[The value of adjuvant irradiation in patients with cervical carcinoma in histopathological stage Ib and negative lymph nodes].
The present retrospective study attempts to evaluate the significance of adjuvant radiotherapy as a prognostic factor for stage Ib cervical carcinoma without lymph node metastases in addition to factors such as age, histological type, histological grading and tumor size. Between 1975 and 1987 224 patients were operated at our department or referred to postoperative radiotherapy and fulfilled the inclusion criteria: histopathological stage Ib, radical hysterectomy with pelvic lymphadenectomy and negative pelvic lymph nodes. The multivariate analysis confirmed that tumor size (tumor infiltration of the cervix greater than 2/3 vs less than 2/3: RR = 4.48) and histological grading (G3 vs G1 + G2: RR = 3.12) are significant prognostic parameters for survival. Postoperative adjuvant irradiation is a marginal significant factor for survival in stage Ib cervical carcinoma and negative nodes (RR = 3.22; p = 0.057). For women with negative nodes but high-risk prognostic factors in the cervix, a prospective randomized trial proving the value of postoperative irradiation would be of therapeutic interest.


Double-dose versus standard-dose clopidogrel and high-dose versus low-dose aspirin in individuals undergoing percutaneous coronary intervention for acute coronary syndromes (CURRENT-OASIS 7): a randomised factorial trial.
Clopidogrel and aspirin are the most commonly used antiplatelet therapies for percutaneous coronary intervention (PCI). We assessed the effect of various clopidogrel and aspirin regimens in prevention of major cardiovascular events and stent thrombosis in patients undergoing PCI. The CURRENT-OASIS 7 trial was undertaken in 597 centres in 39 countries. 25,086 individuals with acute coronary syndromes and intended early PCI were randomly assigned to double-dose (600 mg on day 1, 150 mg on days 2-7, then 75 mg daily) versus standard-dose (300 mg on day 1 then 75 mg daily) clopidogrel, and high-dose (300-325 mg daily) versus low-dose (75-100 mg daily) aspirin. Randomisation was done with a 24 h computerised central automated voice response system. The clopidogrel dose comparison was double-blind and the aspirin dose comparison was open label with blinded assessment of outcomes. This prespecified analysis is of the 17,263 individuals who underwent PCI. The primary outcome was cardiovascular death, myocardial infarction, or stroke at 30 days. Analyses were by intention to treat, adjusted for propensity to undergo PCI. This trial is registered with ClinicalTrials.gov, number NCT00335452. 8560 patients were assigned to double-dose and 8703 to standard-dose clopidogrel (8558 and 8702 completed 30-day follow-up, respectively), and 8624 to high-dose and 8639 to low-dose aspirin (8622 and 8638 completed 30-day follow-up, respectively). Compared with the standard dose, double-dose clopidogrel reduced the rate of the primary outcome (330 events [3·9%] vs 392 events [4·5%]; adjusted hazard ratio 0·86, 95% CI 0·74-0·99, p=0·039) and definite stent thrombosis (58 [0·7%] vs 111 [1·3%]; 0·54 [0·39-0·74], p=0·0001). High-dose and low-dose aspirin did not differ for the primary outcome (356 [4·1%] vs 366 [4·2%]; 0·98, 0·84-1·13, p=0·76). Major bleeding was more common with double-dose than with standard-dose clopidogrel (139 [1·6%] vs 99 [1·1%]; 1·41, 1·09-1·83, p=0·009) and did not differ between high-dose and low-dose aspirin (128 [1·5%] vs 110 [1·3%]; 1·18, 0·92-1·53, p=0·20). In patients undergoing PCI for acute coronary syndromes, a 7-day double-dose clopidogrel regimen was associated with a reduction in cardiovascular events and stent thrombosis compared with the standard dose. Efficacy and safety did not differ between high-dose and low-dose aspirin. A double-dose clopidogrel regimen can be considered for all patients with acute coronary syndromes treated with an early invasive strategy and intended early PCI. Sanofi-Aventis and Bristol-Myers Squibb.


Peptide-nanoparticle ligation mediated by cutinase fusion for the development of cancer cell-targeted nanoconjugates.
The relationship between the positioning of ligands on the surface of nanoparticles and the structural features of nanoconjugates has been underestimated for a long time, albeit of primary importance to promote specific biological recognition at the nanoscale. In particular, it has been formerly observed that a proper molecular orientation can play a crucial role, first optimizing ligand immobilization onto the nanoparticles and, second, improving the targeting efficiency of the nanoconjugates. In this work, we present a novel strategy to afford peptide-oriented ligation using genetically modified cutinase fusion proteins, which combines the presence of a site-directed "capture" module based on an enzymatic unit and a "targeting" moiety consisting of the ligand terminal end of a genetically encoded polypeptide chain. As an example, the oriented presentation of U11 peptide, a sequence specific for the recognition of urokinase plasminogen activator receptor (uPAR), was achieved by enzyme-mediated conjugation with an irreversible inhibitor of cutinase, an alkylphosphonate p-nitrophenol ester linker, covalently bound to the surface of iron oxide nanoparticles. The targeting efficiency of the resulting protein-nanoparticle conjugates was assessed using uPAR-positive breast cancer cells exploiting confocal laser scanning microscopy and quantitative fluorescence analysis of confocal images. Ultrastructural analysis of transmission electron micrographs provided evidence of a receptor-mediated pathway of endocytosis. Our results showed that, despite the small average number of targeting peptides presented on the nanoparticles, our ligand-oriented nanoconjugates proved to be very effective in selectively binding to uPAR and in promoting the uptake in uPAR-positive cancer cells.


Task-oriented interventions for children with developmental co-ordination disorder.
Developmental co-ordination disorder (DCD) is a common childhood disorder, which can persist into adolescence and adulthood. Children with DCD have difficulties in performing the essential motor tasks required for self-care, academic, social and recreational activities. To assess the effectiveness of task-oriented interventions on movement performance, psychosocial functions, activity, and participation for children with DCD and to examine differential intervention effects as a factor of age, sex, severity of DCD, intervention intensity, and type of intervention. In March 2017, we searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, 13 other databases, and five trials registers. We also searched reference lists, and contacted members of the mailing list of the International Conference on DCD to identify additional studies. We included all randomised controlled trials (RCTs) and quasi-RCTs that compared the task-oriented intervention with either an inactive control intervention or an active control intervention in children and adolescents aged four to 18 years with a diagnosis of DCD.Types of outcome measures included changes in motor function, as assessed by standardised performance outcome tests and questionnaires; adverse events; and measures of participation. All review authors participated in study selection, data extraction, and assessments of risk of bias and quality, and two review authors independently performed all tasks. Specifically, two review authors independently screened titles and abstracts to eliminate irrelevant studies, extracted data from the included studies, assessed risk of bias, and rated the quality of the evidence using the GRADE approach. In cases of ambiguity or information missing from the paper, one review author contacted trial authors. This review included 15 studies (eight RCTs and seven quasi-RCTs). Study characteristicsThe trials included 649 participants of both sexes, ranging in age from five to 12 years.The participants were from Australia, Canada, China, Sweden, Taiwan, and the UK.Trials were conducted in hospital settings; at a university-based clinic, laboratory, or centre; in community centres; at home or school, or both at home and school.The durations of task-oriented interventions were mostly short term (less than six months), with the total number of sessions ranging from five to 50. The length of each session ranged from 30 to 90 minutes, and the frequencies ranged from once to seven times per week.We judged the risk of bias as moderate to high across the studies. Some elements were impossible to achieve (such as blinding of administering personnel or participants). primary outcomesA meta-analysis of two RCTs and four quasi-RCTs found in favour of task-oriented interventions for improved motor performance compared to no intervention (mean difference (MD) -3.63, 95% confidence interval (CI) -5.88 to -1.39; P = 0.002; I2 = 43%; 6 trials, 169 children; very low-quality evidence).A meta-analysis of two RCTs found no effect of task-oriented interventions for improved motor performance compared to no intervention (MD -2.34, 95% CI -7.50 to 2.83; P = 0.38; I2 = 42%; 2 trials, 51 children; low-quality evidence).Two studies reported no adverse effects or events. Through personal correspondence, the authors of nine studies indicated that no injuries had occurred. secondary outcomesDue to the limited number of studies with complete and consistent data, we were unable to perform any meta-analyses on our secondary measures or any subgroup analysis on age, sex, severity of DCD, and intervention intensity. We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect. The conclusions drawn from previous reviews, which unanimously reported beneficial effects of intervention, are inconsistent with our conclusions. This review highlights the need for carefully designed and executed RCTs to investigate the effect of interventions for children with DCD.


A Unified Description of Intrinsically Disordered Protein Dynamics under Physiological Conditions Using NMR Spectroscopy.
Intrinsically disordered proteins (IDPs) are flexible biomolecules whose essential functions are defined by their dynamic nature. Nuclear magnetic resonance (NMR) spectroscopy is ideally suited to the investigation of this behavior at atomic resolution. NMR relaxation is increasingly used to detect conformational dynamics in free and bound forms of IDPs under conditions approaching physiological, although a general framework providing a quantitative interpretation of these exquisitely sensitive probes as a function of experimental conditions is still lacking. Here, measuring an extensive set of relaxation rates sampling multiple-time-scale dynamics over a broad range of crowding conditions, we develop and test an integrated analytical description that accurately portrays the motion of IDPs as a function of the intrinsic properties of the crowded molecular environment. In particular we observe a strong dependence of both short-range and long-range motional time scales of the protein on the friction of the solvent. This tight coupling between the dynamic behavior of the IDP and its environment allows us to develop analytical expressions for protein motions and NMR relaxation properties that can be accurately applied over a vast range of experimental conditions. This unified dynamic description provides new insight into the physical behavior of IDPs, extending our ability to quantitatively investigate their conformational dynamics under complex environmental conditions, and accurately predicting relaxation rates reporting on motions on time scales up to tens of nanoseconds, both in vitro and in cellulo.


