normal mediastinum. This study consists of a retrospective, single-institution, tertiary care referral center review of a prospectively maintained database. Patients were identified from a cohort between January 2009 and December 2014. One hundred and sixty-one patients with biopsy-proven, non-small-cell lung cancer were identified in whom both the preendosonography CT and PET-CT were negative for mediastinal LN metastases. Combined endosonography (EBUS + EUS-FNA) was performed in all patients. Z test was used for statistical analysis. A P value of <0.05 was considered statistically significant. A total of 161 consecutive patients were included. Patients were staged if they had central tumor, tumor size >3 cm, N1 lymph node involvement on PET-CT/CT, or if there was low SUV (<2.5) in the primary tumor. A total of 416 lymph nodes were biopsied in the 161 patients using combined endosonography; 147 with EBUS and 269 with EUS. Mean and median number of lymph nodes biopsied per patient using combined EBUS/EUS was 2.5 and 3, respectively (mean and median EBUS: 0.91 and 2.5; mean and median EUS 1.6 and 3). Endosonographic staging upstaged 13% of patients with radiologically normal lymph nodes in the mediastinum, hilum, lobar, and sublobar regions (confidence interval 8.22-19.20). Twenty-one out of 161 patients (13%) with radiologically normal mediastinum were positive on combined EBUS/EUS staging. Out of 21 patients upstaged on endosonography, 15 (71%) had tumor size >3 cm. Six (28%) had occult N1 disease. Thirteen (61%) had occult N2 disease and 2 (9%) had adrenal involvement. None of the upstaged patients had N1 LN involvement on PET-CT or CT scan. Combined endosonographic lymph node staging should be considered in the pretreatment staging of high-risk patients with non-small-cell lung cancer in the presence of radiologically normal mediastinal lymph nodes due to the significant rate of radiologically occult lymph node metastases.


The Effect Of Labor Unions On Nursing Home Compliance With OSHA's Workplace Injury And Illness Reporting Requirement.
All US nursing homes are required to report workplace injury and illness data to the Occupational Safety And Health Administration (OSHA). Nevertheless, the compliance rate for US nursing homes during the period 2016-21 was only 40 percent. We examined whether unionization increases the probability that nursing homes will comply with that requirement. Using a difference-in-differences design and proprietary data on union status from the Service Employees International Union for all forty-eight continental US states from the period 2016-21, we found that two years after unionization, nursing homes were 31.1 percentage points more likely than nonunion nursing homes to report workplace injury and illness data to OSHA. Data on injuries occurring in specific workplaces play a central role in injury prevention. Further unionization could help improve workplace safety in nursing homes, a sector with one of the highest occupational injury and illness rates in the US.


[Physiologic particularities of muscle impairments in the patient with COPD].
Patients with chronic obstructive pulmonary disease (COPD) frequently have skeletal muscle dysfunction, of either respiratory muscles or those located of the limbs. This dysfunction may appear even at relatively early stages and it conditions symptoms and patient's quality of life. In the case of respiratory muscles, factors that seem to determine muscle dysfunction are, particularly, changes in thorax configuration and an unbalance between decreased energy availability and increased energy demands by the muscle. However, respiratory muscles show signs of structural and metabolic adaptation to this situation, partially compensating the above-mentioned deleterious effects. However, at muscles of the limbs, particularly of the lower limbs, dysfunction seems to be essentially due to deconditioning by physical activity reduction. Structural changes in these muscles are involutional in nature. At both respiratory and peripheral muscles, other factors such as nutritional impairments, inflammation, oxidative stress, some drugs, and the presence of comorbidity seem to play a relevant role. All of them will condition both dysfunction and structural changes, which will be heterogeneous for the different muscle groups in each patient.


Axonal regeneration and synapse formation in the superior colliculus by retinal ganglion cells in the adult rat.
In adult rats, one optic nerve was transected and replaced by a 4 cm segment of autologous peripheral nerve (PN) that linked one eye and the superior colliculus (SC) along a predominantly extracranial course. Retrograde and orthograde studies with the tracers HRP or rhodamine-B-isothiocyanate (RITC), as well as immunocytochemical neuronal labels, indicated the following: (1) Regenerating axons from the axotomized retinal ganglion cells extended along the entire PN grafts, covering a distance nearly twice that of the normal retinotectal projection of intact rats. (2) Some of these axons penetrated the SC and formed terminal arborizations up to 500 microns from the end of the graft. (3) By electron microscopy, the arborizations of these regenerated axons in the SC were seen as small HRP-labeled axonal profiles that contacted neuronal processes in the SC; some of these contacts showed pre- and postsynaptic membrane specializations. These findings indicate that injured retinal ganglion cells in the adult rat are not only able to regrow lengthy axons, but may also form synapses in the SC.