Effect of pH and human saliva on protease production by Candida albicans.
The elaboration of extracellular proteolytic activity by Candida albicans during growth in laboratory broth or in human whole salivary supernatant was investigated. Growth of the organism in broth at pH 3 to 7 followed by assay of culture supernatants at pH 4 (optimum for activity) indicated protease was only present in cultures grown at a pH of less than 5. In contrast, growth in sterile human whole salivary supernatant over the pH range of 3 to 7 uniformly failed to result in production of protease. Growth of the organism at pH 4 in broth supplemented with saliva resulted in a saliva-dependent inhibition of protease production. Although the addition of up to 16% (vol/vol) saliva had essentially no effect on growth, 4% saliva caused a 50% reduction in proteolysis of substrate protein. Due to the low pH requirement for protease production and activity and the demonstration that saliva is a potent inhibitor of protease synthesis, we conclude C. albicans most likely does not produce extracellular protease in the human oral cavity.


Examination of the short-term efficacy of a parent-based intervention to prevent skin cancer.
The research evaluated an intervention strategy designed to prevent skin cancer in young adolescents. The intervention used parents as change agents to effectively communicate the risks of skin cancer and encourage their children to avoid high-risk sun-related behaviors while increasing positive sun-safe behaviors. Three hundred and forty parents in two regions of the United States were educated about the dangers of risky sun behaviors and how to convey information about skin cancer prevention to their children. Parents were then encouraged to talk with their children about these issues over a 1-month period prior to the onset of summer. Following this time period, children whose parents received and implemented the intervention materials were compared with a control sample of 129 children. These two groups were matched on age, gender, and school on number of sunburns and sunburn severity, attitudes and beliefs, and sunbathing behavior. Children in the treatment condition differed significantly from controls in the predicted directions on all outcome variables. The findings are discussed in terms of reducing skin cancer risk behaviors of children via parent-based intervention approaches.


Realities and ideals: Experiences and needs of pediatric oncology nurses in communication processes with children and their families at the end-of-life period: A photovoice qualitative study.
Effective communication in end-of-life care for pediatric cancer patients is crucial. Yet, limited research focuses on the communication experiences of pediatric oncology nurses during this period. This study aims to investigate the communication experiences and needs of these nurses with children and their families during the end-of-life period. A qualitative study design with photo voice methodology was followed. The research was conducted with 16 pediatric oncology nurses working in the pediatric oncology wards of a university hospital between January and May 2023. Data were collected the "Characteristic Information Form", "Semi-Structured Interview Form", and photovoice methodology. Data were analyzed through reflexive thematic analysis. Most of the nurses are at the undergraduate level, and their working experience in pediatric oncology wards ranges from 4 months to 17 years. Seven main themes emerged: Optimistic Communication-Interaction, Mindfulness, Active Coping, Behavioral Actions, Death Uncertainty Dilemma, Interpersonal and Environmental Factors, and Discrepancy between Ideals and Reality. The study sheds light on the importance of pediatric oncology nurses' ideals versus realities upstream approach in communicating with end-of-life children and their families, empowering pediatric oncology nurses on the journey to ideal end-of-life care.


Changes in Provider Prescribing Patterns After Implementation of an Emergency Department Prescription Opioid Policy.
Prescription opioid-associated abuse and overdose is a significant cause of morbidity and mortality in the United States. Opioid prescriptions generated from emergency departments (EDs) nationwide have increased dramatically over the past 20 years, and opioid-related overdose deaths have become an epidemic, according to the Centers for Disease Control and Prevention. Our aim was to determine the effectiveness of implementing a prescription policy for opioids on overall opioid prescribing patterns in a hospital ED. The ED provider group of an academic, non-university-affiliated urban hospital with 23,000 annual patient visits agreed to opioid prescribing guidelines for chronic pain with the goal of limiting prescriptions that may be used for abuse or diversion. These guidelines were instituted in the ED through collaborative staff meetings and educational and training sessions. We used the electronic medical record to analyze the number and type of opioid discharge prescriptions during the study period from 2006-2014, before and after the prescribing guidelines were instituted in the ED. The number of patients discharged with a prescription for opioids decreased 39.6% (25.7% to 15.6%; absolute decrease 10.2%; 95% confidence interval [CI] 9.6-10.7; p < 0.001) after the intervention. The improvements were sustained 2.5 years after the intervention. Decreases were seen in all major opioids (hydrocodone, oxycodone, hydromorphone, and codeine). The number of pills per prescription also decreased 14.8%, from 19.5% to 16.6% (absolute decrease 2.9; 95% CI 2.6-3.1; p < 0.001). Implementation of an ED prescription opioid policy was associated with a significant reduction in total opioid prescriptions and in the number of pills per prescription.


A wavelet transform with point-symmetric extension at tile boundaries.
This paper presents a low-complexity wavelet transform that utilizes point-symmetric extension at the image tile boundaries. The proposed approach is considered as an alternative to the well-known symmetric signal extension in dealing with the boundary artifacts that manifest when tiles of images are lossy compressed. The new solution developed for odd-length filters preserves the perfect reconstruction property of the filter banks and deals efficiently with blocking artifacts without requiring any post processing technique or additional information from the neighboring tiles. It is shown that point-symmetric extension at the tile boundaries does not need to be applied explicitly, but instead the equivalent boundary filters can be derived. The lifting-based implementation of the filters provides a very simple way of changing filter parameters at the boundaries that suits both hardware and software platforms.


NADPH oxidase complex-derived reactive oxygen species, the actin cytoskeleton, and Rho GTPases in cell migration.
Rho GTPases are historically known to be central regulators of actin cytoskeleton reorganization. This affects many processes including cell migration. In addition, members of the Rac subfamily are known to be involved in reactive oxygen species (ROS) production through the regulation of NADPH oxidase (Nox) activity. This review focuses on relationships between Nox-regulated ROS, Rho GTPases, and cytoskeletal reorganization, in the context of cell migration. It has become clear that ROS participate in the regulation of certain Rho GTPase family members, thus mediating cytoskeletal reorganization. The role of the actin cytoskeleton in providing a scaffold for components of the Nox complex needs to be examined in the light of these new advances. During cell migration, Rho GTPases, ROS, and cytoskeletal organization appear to function as a complex regulatory network. However, more work is needed to fully elucidate the interactions between these factors and their potential in vivo importance. Ultrastructural analysis, that is, electron microscopy, particularly immunogold labeling, will enable direct visualization of subcellular compartments. This in conjunction with the analysis of tissues lacking specific Rho GTPases, and Nox components will facilitate a detailed examination of the interactions of these structures with the actin cytoskeleton. In combination with the analysis of ROS production, including its subcellular location, these data will contribute significantly to our understanding of this intricate network under physiological conditions. Based on this, in vivo and in vitro studies can then be combined to elucidate the signaling pathways involved and their targets.


Changes of lysosomes in the earliest stages of the development of atherosclerosis.
One of hypotheses of atherosclerosis is based on a presumption that the zones prone to the development of atherosclerosis contain lysosomes which are characterized by enzyme deficiency and thus, are unable to dispose of lipoproteins. The present study was undertaken to investigate the characteristics and changes of lysosomes in the earliest stages of the development of atherosclerosis. Electron microscopic immunocytochemistry revealed that there were certain changes in the distribution of CD68 antigen in lysosomes along the 'normal intima-initial lesion-fatty streak' sequence. There were no significant changes found in the key mRNAs encoding for the components of endosome/lysosome compartment in initial atherosclerotic lesions, but in fatty streaks, the contents of EEA1 and Rab5a mRNAs were found to be diminished while the contents of CD68 and p62 mRNAs were increased, compared with the intact tissue. The study reinforces a view that changes occurring in lysosomes play a role in atherogenesis from the very earlier stages of the disease.


Women's knowledge of and attitudes to first and second trimester screening for Down's syndrome.
One hundred women were interviewed at their first hospital antenatal visit to assess their knowledge of, and attitudes to, first versus second trimester screening for Down's syndrome. Overall, the women had limited knowledge of Down's syndrome, and the prenatal screening and diagnostic tests that are available. However, when informed, the majority of women expressed a clear preference for first trimester screening tests for Down's syndrome, regardless of the rate of miscarriage of Down's syndrome pregnancies between 10 and 15 weeks of gestation. These findings have implications for the planning of prenatal Down's syndrome screening programmes.


Phase 1 studies of the safety and immunogenicity of electroporated HER2/CEA DNA vaccine followed by adenoviral boost immunization in patients with solid tumors.
DNA electroporation has been demonstrated in preclinical models to be a promising strategy to improve cancer immunity, especially when combined with other genetic vaccines in heterologous prime-boost protocols. We report the results of 2 multicenter phase 1 trials involving adult cancer patients (n=33) with stage II-IV disease. Patients were vaccinated with V930 alone, a DNA vaccine containing equal amounts of plasmids expressing the extracellular and trans-membrane domains of human HER2, and a plasmid expressing CEA fused to the B subunit of Escherichia coli heat labile toxin (Study 1), or a heterologous prime-boost vaccination approach with V930 followed by V932, a dicistronic adenovirus subtype-6 viral vector vaccine coding for the same antigens (Study 2). The use of the V930 vaccination with electroporation alone or in combination with V932 was well-tolerated without any serious adverse events. In both studies, the most common vaccine-related side effects were injection site reactions and arthralgias. No measurable cell-mediated immune response (CMI) to CEA or HER2 was detected in patients by ELISPOT; however, a significant increase of both cell-mediated immunity and antibody titer against the bacterial heat labile toxin were observed upon vaccination. V930 vaccination alone or in combination with V932 was well tolerated without any vaccine-related serious adverse effects, and was able to induce measurable immune responses against bacterial antigen. However, the prime-boost strategy did not appear to augment any detectable CMI responses against either CEA or HER2. Study 1 - ClinicalTrials.gov, NCT00250419; Study 2 - ClinicalTrials.gov, NCT00647114.


Towards a semantic PACS: Using Semantic Web technology to represent imaging data.
The DICOM standard is ubiquitous within medicine. However, improved DICOM semantics would significantly enhance search operations. Furthermore, databases of current PACS systems are not flexible enough for the demands within image analysis research. In this paper, we investigated if we can use Semantic Web technology, to store and represent metadata of DICOM image files, as well as linking additional computational results to image metadata. Therefore, we developed a proof of concept containing two applications: one to store commonly used DICOM metadata in an RDF repository, and one to calculate imaging biomarkers based on DICOM images, and store the biomarker values in an RDF repository. This enabled us to search for all patients with a gross tumor volume calculated to be larger than 50 cc. We have shown that we can successfully store the DICOM metadata in an RDF repository and are refining our proof of concept with regards to volume naming, value representation, and the applications themselves.


Ablating Ion Velocity Distributions in Short-Pulse-Heated Solids via X-Ray Doppler Shifts.
Solids ablate under laser irradiation, but experiments have not previously characterized the initiation of this process at ultrarelativistic laser intensities. We present first measurements of bulk ion velocity distributions as ablation begins, captured as a function of depth via Doppler-shifted x-ray line emission from two viewing angles. Bayesian analysis indicates that bulk ions are either nearly stationary or flowing outward at the plasma sound speed. The measurements quantitatively constrain the laser-plasma ablation mechanism, suggesting that a steplike electrostatic potential structure drives solid disassembly.


The mouse that roared: neural mechanisms of social hierarchy.
Hierarchical social status greatly influences behavior and health. Human and animal studies have begun to identify the brain regions that are activated during the formation of social hierarchies. They point towards the prefrontal cortex (PFC) as a central regulator, with brain areas upstream of the PFC conveying information about social status, and downstream brain regions executing dominance behavior. This review summarizes our current knowledge on the neural circuits that control social status. We discuss how the neural mechanisms for various types of dominance behavior can be studied in laboratory rodents by selective manipulation of neuronal activity or synaptic plasticity. These studies may help in finding the cause of social stress-related mental and physical health problems.


[Fibrinolysis system in patients with sepsis in state of myelotoxic agranulocytosis].
Hemostasis disorders are the part of multiple organ failure (mOF) in sepsis. This work objective is to evaluate the system parameters in septic patients. 55 oncohaematological patients were included in study: 45 with sepsis and 10 patients in control group (no signs of infection). Septic patients were subdivided into septic patients without multiple organ failure, patient with multiple organ failure and patients with septic shock. The C-reactive protein (CRP), procalcitonine (pCT), interleukine-6 (IL-6) serum concentration and fibrinolysis parameters were measured Patients were examined daily during first 5 days, later once a week during 28 days, control group was examined one time. Levels of CRP IL-6 and PCT were raised since 1st day. PCT and IL-6 concentrations were higher in sepsis and MOF group and septic shock group, than in sepsis without MOF group. CRP was raised in all patients. PCT went to normal at 7th day, CRP and IL-6 have started to decrease after 7th day, but both were higher than in control group. T-PA and plasmin inhibitors were comparable to control group and haven't changed significantly. Septic shock patients and patients with MOF have shown a decrease of plasminogen activity. Patients without MOF have shown an initially decreased plasminogen activity, but after 2 days it was similar to control group. PAI-I activity was increased only in septic shock and MOF groups in first days, and was similar to control group in cases of no MOF. Exended XIIa-dependent fibrinolysis time in average was present in all septic patients since 1st day, and extended twice in MOF and septic shock groups. Clot lysis time tended to decrease starting from 8th day, but it was longer than in control group till 28th day. A raised D-dimer concentration compared to control group was present in 75% of patients, but no difference was found among subgroups. A raised D-dimer serum concentration was relevant for prognosis. The most sensitive diagnostic test in sepsis is XIIa-dependent fibrinolysis. Plasminogen and PAI-I activity changes are mostly present inpatient with MOF and septic shock. The 28-day survival rate was 60% in MOF and septic shock groups and 95% in no MOF groups. A raised D-dimer concentration was found in 75% of septic patients.


Evaluation of a novel biodegradable polymer for the generation of a dermal matrix.
Dermal skin substitutes can be used to overcome the immediate problem of donor site shortage in the treatment of major skin loss conditions, such as burn injury. In this study, the biocompatibility, safety, and potential of three variants of NovoSorb (a family of novel biodegradable polyurethanes) as dermal scaffolds were determined in a series of in vitro and in vivo systems. All three polymers exhibited minimal cytotoxic effects on human skin cells, allowing keratinocytes, dermal fibroblasts, and microvascular endothelial cells to grow normally in coculture. Subcutaneous implantation of the polymers in rats demonstrated no systemic toxic effects of the materials or their degradation products. The anticipated local foreign body reaction compared favorably with commercially available medical sutures. Assessment of a three-dimensional polymer matrix followed. The success of sequential culturing of dermal fibroblasts and keratinocytes within the matrix indicated that the generation of a cultured skin substitute is achievable. The polymeric matrix also provided a scaffold for the guided formation of a cultured microvasculature. When engrafted onto a surgically created full-thickness sheep wound, the noncellular matrix integrated, healed with an epidermis supported by a basement membrane, and was capable of withstanding wound contraction. The resistance to contraction compared favorably with a commercially available collagen-based dermal matrix (Integra). These results suggest that the NovoSorb matrix could form the basis of an elegant two-stage burn treatment strategy, with an initial noncellular biodegradable temporizing matrix to stabilize the wound bed followed by the application of cultured skin substitute.


Traumatic open globe injury in young pediatric patients: characterization of a novel prognostic score.
Open globe injury is a common cause of monocular blindness in children. Current formulas to predict outcomes of open globe injury often rely heavily on visual acuity and presence of an afferent pupillary defect, examination elements that are difficult to assess in young children. We aimed to analyze the features of open globe injuries in children aged 0-6 years to facilitate development of a novel algorithm for predicting visual outcomes in this age group. The medical records of patients 0-6 years of age presenting at a single institution with open globe injury from 2000 to 2013 were retrospectively reviewed. Epidemiology, physical examination, and intervention data were used to develop a prognostic algorithm. A total of 28 patients were included. Mean age at presentation was 4.2 years (range, 1.9-6.7). Glass was the most common mechanism of injury. Associated findings included uveal prolapse (93%), choroidal detachment (39%), hyphema (32%), and retinal detachment (11%). In addition to primary repair, 43% patients required a lensectomy, and 7% underwent surgery to repair retinal detachment. Complicating cataract (P < 0.005) and a wound >6 mm (P < 0.05) were associated with a final visual acuity worse than 20/40. A novel algorithm for predicting visual outcome was devised with a sensitivity of 81% and a specificity of 92%. Patients 0-6 years of age with open globe injuries present unique risk factors for poor outcome. The trauma score generated by our algorithm is not reliant on presenting visual acuity and may be useful in predicting prognosis in very young children.


Chronic administration of sildenafil modified the impaired VEGF system and improved the erectile function in rats with diabetic erectile dysfunction.
Men frequently develop diabetic erectile dysfunction (DMED), as a result of endothelial dysfunction. DMED patients often have reduced efficacy with phosphodiesterase type 5 inhibitors therapy. To determine whether chronic sildenafil administration can modify the impaired vascular endothelial growth factor (VEGF) system and improve the erectile function in rats with diabetic erectile dysfunction. A group of Sprague Dawley rats (n = 30) with DMED were induced by intraperitoneal injection of streptozotocin (40 mg/kg) and screened by subcutaneous injection of Apomorphine (100 mg/kg). They were then exposed to either vehicle or sildenafil (prescribed in our hospital, 5 mg/kg and 10 mg/kg, respectively) for 10 weeks. An additional nondiabetic and age-matched control group (n = 10) was also allocated and given the routine diet for the same period. Assessments were performed to both groups at 36 hours after the last dose of sildenafil. Penile intracavernous pressure (ICP), mean arterial pressure (MAP), penile tissue morphology, immunohistologic analysis, and Western blot analysis of VEGF, VEGFR1, and eNOS were determined. Functional, morphological, and proteomical changes on penile structures by the chronic Sildenafil (5 mg/kg and 10 mg/kg, respectively) administration were determined. A significant increase of ICP, ICP/MAP ratio, and area under the curve were observed in the both groups treated by sildenafil (5 mg/kg and 10 mg/kg, respectively), compared with the DMED rats without receiving Sildenafil. Immunohistochemical staining of their penile tissue showed a decrease in VEGF, VEGFR1, and eNOS staining in the controlled group compared with an improvement in the chronic sildenafil administration group. Western blot analysis demonstrated exactly the same results. We demonstrated that daily sildenafil administration can restore the impaired VEGF system in the penis of DMED rats and progressively improve both erectile function and endothelial function, suggesting a potential general mechanism of improved signaling through the VEGF/eNOS signaling cascade.


The Attraction of Water for Itself at Hydrophobic Quartz Interfaces.
Structural forces within aqueous water at a solid interface can significantly change surface reactivity and the affinity of solutes toward it. We show using molecular dynamics simulations how hydrophilic and hydrophobic quartz surfaces perturb the orientational structure of aqueous water, ultimately strengthening dipolar forces between molecules in proximity to the interface. When derived as a function of distance from each surface, it was found that both surfaces indirectly enhance the long-range dipolar attraction of water for itself toward the interfacial region. This was found to be longer-ranged for water molecules solvating the hydrophobic surface than those solvating the hydrophilic surface, with a range of up to 2.5 nm from the hydrophobic surface. Our results give direct quantification of surface-induced changes in solvent-solvent attraction, ultimately providing a counterintuitive addition to the balance of hydrophobic forces at aqueous-solid interfaces.


Limited utility of dried-blood- and plasma spot-based screening for antiretroviral treatment failure with Cobas Ampliprep/TaqMan HIV-1 version 2.0.
The 2013 WHO antiretroviral therapy (ART) guidelines recommend dried blood spots (DBS) as an alternative specimen type for viral load (VL) monitoring. We assessed the programmatic utility of screening for antiretroviral (ARV) treatment failure (TF) at 5,000 and 1,000 copies/ml using DBS and dried plasma spots (DPS) with a commonly used VL assay, the Roche Cobas Ampliprep/Cobas TaqMan V.2.0 (CAP/CTM). Plasma, DBS, and DPS were prepared from 839 whole-blood specimens collected from patients on ART for ≥ 6 months at three public facilities in Namibia. Using the CAP/CTM test, VL were measured in plasma, DBS, and DPS, and the results were compared using the plasma VL as the reference standard. The clinical sensitivities, specificities, and positive (PPV) and negative predictive values (NPV) of DBS at ARV TF diagnostic thresholds of 5,000 copies/ml and 1,000 copies/ml were 0.99, 0.55, 0.33, and 0.99 and 0.99, 0.26, 0.29, and 0.99, respectively, and for DPS at TF diagnostic thresholds of 5,000 copies/ml and 1,000 copies/ml, they were 0.88, 0.98, 0.92, and 0.97 and 0.91, 0.96, 0.89, and 0.97, respectively. The prevalences of TF were overestimated in DBS by 33% and 57% at these two thresholds, respectively. A high rate of false-positive results would occur if the CAP/CTM with DBS were to be used to screen for ARV TF. WHO recommendations for DBS-based VL monitoring should be specific to the VL assay version and type. Despite the better performance of DPS, the programmatic utility for TF screening may be limited by requirements for processing the whole blood at the collection site.