Coarse-to-Fine Contrastive Learning on Graphs.
Inspired by the impressive success of contrastive learning (CL), a variety of graph augmentation strategies have been employed to learn node representations in a self-supervised manner. Existing methods construct the contrastive samples by adding perturbations to the graph structure or node attributes. Although impressive results are achieved, it is rather blind to the wealth of prior information assumed: with the increase of the perturbation degree applied on the original graph: 1) the similarity between the original graph and the generated augmented graph gradually decreases and 2) the discrimination between all nodes within each augmented view gradually increases. In this article, we argue that both such prior information can be incorporated (differently) into the CL paradigm following our general ranking framework. In particular, we first interpret CL as a special case of learning to rank (L2R), which inspires us to leverage the ranking order among positive augmented views. Meanwhile, we introduce a self-ranking paradigm to ensure that the discriminative information among different nodes can be maintained and also be less altered to the perturbations of different degrees. Experiment results on various benchmark datasets verify the effectiveness of our algorithm compared with the supervised and unsupervised models.


Implementation and evaluation of a palliative care resource scheme within a district general hospital.
This article explores the development, implementation and evaluation of a palliative care resource scheme in a district general hospital in Mid Gamorgan, Wales. The evolution of the resource scheme and how the hospital specialist palliative care team identified the need for improved patient care on hospital wards is discussed, in addition to how using their specialist role combined with education can implement change. The project evolved from initially recruiting two nurses on an in-house educational programme, to what has since become a formal arrangement with the local university, whereby students can access taught palliative care modules at degree and diploma levels as part of a distance learning degree in cancer care and a distance learning post- graduate certificate in palliative care. The resource enhances the knowledge of the practitioners who have completed it and also formalizes and expands the working links between education and clinical practice. It is hoped to continue and develop the scheme to further enhance the collaborative partnerships.


Peripheral nervous system in the larynx. An anatomical study of the motor, sensory and autonomic nerve fibers.
The laryngeal peripheral nervous system is presented on the basis of our results in the cat, following 10 years of investigation using mainly tracer techniques. The present paper focused on the localization of each laryngeal motoneuron, the myotopical arrangements of motoneurons innervating the pharyngeal and esophageal striated muscles within the nucleus ambiguus in the motor nerve supply, and also on the location of neurons, the distribution and density of nerve fibers, the area and laterality of the innervation, and the pathway to the larynx in the sensory and sympathetic nerve supplies. Regarding the parasympathetic nerve supply, the neural ganglia and the ganglionic cells in and around the laryngeal nerves and in the laryngeal framework are demonstrated. Most of this innervation, however, is still unclear. Discussions from the literature are also reported.


Ankle fractures of the geriatric patient: a narrative review.
The present narrative review provides a summary of current concepts for the treatment of ankle fractures in elderly patients. Despite a high complication rate, open reduction and internal fixation is the gold standard for operative care. However, individual patient-based treatment decision considering the soft-tissue status, the fracture pattern, as well as the patient's mobility and comorbidities is mandatory to achieve sufficient patient outcomes. Due to high complication rates after surgery in the past, techniques such as fibular nails or minimal invasive techniques should be considered.


Transbronchial Lung Cryobiopsy in Idiopathic Pulmonary Fibrosis: A State of the Art Review.
Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease associated with significant morbidity and mortality. The diagnosis of IPF involves a combination of clinical history, radiological imaging and examination of histopathological samples in appropriate cases. Historically, transbronchial biopsy (TBB) has been used to obtain histological samples; however this lacks diagnostic accuracy. At present, surgical lung biopsy (SLB) is the gold standard technique for obtaining specimen samples; however this carries a significant mortality risk. Transbronchial lung cryobiopsy (TBLC) is a new technique that has been pioneered in the management of lung malignancy and offers a potential alternative to SLB. The technique employs a freezing probe, which is used to obtain lung tissue samples that are larger and better quality than traditional TBB samples. This affords TBLC an estimated diagnostic yield of 80% in interstitial lung disease. However, with limited evidence directly comparing TBLC to SLB, the diagnostic accuracy of the procedure has been uncertain. Common complications of TBLC include pneumothorax and bleeding. Mortality in TBLC is low compared with SLB, with exacerbation of IPF frequently reported as the cause. TBLC represents an exciting potential option in the diagnostic pathway in IPF; however its true value has yet to be determined.


One hundred years of growth: the evolution of height, mass, and body composition in Australian children, 1899-1999.
This paper summarizes 41 reports on the height and mass of Australian children aged between 5.00 and 16.99 years between 1899 and 1999. In all, data on 644,613 children were collated, including individual data on 68,196 children. After primary data treatment to correct for methodological and statistical artifacts, regressions were calculated to quantify the rate of change of height and mass over time. Distributional analysis was used to probe for changes in skewness of mass values, indicative of differentially greater increases at higher percentiles. In addition, studies reporting skin fold measurements were analyzed to assess changes in subcutaneous adiposity since 1976. The results show that height has been increasing at a rate of about 1.02 cm.decade(-1), and mass at a rate of about 0.99 kg.decade(-1). The height and mass of children continue to increase, after a slowing down in the rate of increase between 1950 and 1980. Increases in mass at the higher percentiles have been much greater than at lower percentiles, particularly since the mid-1980s, suggesting that the incidence of obesity is increasing in Australian children. Furthermore, a steady linear increase in subcutaneous skin fold thicknesses since 1976 suggests that the overall level of fatness is increasing in Australian children. These findings indicate that Australian children are following trends becoming evident elsewhere in the developed world, and that we may see an increasingly large subset of increasingly obese children in the early years of the 21st century.