20-Gbit/s directly modulated photonic crystal nanocavity laser with ultra-low power consumption.
We have demonstrated an ultracompact buried heterostructure photonic crystal (PhC) laser, consisting of an InGaAsP-based active region (5.0 x 0.3 x 0.15 μm3) buried in an InP layer. By employing a buried heterostructure with an InP layer, we can greatly improve thermal resistance and carrier confinement. We therefore achieved a low threshold input power of 6.8 μW and a maximum output power in the output waveguide of -10.3 dBm by optical pumping. The output light is effectively coupled to the output waveguide with a high external differential quantum efficiency of 53%. We observed a clear eye opening for a 20-Gbit/s NRZ signal modulation with an absorbed input power of 175.2 μW, resulting in an energy cost of 8.76 fJ/bit. This is the smallest reported energy cost for any type of semiconductor laser.


Association of diet, exercise, and smoking modification with risk of early cardiovascular events after acute coronary syndromes.
Although preventive drug therapy is a priority after acute coronary syndrome, less is known about adherence to behavioral recommendations. The aim of this study was to examine the influence of adherence to behavioral recommendations in the short term on risk of cardiovascular events. The study population included 18 809 patients from 41 countries enrolled in the Organization to Assess Strategies in Acute Ischemic Syndromes (OASIS) 5 randomized clinical trial. At the 30-day follow-up, patients reported adherence to diet, physical activity, and smoking cessation. Cardiovascular events (myocardial infarction, stroke, cardiovascular death) and all-cause mortality were documented to 6 months. About one third of smokers persisted in smoking. Adherence to neither diet nor exercise recommendations was reported by 28.5%, adherence to either diet or exercise by 41.6%, and adherence to both by 29.9%. In contrast, 96.1% of subjects reported antiplatelet use, 78.9% reported statin use, and 72.4% reported angiotensin-converting enzyme/angiotensin receptor blocker use. Quitting smoking was associated with a decreased risk of myocardial infarction compared with persistent smoking (odds ratio, 0.57; 95% confidence interval, 0.36 to 0.89). Diet and exercise adherence was associated with a decreased risk of myocardial infarction compared with nonadherence (odds ratio, 0.52; 95% confidence interval, 0.4 to 0.69). Patients who reported persistent smoking and nonadherence to diet and exercise had a 3.8-fold (95% confidence interval, 2.5 to 5.9) increased risk of myocardial infarction/stroke/death compared with never smokers who modified diet and exercise. Adherence to behavioral advice (diet, exercise, and smoking cessation) after acute coronary syndrome was associated with a substantially lower risk of recurrent cardiovascular events. These findings suggest that behavioral modification should be given priority similar to other preventive medications immediately after acute coronary syndrome. Clinical Trial Registration Information- URL: http://clinicaltrials.gov/ct2/show/NCT00139815. Unique identifier: NCT00139815.


Phylogenomics and comparative genomics of Lactobacillus salivarius, a mammalian gut commensal.
The genus Lactobacillus is a diverse group with a combined species count of over 200. They are the largest group within the lactic acid bacteria and one of the most important bacterial groups involved in food microbiology and human nutrition because of their fermentative and probiotic properties. Lactobacillus salivarius, a species commonly isolated from the gastrointestinal tract of humans and animals, has been described as having potential probiotic properties and results of previous studies have revealed considerable functional diversity existing on both the chromosomes and plasmids. Our study consists of comparative genomic analyses of the functional and phylogenomic diversity of 42 genomes of strains of L. salivarius using bioinformatic techniques. The main aim of the study was to describe intra-species diversity and to determine how this diversity is spread across the replicons. We found that multiple phylogenomic and non-phylogenomic methods used for reconstructing trees all converge on similar tree topologies, showing that different metrics largely agree on the evolutionary history of the species. The greatest genomic variation lies on the small plasmids, followed by the repA-type circular megaplasmid, with the chromosome varying least of all. Additionally, the presence of extra linear and circular megaplasmids is noted in several strains, while small plasmids are not always present. Glycosyl hydrolases, bacteriocins and proteases vary considerably on all replicons while two exopolysaccharide clusters and several clustered regularly interspaced short palindromic repeats-associated systems show a lot of variation on the chromosome. Overall, despite its reputation as a mammalian gastrointestinal tract specialist, the intra-specific variation of L. salivarius reveals potential strain-dependant effects on human health.


[Clinical variants of chronic ischemic syndrome of the lower extremities].
Analysis is made of 1,014 cases with occlusive lesion of the bifurcation of the aorta and iliofemoral segment in patients with chronic ischemic syndrome of the lower limbs. The cause of high arterial occlusion with atherosclerosis in 95.5% of patients and nonspecific aortitis in 12 cases. A group of 20 patients with selective lesion of the femoral segment, which is distinguished from atherosclerosis obliterans, endarteritis with ascending thrombosis, and nonspecific aortitis by its clinico-angiographic and morphological manifestations, was analyzed in detail. This form of arterial occlusion is called "segmental thromboarteritis". The results of reconstructive operations in most patients with "segmental thromboarteritis" proved unfavourable.


Afferent signalling of gastric acid challenge.
Gastric acid is a factor in the pain associated with peptic ulcer and other acid-related disorders including functional dyspepsia, given that antisecretory treatment is a mainstay in the treatment of upper abdominal pain. However, the molecular sensors, afferent pathways and central processing systems of gastric chemonociception are little known. This article reviews emerging evidence that vagal afferent pathways play a pivotal role in gastric chemonociception. Exposure of the rat gastric mucosa to backdiffusing concentrations of luminal acid is signalled to the brainstem, but not spinal cord, as visualized by functional neuroanatomy based on the rapid expression of c-fos. This observation is complemented by the finding that the visceromotor response to gastric acid challenge is suppressed by vagotomy, but not splanchnectomy. The gastric acid-induced expression of c-fos in the brainstem is reduced by inhibition of gastric acid secretion and enhanced by pentagastrin-evoked stimulation of gastric acid secretion. These data indicate that endogenous acid modulates the sensory gain of acid-sensitive vagal afferents. Further consistent with a role of these neurons in gastric nociception is the finding that exposure to proinflammatory cytokines and the induction of experimental gastritis or gastric ulceration sensitizes vagal afferent pathways to gastric acid. Taken together, these observations are of relevance to the understanding and treatment of gastric hyperalgesia and dyspeptic pain.


Experimental demonstration of slow and superluminal light in semiconductor optical amplifiers.
Tunable delays in semiconductor optical amplifiers are achieved via four wave mixing between a strong pump beam and a modulated probe beam. The delay of the probe beam can be controlled both electrically, by changing the SOA bias, and optically, by varying the pump power or the pump-probe detuning. For sinusoidal modulated signal at 0.5 GHz, a tunable delay of 1.6 ns is achieved. This corresponds to a RF phase change of 1.6 pi. For 1.3 ns optical pulses propagating through the SOA a delay of 0.59 ns is achieved corresponding to a delay-bandwidth product exceeding 0.45. For both the cases, slow light and superluminal light are observed as the pump-probe detuning is varied.


Diagnostic method for malignant pleural effusion distinguishing malignant mesothelioma from lung cancer using pleural carcinoembryonic antigen and hyaluronic acid levels.
Malignant mesothelioma (MM) is difficult to diagnose because of the lack of parenchymal opacities, often revealing minimal or absent pleural thickening. Furthermore, pleural effusion has diverse differential diagnoses, including malignancies, infections, as well as collagen vascular and other benign diseases. In general practice, lung cancer (LC) is the most common malignancy causing pleural effusion; therefore, a simple method using pleural diagnostic markers to differentiate between LC and mesothelioma is crucial.We retrospectively reviewed the data of 530 adult patients diagnosed with pleural effusion between January 2010 and December 2020 in an outpatient or inpatient setting. Patients with pathologically diagnosed MM or LC with cytologically positive (class IV or V) pleural effusion were analyzed, and the characteristics of these 2 diseases were compared.During the study period, 27 patients diagnosed with MM and 100 patients diagnosed with LC were enrolled. Receiver operating characteristic curve analysis demonstrated that pleural carcinoembryonic antigen (CEA) and hyaluronic acid (HA) could discriminate MM from LC with an area under the curve of 0.925 (95% confidence interval [CI]: 0.879-0.972, P < .001) and 0.815 (95% CI: 0.686-0.943, P < .001), respectively. To diagnose MM, the accuracy of pleural HA >30,000 ng/mL revealed a sensitivity of 75.0%, specificity of 72.6%, and odds ratio of 7.94 (95% CI: 2.5-25.2, P = .001); pleural CEA <6.0 ng/mL revealed a sensitivity of 95.2%, specificity of 84.9%, smaller negative likelihood ratio of 0.06, and odds ratio of 112.5% (95% CI: 14.4-878.1, P < .001). Multiple logistic regression analysis revealed that these 2 parameters could discriminate MM from LC, with a hazard ratio of 23.6 (95% CI: 2.437-228.1, P = .006) and 252.3 (95% Cl: 16.4-3888.1, P < .001), respectively, and their combination had a high specificity of 98.3%.Pleural CEA (≥6.0 ng/mL) can rule out MM with a high degree of certainty, and the positive results for combination of pleural CEA <6.0 ng/mL and HA >30,000 ng/mL can confirm MM with high specificity, prior to cytological or pathological examinations.


Potential Impacts of Climate Change on the Toxicity of Pesticides towards Earthworms.
This review examined one of the effects of climate change that has only recently received attention, i.e., climate change impacts on the distribution and toxicity of chemical contaminants in the environment. As ecosystem engineers, earthworms are potentially threatened by the increasing use of pesticides. Increases in temperature, precipitation regime changes, and related extreme climate events can potentially affect pesticide toxicity. This review of original research articles, reviews, and governmental and intergovernmental reports focused on the interactions between toxicants and environmental parameters. The latter included temperature, moisture, acidification, hypoxia, soil carbon cycle, and soil dynamics, as altered by climate change. Dynamic interactions between climate change and contaminants can be particularly problematic for organisms since organisms have an upper and lower physiological range, resulting in impacts on their acclimatization capacity. Climate change variables such as temperature and soil moisture also have an impact on acidification. An increase in temperature will impact precipitation which might impact soil pH. Also, an increase in precipitation can result in flooding which can reduce the population of earthworms by not giving juvenile earthworms enough time to develop into reproductive adults. As an independent stressor, hypoxia can affect soil organisms, alter bioavailability, and increase the toxicity of chemicals in some cases. Climate change variables, especially temperature and soil moisture, significantly affect the bioavailability of pesticides in the soil and the growth and reproduction of earthworm species.


Common HIV-1 peptide variants mediate differential binding of KIR3DL1 to HLA-Bw4 molecules.
Epidemiological studies have shown the protective effect of KIR3DL1/HLA-Bw4 genotypes in human immunodeficiency virus type 1 (HIV-1) infection; however, the functional correlates for the protective effect remain unknown. We investigated whether human leukocyte antigen (HLA)-Bw4-presented HIV-1 peptides could affect the interaction between the inhibitory natural killer (NK) cell receptor KIR3DL1 and its ligand HLA-Bw4. Distinct HIV-1 epitopes differentially modulated the binding of KIR3DL1 to HLA-Bw4. Furthermore, cytotoxic T lymphocyte (CTL) escape mutations within the immunodominant HLA-B57 (Bw4)-restricted Gag epitope TSTLQEQIGW abrogated KIR3DL1 binding to HLA-B57, suggesting that sensing of CTL escape variants by NK cells can contribute to the protective effect of the KIR3DL1/HLA-Bw4 compound genotype.


Corneal first surface optical aberrations and visual performance.
Wavefront analysis has demonstrated that refractive surgery-induced corneal first surface aberrations are large, are dominated by symmetric aberrations (spherical-like aberrations), and are correlated to measures of visual performance. It is not clear whether the correlation between corneal first surface aberrations and visual performance can be generalized to other corneal conditions where large asymmetric aberrations (coma-like aberrations) may dominate the aberration structure. The purpose of the research reported here was to determine the general utility of corneal first surface wavefront analysis in predicting visual performance. Patients were 13 normals and 78 patients with a variety of corneal conditions including surgically removed pterygia, penetrating keratoplasty, keratoconus, radial keratotomy, laser in situ keratomileusis, and others. Videokeratographs were taken for all patients and used to calculate corneal first surface wavefront variance for 3 and 7 mm pupils. Similarly, visual performance was quantified by measurements of contrast sensitivity and high and low contrast acuities through both 3 and 7 mm pupils. Statistically significant correlations existed between all three measures of visual performance and the corneal wavefront variance. All relationships were stronger for the 7 mm diameter-pupil condition than the 3 mm pupil. Regardless of the cause, corneas with increased wavefront variance showed a quantifiable decrease in visual performance that was pupil size dependent.


Hypoxia-inducible factor-1 inhibition in combination with temozolomide treatment exhibits robust antitumor efficacy in vivo.
Inhibiting hypoxia-inducible factor-1 (HIF-1) represents a unique mechanism for cancer therapy. It is conceived that HIF-1 inhibitors may synergize with many classes of cancer therapeutic agents, such as angiogenesis inhibitors and cytotoxic drugs, to achieve a more robust tumor response. However, these hypotheses have not been rigorously tested in tumor models in vivo. The present study was carried out to evaluate the antitumor efficacy of combining HIF-1 inhibition with angiogenesis inhibitors or cytotoxic agents. Using a D54MG-derived tumor model that allows knockdown of HIF-1alpha on doxycycline treatment, we examined the tumor responses to chemotherapeutic agents, including the angiogenesis inhibitor ABT-869 and cytotoxic agents 1,3-bis(2-chloroethyl)-1-nitrosourea and temozolomide, in the presence or absence of an intact HIF-1 pathway. Surprisingly, inhibiting HIF-1 in tumors treated with the angiogenesis inhibitor ABT-869 did not produce much added benefit compared with ABT-869 treatment alone, suggesting that the combination of an angiogenesis inhibitor with a HIF-1 inhibitor may not be a robust therapeutic regimen. In contrast, the cytotoxic drug temozolomide, when used in combination with HIF-1alpha knockdown, exhibited a superadditive and likely synergistic therapeutic effect compared with the monotherapy of either treatment alone in the D54MG glioma model. Our results show that the DNA alkylating agent temozolomide exhibits robust antitumor efficacy when used in combination with HIF-1 inhibition in D54MG-derived tumors, suggesting that the combination of temozolomide with HIF-1 inhibitors might be an effective regimen for cancer therapy. In addition, our results also show that the RNA interference-based inducible knockdown model can be a valuable platform for further evaluation of the combination treatment of other cancer therapeutics with HIF-1 inhibition.


Bi-Linear Regression for O Quantification: Modeling across the Elution Profile.
MOTIVATION: Interpreting and quantifying labeled mass-spectrometry data is complex and requires automated algorithms, particularly for large scale proteomic profiling. Here, we propose the use of bi-linear regression to quantify relative abundance across the elution profile in a unified model. The bi-linear regression model takes advantage of the fact that while peptides differ in overall abundance across the elution profile multiplicatively, the relative abundance between the mixed samples remains constant across the elution profile. We describe how to apply bi-linear regression models to (18)O stable-isotope labeled data, which allows for the direct comparison of two samples simultaneously. Interpretation of model parameters is also discussed. The incorporation rate of the labeling isotope is estimated as part of the modeling process and can be used as a measure of data quality. Application is demonstrated in a controlled experiment as well as in a complex mixture. RESULTS: Bi-linear regression models allow for more precise and accurate estimates of abundance, in comparison to methods that treat each spectrum independently, by taking into account the abundance of the molecule throughout the entire elution profile, with precision increased by one-to-two orders of magnitude.


Effects of Hyperbaric Oxygen and Preconditioning on Wound Healing in Colonic Anastomoses.
The purpose of this study was to evaluate the effects of hyperbaric oxygen (HBO) and HBO preconditioning (pre-HBO) on experimental wound healing and tensile strength in the colonic anastomosis of rats. A total of 21 Sprague-Dawley rats were divided into three random groups of equal numbers: sham operation, pre-HBO, and HBO. Sham group was given standard left colon resection and end-to-end anastomosis; pre-HBO group received HBO as one dose + colonic resection + anastomosis; HBO group was given colonic resection + anastomosis + HBO. HBO was administrated at 24-hr intervals and relaparatomy was performed on the fifth day. Malondialdehyde (MDA), myeloperoxidase (MPO), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), interleukin (IL)-10, IL-6, tumor necrosis factor-alpha (TNF-α), and hydroxy (OH)-proline levels and anastomotic burst pressure were evaluated. Burst pressure and OH-proline levels markedly increased in the HBO group compared with the sham and pre-HBO groups. When compared with the sham group, MDA and MPO levels were significantly decreased in the HBO and pre-HBO groups. In contrast to these findings, SOD and GSH-Px levels were increased in the HBO group as compared with the sham and pre-HBO groups. TNF-α, IL-6, and IL-10 values were detected at low levels in the HBO group as compared with other groups. HBO administration accelerated wound healing and strengthened the anastomotic tissue. In the light of these results, the HBO administration has beneficial effects and contributed to wound healing in colonic anastomosis. But, as expected, pre-HBO did not alter the results significantly.


Desorption electrospray ionisation mass spectrometry reveals in situ modification of a hindered amine light stabiliser resulting from direct N-OR bond cleavage.
Detection and characterisation of structural modifications of a hindered amine light stabiliser (HALS) directly from a polyester-based coil coating have been achieved by desorption electrospray ionisation mass spectrometry (DESI-MS) for the first time. In situ detection is made possible by exposing the coating to an acetone vapour atmosphere prior to analysis. This is a gentle and non-destructive treatment that allows diffusion of analyte to the surface without promoting lateral migration. Using this approach a major structural modification of the HALS TINUVIN®123 (bis(1-octyloxy-2,2,6,6-tetramethyl-4-piperidyl) sebacate) was discovered where one N-ether piperidine moiety (N-OC(8)H(17)) is converted to a secondary piperidine (N-H). With the use of 2-dimensional DESI-MS imaging the modification was observed to arise during high curing temperatures (ca. 260 °C) and under simulated physiological conditions (80 °C, full solar spectrum). It is proposed that the secondary piperidine derivative is a result of a highly reactive aminyl radical intermediate produced by N-O homolytic bond cleavage. The nature of the bond cleavage is also suggested by ESR spin-trapping experiments employing α-phenyl-N-tert-butyl nitrone (PBN) in toluene at 80 °C. The presence of a secondary piperidine derivative in situ and the implication of N-OR competing with NO-R bond cleavage suggest an alternative pathway for generation of the nitroxyl radical-an essential requirement in anti-oxidant activity that has not previously been described for the N-ether sub-class of HALS.


Organizing for thoughtful food: a meshwork approach.
This paper provides an alternative narrative for organizing food systems. It introduces meshwork as a novel theoretical lens to examine the ontological assumptions underlying the shadow and informal dynamics of organizing food. Through a longitudinal qualitative case study, we place relationality and becoming at the centre of organizing food and food systems, demonstrating how entangled relationships can create a complex ontology through the meshwork knots, threads and weave. We show how issues of collective concern come together to form dynamic knots of interactions, how the threads within the meshwork indicate processes of movement, and how the weave suggests degrees of food system resilience-but always in flow. This theoretical approach thus provides a platform for addressing thoughtful concerns about "food matters" including the integrity of our global food system, the negative health and environmental impacts of industrialized food production, and food safety issues.


Characterizing scientific production of Italian Oral Surgery professionals through evaluation of bibliometric indices.
The aim of this study was to characterize the scientific production of Italian Oral Surgery professionals by evaluating different bibliometric indices. The bibliometric evaluation was conducted on the Scopus Database upon all the Active Members joining three important Italian scientific societies in Oral Surgery (SIdCO, SIO, and SICOI). The scientific production was analysed by considering the number of total publications, number of total citations, h-index, and hc-index. Moreover, the overall sample was divided into two groups (Academics and Not Academics), according to the fact the professionals had or not a university position, and then into sub-groups according to the different career lengths. Statistical analyses were performed to compare the scientific productivity amongst groups. For all the considered parameters a lack of homogeneity between groups was reported, and significantly greater mean values were recorded for the Academics compared to the Not Academics Group. Moreover, the h-index values increased more regularly as the career length progressed than the hc-index values, even if the last seemed to be less variable. h- and hc-indices are both stable bibliometric parameters, but as the hc-index values are related not only to the number of citation but also to their age, it seems to be less influenced by the authors' career length. Bibliometric analysis of the scientific production in dentistry may facilitate the recognition of factors that may further enhance research activity and clinical performance and be useful for a comparative assessment of authors or research groups in terms of quality and quantity of the scientific production.


Mu- and delta-opioid receptor antagonists decrease proliferation and increase neurogenesis in cultures of rat adult hippocampal progenitors.
Opioids have previously been shown to affect proliferation and differentiation in various neural cell types. In the present study, cultured rat adult hippocampal progenitors (AHPs) were shown to release beta-endorphin. Membrane preparations of AHPs were found to bind [125I]beta-endorphin, and immunoreactivity for mu- and delta-opioid receptors (MORs and DORs), but not for kappa-opioid receptors (KORs), was found on cells in culture. Both DNA content and [3H]thymidine incorporation were reduced after a 48-h incubation with 100 microM naloxone, 10 micro m naltrindole or 10 microM beta-funaltrexamine, but not nor-binaltorphimine, suggesting proliferative actions of endogenous opioids against MORs and DORs on AHPs. Furthermore, analysis of gene and protein expression after incubation with MOR and DOR antagonists for 48 h using RT-PCR and Western blotting suggested decreased signalling through the mitogen-activated protein kinase (MAPK) pathway and lowered levels of genes and proteins that are important in cell cycling. Cultures were incubated with naloxone (10 or 100 microM) for 10 days to study the effects on differentiation. This resulted in an approximately threefold increase in neurogenesis, a threefold decrease in astrogliogenesis and a 50% decrease in oligodendrogenesis. In conclusion, this study suggests that reduced signalling through MORs and DORs decreases proliferation in rat AHPs, increases the number of in vitro-generated neurons and reduces the number of astrocytes and oligodendrocytes in culture.


Molecular analysis of chondrocytes cultured in agarose in response to dynamic compression.
Articular cartilage is exposed to high mechanical loads under normal physiological conditions and articular chondrocytes regulate the composition of cartilaginous matrix, in response to mechanical signals. However, the intracellular pathways involved in mechanotransduction are still being defined. Using the well-characterized chondrocyte/agarose model system and dynamic compression, we report protocols for preparing and characterizing constructs of murine chondrocytes and agarose, and analyzing the effect of compression on steady-state level of mRNA by RT-PCR, gene transcription by gene reporter assay, and phosphorylation state of signalling molecules by Western-blotting. The mouse model is of particular interest because of the availability of a large choice of bio-molecular tools suitable to study it, as well as genetically modified mice. Chondrocytes cultured in agarose for one week were surrounded by a newly synthesized pericellular matrix, as revealed by immunohistochemistry prior to compression experiments. This observation indicates that this model system is suitable to study the role of matrix molecules and trans-membrane receptors in cellular responsiveness to mechanical stress. The chondrocyte/agarose constructs were then submitted to dynamic compression with FX-4000C Flexercell Compression Plus System (Flexcell). After clearing proteins off agarose, Western-blotting analysis showed transient activation of Mitogen-activated protein kinases (MAPK) in response to dynamic compression. After assessment by capillary electrophoresis of the quality of RNA extracted from agarose, steady-state levels of mRNA expression was measured by real time PCR. We observed an up-regulation of cFos and cJun mRNA levels as a response to compression, in accordance with the mechanosensitive character observed for these two genes in other studies using cartilage explants submitted to compression. To explore further the biological response of mouse chondrocytes to the dynamic compression at the transcriptional level, we also developed an approach for monitoring changes in gene transcription in agarose culture by using reporter promoter constructs. A decrease in promoter activity of the gene coding for type II procollagen, the most abundant protein in cartilage, was observed in response to dynamic loading. The protocols developed here offer the possibility to perform an integrated analysis of the molecular mechanisms of mechanotransduction in chondrocytes, at the gene and protein level.


Pathogenicity of a Hong Kong-origin H5N1 highly pathogenic avian influenza virus for emus, geese, ducks, and pigeons.
The H5N1 type A influenza viruses that emerged in Hong Kong in 1997 are a unique lineage of type A influenza viruses with the capacity to transmit directly from chickens to humans and produce significant disease and mortality in both of these hosts. The objective of this study was to ascertain the susceptibility of emus (Dramaius novaehollandiae), domestic geese (Anser anser domesticus), domestic ducks (Anas platyrhynchos), and pigeons (Columba livia) to intranasal (i.n.) inoculation with the A/chicken/Hong Kong/220/97 (H5N1) highly pathogenic avian influenza virus. No mortality occurred within 10 days postinoculation (DPI) in the four species investigated, and clinical disease, evident as neurologic dysfunction, was observed exclusively in emus and geese. Grossly, pancreatic mottling and splenomegaly were identified in these two species. In addition, the geese had cerebral malacia and thymic and bursal atrophy. Histologically, both the emus and geese developed pancreatitis, meningoencephalitis, and mild myocarditis. Influenza viral antigen was demonstrated in areas with histologic lesions up to 10 DPI in the geese. Virus was reisolated from oropharyngeal and cloacal swabs and from the lung, brain, and kidney of the emus and geese. Moderate splenomegaly was observed grossly in the ducks. Viral infection of the ducks was pneumotropic, as evidenced by mild inflammatory lesions in the respiratory tract and virus reisolation from oropharyngeal swabs and from a lung. Pigeons were resistant to HK/220 infection, lacking gross and histologic lesions, viral antigen, and reisolation of virus. These results imply that emus and geese are susceptible to i.n. inoculation with the HK/220 virus, whereas ducks and pigeons are more resistant. These latter two species probably played a minimal epidemiologic role in the perpetuation of the H5N1 Hong Kong-origin influenza viruses.


Strategic planning: a biomedical communications model.
This article describes a biomedical communications approach to strategic planning. This model produces a short-term plan that allows a department to take the competitive advantage, react to technological change, and make timely decisions on new courses of action. The model calls for self-study, involving staff in brainstorming sessions where options are identified and ideas are prioritized into possible strategies for success. The article recommends that an evaluation and monitoring schedule be implemented after decisions have been made.


A repeat proton magnetic resonance spectroscopy study in social phobia.
Peak spectral amplitudes for choline moieties (Cho), creatine (Cr), N-acetylaspartate (NAA), and myo-inositol (mI) were examined using proton magnetic resonance spectroscopy in 19 social-phobia patients and 10 controls. Compared with controls, social phobics demonstrated significantly lower NAA/Cho and higher Cho/Cr, mI/Cr, and mI/NAA amplitudes in cortical gray matter. Higher mI/Cr and mI/NAA amplitudes for social phobics were also observed in subcortical gray matter. Minimal between-group differences were noted for white matter. Symptom severity correlated inversely with amplitudes primarily in subcortical gray matter, and to a lesser extent in cortical gray matter. Inclusion of age and sex in statistical modeling strengthened comparisons with controls but eliminated those for symptom severity. No changes were observed in any amplitude measure following at least 8 weeks of clonazepam treatment, nor was a relationship observed between amplitudes and cumulative clonazepam dose. The possible psychobiological implications of our findings in social phobia are discussed.


The effect of interruption to propofol sedation on auditory event-related potentials and electroencephalogram in intensive care patients.
In this observational pilot study we evaluated the electroencephalogram (EEG) and auditory event-related potentials (ERPs) before and after discontinuation of propofol sedation in neurologically intact intensive care patients. Nineteen intensive care unit patients received a propofol infusion in accordance with a sedation protocol. The EEG signal and the ERPs were measured at the frontal region (Fz) and central region (Cz), both during propofol sedation and after cessation of infusion when the sedative effects had subsided. The EEG signal was subjected to power spectral estimation, and the total root mean squared power and spectral edge frequency 95% were computed. For ERPs, we used an oddball paradigm to obtain the N100 and the mismatch negativity components. Despite considerable individual variability, the root mean squared power at Cz and Fz (P = 0.004 and P = 0.005, respectively) and the amplitude of the N100 component in response to the standard stimulus at Fz (P = 0.022) increased significantly after interruption to sedation. The amplitude of the N100 component (at Cz and Fz) was the only parameter that differed between sedation levels during propofol sedation (deep versus moderate versus light sedation: P = 0.016 and P = 0.008 for Cz and Fz, respectively). None of the computed parameters correlated with duration of propofol infusion. Our findings suggest that use of ERPs, especially the N100 potential, may help to differentiate between levels of sedation. Thus, they may represent a useful complement to clinical sedation scales in the monitoring of sedation status over time in a heterogeneous group of neurologically intact intensive care patients.


Economic evaluations in the hip arthroplasty literature: lessons to be learned.
Readers are increasingly encountering articles dealing with health economic evaluations that compare various surgical strategies, leaving orthopaedists with the challenge of determining which program is cost-efficient and truly pertains to their setting. This study carries out a systematic review of the literature to appraise the quality, quantity, and type of economic evaluation as it pertains to the hip arthroplasty literature. To identify all relevant articles, we conducted a comprehensive computerized bibliographic search of Medline from 1966 to 1996. This search produced 1,611 abstracts that were screened. Studies that were incorporated met the following inclusion criteria: i) formal economic analysis, ii) an intervention specific to hip arthroplasty, and iii) the perspective of the study was evident (ie, patient, provider, society). These studies were appraised with regards to methodologic soundness based on 8 established economic principles. Only 68 articles from the 138 retrieved met the study criteria. Only 2 of the 68 articles met all 8 criteria of a comprehensive economic evaluation. The hip arthroplasty literature is deficient in methodologically sound economic evaluations. Several guidelines are introduced to aid orthopaedists in appraising the various economic studies, and recommendations are made to improve the quality of these studies in the orthopaedic literature. We suggest that the generation of such information should rank high on the priority list of the orthopaedic profession, granting agencies, and governments.


Fc-Elabela fusion protein attenuates lipopolysaccharide-induced kidney injury in mice.
Endotoxemia-induced acute kidney injury (AKI) is a common clinical condition that lacks effective treatments. Elabela (ELA) is a recently discovered kidney peptide hormone, encoded by the gene apela, and has been reported to improve cardio-renal outcomes in sepsis. However, ELA is a small peptide and is largely unsuitable for clinical use because of its short in vivo half-life. In the present study, we evaluated the potential renoprotective effects of a long-acting constant fragment (Fc)-ELA fusion protein in liposaccharide (LPS)-induced AKI in mice. LPS administration in mice for 5 days greatly lowered the gene expression of apela and impaired kidney function, as evidenced by elevated serum creatinine and the ratio of urine protein to creatinine. In addition, renal inflammation and macrophage infiltration were apparent in LPS-challenged mice. Treatment with the Fc-ELA fusion protein partially restored apela expression and attenuated the kidney inflammation. Moreover, LPS treatment induced reactive oxygen species (ROS) production and apoptosis in kidney HK-2 cells as well as in the mouse kidney, which were mitigated by ELA or Fc-ELA treatment. Finally, we found that ELA promoted the survival of HK-2 cells treated with LPS, and this action was abolished by LY204002, a PI3K/Akt inhibitor. Collectively, we have demonstrated that the Fc-ELA fusion protein has significant renoprotective activities against LPS-induced AKI in mice.


Propensity scores using missingness pattern information: a practical guide.
Electronic health records are a valuable data source for investigating health-related questions, and propensity score analysis has become an increasingly popular approach to address confounding bias in such investigations. However, because electronic health records are typically routinely recorded as part of standard clinical care, there are often missing values, particularly for potential confounders. In our motivating study-using electronic health records to investigate the effect of renin-angiotensin system blockers on the risk of acute kidney injury-two key confounders, ethnicity and chronic kidney disease stage, have 59% and 53% missing data, respectively. The missingness pattern approach (MPA), a variant of the missing indicator approach, has been proposed as a method for handling partially observed confounders in propensity score analysis. In the MPA, propensity scores are estimated separately for each missingness pattern present in the data. Although the assumptions underlying the validity of the MPA are stated in the literature, it can be difficult in practice to assess their plausibility. In this article, we explore the MPA's underlying assumptions by using causal diagrams to assess their plausibility in a range of simple scenarios, drawing general conclusions about situations in which they are likely to be violated. We present a framework providing practical guidance for assessing whether the MPA's assumptions are plausible in a particular setting and thus deciding when the MPA is appropriate. We apply our framework to our motivating study, showing that the MPA's underlying assumptions appear reasonable, and we demonstrate the application of MPA to this study.


Glanzmann thrombasthenia. Cooperation between sequence variants in cis during splice site selection.
Glanzmann thrombasthenia (GT), an autosomal recessive bleeding disorder, results from abnormalities in the platelet fibrinogen receptor, GP(IIb)-IIIa (integrin alpha(IIb)beta3). A patient with GT was identified as homozygous for a G-->A mutation 6 bp upstream of the GP(IIIa) exon 9 splice donor site. Patient platelet GP(IIIa) transcripts lacked exon 9 despite normal DNA sequence in all of the cis-acting sequences known to regulate splice site selection. In vitro analysis of transcripts generated from mini-gene constructs demonstrated that exon skipping occurred only when the G-->A mutation was cis to a polymorphism 116 bp upstream, providing precedence that two sequence variations in the same exon which do not alter consensus splice sites and do not generate missense or nonsense mutations, can affect splice site selection. The mutant transcript resulted from utilization of a cryptic splice acceptor site and returned the open reading frame. These data support the hypothesis that pre-mRNA secondary structure and allelic sequence variants can influence splicing and provide new insight into the regulated control of RNA processing. In addition, haplotype analysis suggested that the patient has two identical copies of chromosome 17. Markers studied on three other chromosomes suggested this finding was not due to consanguinity. The restricted phenotype in this patient may provide information regarding the expression of potentially imprinted genes on chromosome 17.


Excess nitrate induces nodule greening and reduces transcript and protein expression levels of soybean leghaemoglobins.
Efficient biological nitrogen fixation (BNF) requires leghaemoglobin (Lb) to modulate oxygen pressure in nodules. Excess N supply severely inhibits BNF through effects on Lb during nodulation. As yet, a systematic identification and characterization of Lb-encoding genes in soybean has not been reported. The effects of N on BNF were studied in soybean plants inoculated with rhizobia and exposed to excess or low N availability in hydroponic cultures. To identify soybean Lb proteins, BLAST searches were performed on the Phytozome website. Bioinformatic analysis of identified GmLbs was then carried out to investigate gene structure, protein homology and phylogenetic relationships. Finally, quantitative real-time PCR was employed to analyse the expression patterns of soybean Lb genes in various tissues and in response to high N availability. Excess N significantly accelerated nodule senescence and the production of green Lb in nodules. In total, seven haemoglobin (Hb) genes were identified from the soybean genome, with these Hb genes readily split into two distinct clades containing predominantly symbiosis-associated or non-symbiotic Hb members. Expression analysis revealed that all of the symbiosis-associated Lbs except GmLb5 were specifically expressed in nodules, while the non-symbiotic GmHbs, GmHb1 and GmHb2, were predominantly expressed in leaves and roots, respectively. Among identified GmLbs, GmLb1-4 are the major Lb genes acting in soybean nodulation, and each one is also significantly suppressed by exposure to excess N. Taken together, the results show that excess N inhibits BNF by reducing nodule formation, Lb concentration and nitrogenase activity. The characteristics of the entire Hb family were analysed, and we found that GmLb1-4 are closely associated with nodule development and N2 fixation. This works forms the basis for further investigations of the role of Lbs in soybean nodulation.


Time-resolved and nonlinear optical imaging for medical applications.
In this article, we have presented an overview of emerging novel techniques for early-light transillumination imaging as well as nonlinear optical tomography of body organs. The use of light for probing and imaging biomedical media offers the promise for development of safe, noninvasive, and inexpensive clinical imaging modalities with diagnostic ability. The strong scattering of light by biological tissues buries the shadowgram formed by forward-propatating image-bearing photons in the background noise of multiple-scattered light. Several methods for extraction of image-bearing light that capitalize on spatial, temporal and polarization characteristics of transmitted light are reviewed. More recently emerging nonlinear-optical histopathology methods for imaging subsurface structures of tissues in terms of its local spatial symmetry and molecular content are introduced. The progress made so far indicates that some of these techniques are apt to make a transition from laboratory to useful clinical modalities.


Tackling late HIV diagnosis: Lessons from the UK in the COVID-19 era.
Late diagnosis of HIV is associated with increased morbidity and mortality, and an increased risk of non-infectious comorbidities. On a societal level, late diagnosis leads to higher treatment and healthcare costs and is a major driver of HIV transmission. Despite improvements in other areas of the HIV care pathway, late diagnosis remains an individual and public health concern globally. To examine the barriers to HIV testing and highlight successful strategies to improve prompt diagnosis. This review describes the prevalence of late diagnosis in the UK and discusses key factors that contribute to late diagnosis, including the effect of the COVID-19 pandemic. Late HIV diagnosis is lower in the UK than in most other European countries. In this review, pilot projects and ongoing initiatives that have reduced late diagnosis in the UK are highlighted; moreover, further strategies for improving prompt diagnosis are suggested. Insufficient testing is the fundamental reason for late HIV diagnosis, with societal, systemic, and individual factors all contributing to inadequate testing. Improving access to testing, removing barriers to health-seeking behaviour, and ensuring all people with HIV indicator conditions are promptly tested are key to reducing the rates of late diagnosis globally.


Risk stratification analysis of operative mortality in isolated coronary artery bypass graft patients in Pakistan: comparison between additive and logistic EuroSCORE models.
We compared the performances of the additive and logistic EuroSCORE in predicting mortality in patients undergoing isolated coronary artery bypass grafting at a single institution in Pakistan. Both models were applied to 2004 patients, operated upon at the Aga Khan University Hospital from January 2006 to July 2010. The actual mortality (3.8%) was significantly different from the additive (4.35%) and the logistic (6.41%) estimates. On the basis of degree of risk, actual mortality was 0.6% in the low-risk (additive EuroSCORE 0-4), 4.2% in the medium-risk (EuroSCORE 5-9) and 19.1% in the high-risk (EuroSCORE 10-19) group. With the low risks, both systems slightly overestimated mortality, with the logistic EuroSCORE being more accurate. At a EuroSCORE of between 10 and 19, the additive EuroSCORE underestimated and logistic EuroSCORE overestimated mortality. Both models satisfactorily discriminated outcomes (receiver operating characteristics areas of 0.866 and 0.859 for the additive and the logistic model, respectively). The Hosmer-Lemeshow test showed that calibration was good for the additive model (P=0.424) but turned out to be inadequate for the logistic model (P<0.001). We conclude that the additive EuroSCORE is a more accurate model for risk assessment compared to the logistics model in the Pakistani population.


Cu- and Al-Decorated Monolayer TiSe2 for Enhanced Gas Detection Sensitivity: A DFT Study.
The rapid industrial development has contributed to worsening global pollution, necessitating the urgent development of highly sensitive, cost-effective, and portable gas sensors. In this work, the adsorption of CO, CO2, H2S, NH3, NO, NO2, O2, and SO2 gas molecules on pristine and Cu- and Al-decorated monolayer TiSe2 has been investigated based on first-principles calculations. First, the results of the phonon spectrum and ab initio molecular dynamics simulations demonstrated that TiSe2 is dynamically stable. In addition, compared to pristine TiSe2 (-0.029 to -0.154 eV), the adsorption energy of gas molecules (excluding CO2) significantly decreased after decorated with Cu or Al (-0.212 to -0.977 eV in Cu-decorated TiSe2, -0.438 to -2.896 eV in Al-decorated TiSe2). Among them, NH3 and NO2 have the lowest adsorption energies in Cu and Al-decorated TiSe2, respectively. Further research has shown that the decrease in adsorption energy of gas molecules is mainly due to orbital hybridization and charge transfer between decorated Cu and Al atoms and gas molecules. These findings suggest that TiSe2 decorated with Cu and Al can effectively improve its sensitivity to NH3 and NO2, respectively, making it promising in gas sensing applications.


Contraception Use Among Reproductive-Age Women With Rheumatic Diseases.
To determine contraception use among a cohort of reproductive-age women (ages 18-50 years) with rheumatic diseases. We conducted a study of administrative data from a single, large medical center between the years 2013 and 2014. Women who had 1 of 21 possible rheumatic disease diagnoses and had at least 2 outpatient rheumatology visits were included in this analysis. We used logistic regression analyses to evaluate adjusted associations between the use of prescription contraception, use of potentially fetotoxic medications, and visits with rheumatologists, primary care providers, and gynecologists. Of 2,455 women in this sample, 32.1% received any prescription contraception, and 7.9% of women used highly effective prescription methods (intrauterine devices, implants, and surgical sterilization). More than 70% of women took ≥1 type of fetotoxic medication during the 2-year study timeframe. Fetotoxic medication use was not associated with overall use of prescription contraception, but was associated with the use of highly effective contraceptive methods (adjusted odds ratio [OR] 2.26 [95% confidence interval (95% CI) 1.44-3.54]). Women who saw gynecologists or primary care providers were more likely to use prescription contraception overall (adjusted OR 3.35 [95% CI 2.77-4.05] and 1.43 [95% CI 1.18-1.73], respectively). Women who saw gynecologists were more likely to use highly versus moderately effective contraceptive methods (adjusted OR 2.35 [95% CI 1.41-3.94]). Rheumatology visits were not associated with use of prescription contraception in any models. This is the largest study to date to describe contraceptive use among reproductive-age women with rheumatic diseases, and the findings reveal low use of prescription contraception. Urgent efforts are needed to improve contraceptive care and access for some women with rheumatic diseases.


Longitudinal growth of Bangladeshi infants during the first year of life.
The growth in length and weight of 91 poor urban Bangladeshi infants was monitored at monthly intervals from birth to 1 year. At birth 18%, 22% and 8% were below -2.00 standard deviations of the National Center for Health Statistics (NCHS) height-for-age, weight-for-age and weight-for-height, respectively and at 1 year the percentages were 40%, 40% and 7%. Infant weights over the first 6 months associated positively with both mother's BMI and percentage body fat. Higher mean infant weights from 6 to 12 months were associated with both higher educational status of the mother and monthly family income and the latter two variables provided the best model for predicting weight velocity from birth to 12 months. Internal Z-scores, corrected for day of measurement, provided clear evidence of catch-up/catch-down over the first 6 months with heavier and longer babies at birth showing catch-down while lighter and shorter babies demonstrated catch-up. Infants' weights were almost three times more variable than lengths. Monthly incremental variability of both infant weight and length increased sharply from 6 to 12 months with weight showing significantly more variability. The correlations of birth weight and length with subsequent distances and monthly increment revealed that the first 6 months were dominated by catch-up and catch-down but during the latter half of the year the growth phenomena were influenced mainly by earlier intra-uterine or genetic effects.


Causes of diplopia in the emergency department: diagnostic accuracy of clinical assessment and of head computed tomography.
Studies on frequency and underlying diseases causing binocular diplopia in patients presenting to the emergency department (ED) are lacking. To evaluate the prevalence of different diseases causing diplopia and the role of medical history, clinical examination, and unenhanced head computed tomography (UHCT) in the identification of secondary diplopia. Diplopic patients presenting to the ED were enrolled prospectively. Cardiovascular risk factors and associated neurological signs and symptoms were reported. UHCT was performed in the ED. Secondary diplopia was diagnosed in 93 of 260 (35.8%) diplopic patients. Among patients with secondary diplopia, the most frequent diagnoses were stroke (45.2%), multiple sclerosis (18.3%), brain tumors (11.8%), and cerebral aneurysms (7.5%). The prevalence of cardiovascular risk factors was similar in primary and secondary diplopia. Among the 118 (45.4%) patients without associated neurological signs or symptoms (isolated diplopia), secondary diplopia was diagnosed in 13 (11%); UHCT was negative in all 13 cases, with a derived null sensitivity. Eighty of 142 (56.3%) patients with associated signs or symptoms had secondary diplopia. The presence of signs or symptoms associated with diplopia showed a sensitivity of 87% [95% confidence interval (CI): 80-92%] and a specificity of 63% (95% CI: 59-66%) for the diagnosis of secondary diplopia. In this group, UHCT identified 30 of 80 (37.5%) cases, increasing the specificity to 98% (95% CI: 96-99%). One-third of diplopic patients had secondary diplopia. In patients with isolated diplopia, UHCT does not increase diagnostic sensitivity. In patients with associated neurological signs or symptoms, the prevalence of secondary diplopia was high and UHCT showed incremental diagnostic value.


How well do we recognise non-motor symptoms in a British Parkinson's disease population?
Although awareness of non-motor symptoms in Parkinson's disease (PD) has recently increased, little is known about their recognition and treatment in routine clinical practice. We therefore applied non-motor rating scales for dementia, depression, anxiety and excessive daytime sleepiness to a community-ascertained cohort of 202 PD patients. Hospital case notes were reviewed for evidence that the non-motor problems had been recognized and whether any action had been taken to ameliorate or assess these symptoms. The prevalence of each non-motor problem was as follows: dementia 25.3% (95% CI 19.0, 32.4), depression 37.3% (95% CI 30.6, 44.4), anxiety 31.3% (95% CI 25.0, 38.2), excessive daytime sleepiness 59.4% (95% CI 52.2, 66.3). However, these features were only recognised in 27.2, 38.7, 9.5, and 12.8%, respectively. We did not identify any specific factor that predicted under-recognition. Our study shows that when rating scales are applied to formally assess for non-motor symptoms a large clinical 'iceberg effect' emerges with the majority of symptoms going unrecognised and untreated.


Model complexity control for regression using VC generalization bounds.
It is well known that for a given sample size there exists a model of optimal complexity corresponding to the smallest prediction (generalization) error. Hence, any method for learning from finite samples needs to have some provisions for complexity control. Existing implementations of complexity control include penalization (or regularization), weight decay (in neural networks), and various greedy procedures (aka constructive, growing, or pruning methods). There are numerous proposals for determining optimal model complexity (aka model selection) based on various (asymptotic) analytic estimates of the prediction risk and on resampling approaches. Nonasymptotic bounds on the prediction risk based on Vapnik-Chervonenkis (VC)-theory have been proposed by Vapnik. This paper describes application of VC-bounds to regression problems with the usual squared loss. An empirical study is performed for settings where the VC-bounds can be rigorously applied, i.e., linear models and penalized linear models where the VC-dimension can be accurately estimated, and the empirical risk can be reliably minimized. Empirical comparisons between model selection using VC-bounds and classical methods are performed for various noise levels, sample size, target functions and types of approximating functions. Our results demonstrate the advantages of VC-based complexity control with finite samples.


Scanning electron microscopy of baboon spermatozoa.
Ejaculated baboon sperm was observed by scanning electron microscopy. The plasma membrane was generally smooth except on the acrosome where it was probably slightly wrinkled. The head was short, oval, paddle-shaped and tapering at its anterior end. The anterior segment of the acrosome was surrounded by a marginal thickening; the postacrosomal region was limited anteriorly by the equatorial segment and caudally by the posterior ring. Subsurface structures were visible in the tail, such as the relatively long and regular helix of mitochondria in the middle piece and the columns and ribs of the sheath in the principal piece. The morphology and dimensions of the baboon sperm was compared with that of other Primates and found very close to that of other Cercopithecidae.


Reducing the influence of the partial volume effect on SPECT activity quantitation with 3D modelling of spatial resolution in iterative reconstruction.
Quantitative parameters such as the maximum and total counts in a volume are influenced by the partial volume effect. The magnitude of this effect varies with the non-stationary and anisotropic spatial resolution in SPECT slices. The objective of this investigation was to determine whether iterative reconstruction which includes modelling of the three-dimensional (3D) spatial resolution of SPECT imaging can reduce the impact of the partial volume effect on the quantitation of activity compared with filtered backprojection (FBP) techniques which include low-pass, and linear restoration filtering using the frequency distance relationship (FDR). The iterative reconstruction algorithms investigated were maximum-likelihood expectation-maximization (MLEM), MLEM with ordered subset acceleration (ML-OS), and MLEM with acceleration by the rescaled-block-iterative technique (ML-RBI). The SIMIND Monte Carlo code was used to simulate small hot spherical objects in an elliptical cylinder with and without uniform background activity as imaged by a low-energy ultra-high-resolution (LEUHR) collimator. Centre count ratios (CCRs) and total count ratios (TCRs) were determined as the observed counts over true counts. CCRs were unstable while TCRs had a bias of approximately 10% for all iterative techniques. The variance in the TCRs for ML-OS and ML-RBI was clearly elevated over that of MLEM, with ML-RBI having the smaller elevation. TCRs obtained with FDR-Wiener filtering had a larger bias (approximately 30%) than any of the iterative reconstruction methods but near stationarity is also reached. Butterworth filtered results varied by 9.7% from the centre to the edge. The addition of background has an influence on the convergence rate and noise properties of iterative techniques.


Near-infrared light-triggered prodrug photolysis by one-step energy transfer.
Prodrug photolysis enables spatiotemporal control of drug release at the desired lesions. For photoactivated therapy, near-infrared (NIR) light is preferable due to its deep tissue penetration and low phototoxicity. However, most of the photocleavable groups cannot be directly activated by NIR light. Here, we report a upconversion-like process via only one step of energy transfer for NIR light-triggered prodrug photolysis. We utilize a photosensitizer (PS) that can be activated via singlet-triplet (S-T) absorption and achieve photolysis of boron-dipyrromethene (BODIPY)-based prodrugs via triplet-triplet energy transfer. Using the strategy, NIR light can achieve green light-responsive photolysis with a single-photon process. A wide range of drugs and bioactive molecules are designed and demonstrated to be released under low-irradiance NIR light (100 mW/cm2, 5 min) with high yields (up to 87%). Moreover, a micellar nanosystem encapsulating both PS and prodrug is developed to demonstrate the practicality of our strategy in normoxia aqueous environment for cancer therapy. This study may advance the development of photocleavable prodrugs and photoresponsive drug delivery systems for photo-activated therapy.


Spontaneous dimensional reduction and ground state degeneracy in a simple chain model.
Chain molecules play a key role in the polymer field and in living cells. Our focus is on a new homopolymer model of a linear chain molecule subject to an attractive self-interaction promoting compactness. We analyze the model using simple analytic arguments complemented by extensive computer simulations. We find several striking results: there is a first-order transition from a high-temperature random coil phase to a highly unusual low-temperature phase; the modular ground states exhibit significant degeneracy; the ground state structures exhibit spontaneous dimensional reduction and have a two-layer structure; and the ground states are assembled from secondary motifs of helices and strands connected by tight loops. We discuss the similarities and notable differences between the ground state structures [we call these PoSSuM (Planar Structures with Secondary Motifs)] in the phase and protein native state structures.