Socially-Assistive Robots Using Empathy to Reduce Pain and Distress during Peripheral IV Placement in Children.
Socially-assistive robots (SAR) have been used to reduce pain and distress in children in medical settings. Patients who perceive empathic treatment have increased satisfaction and improved outcomes. We sought to determine if an empathic SAR could be developed and used to decrease pain and fear associated with peripheral IV placement in children. We conducted a pilot study of children receiving IV placement. Participating children were randomized to interact with (1) no robot, or a commercially available 3D printed humanoid SAR robot programmed with (2) empathy or (3) distraction conditions. Children and parents completed demographic surveys, and children used an adapted validated questionnaire to rate the robot's empathy on an 8-point Likert scale. Survey scores were compared by the t-test or chi-square test. Pain and fear were measured by self-report using the FACES and FEAR scales, and video tapes were coded using the CHEOPS and FLACC. Scores were compared using repeated measures 2-way ANOVA. This trial is registered with NCT02840942. Thirty-one children with an average age of 9.6 years completed the study. For all measures, mean pain and fear scores were lowest in the empathy group immediately before and after IV placement. Children were more likely to attribute characteristics of empathy to the empathic condition (Likert score 7.24 v. 4.70; p=0.012) and to report that having the empathic vs. distraction robot made the IV hurt less (7.45 vs. 4.88; p=0.026). Children were able to identify SAR designed to display empathic characteristics and reported it helped with IV insertion pain and fear. Mean scores of self-reported or objective pain and fear scales were the lowest in the empathy group and the highest in the distraction condition before and after IV insertion. This result suggests empathy improves SAR functionality when used for painful medical procedures and informs future research into SAR for pain management.


A novel strategy of "pick the best of the best" for the nondestructive identification of Poria cocos based on near-infrared spectroscopy.
In this paper, a novel strategy of "pick the best of the best" was proposed for the nondestructive identification of different-origin and adulterated Poria cocos with near-infrared spectroscopy. First, various preprocessing methods were divided into three classes: baseline correction, scattering and trend correction, and scaling. The single preprocessing methods with the best predictions in each class were selected. Then, the selected preprocessing methods were combined in pairs according to three classes. The pair combination preprocessing methods with the best predictions and also better predictions than single methods were selected. Finally, the selected pair combination preprocessing method was combined with the methods in the unselected class. The three combination preprocessing methods with the best predictions and also better predictions than pair combination methods were selected as the final prediction. With this strategy, the optimized preprocessing combination can be obtained quickly, and the identification accuracy with principal component analysis method can be greatly improved. 0% identification accuracy of adulterated samples and 12.5% identification accuracy of different-origin samples were obtained with the raw data. However, 100% accuracy of adulterated samples, 93.8% accuracy of calibration dataset, and 75% accuracy of validation dataset can be obtained with the novel strategy. The developed technology can be regarded as a simple, rapid, and accurate nondestructive identification method for different-origin and adulterated samples, and has a broad application prospect in the future.


CFSH: Factorizing sequential and historical purchase data for basket recommendation.
To predict what products customers will buy in next transaction is an important task. Existing work in next-basket prediction can be summarized into two paradigms. One is the item-centric paradigm, where sequential patterns are mined from customers' transactional data and leveraged for prediction. However, these approaches usually suffer from the data sparseness problem. The other is the user-centric paradigm, where collaborative filtering techniques have been applied on customers' historical data. However, these methods ignore the sequential behaviors of customers which is often crucial for next-basket prediction. In this paper, we introduce a hybrid method, namely the Co-Factorization model over Sequential and Historical purchase data (CFSH for short) for next-basket recommendation. Compared with existing methods, our approach conveys the following merits: 1) By mining global sequential patterns, we can avoid the sparseness problem in traditional item-centric methods; 2) By factorizing product-product and customer-product matrices simultaneously, we can fully exploit both sequential and historical behaviors to learn customer and product representations better; 3) By using a hybrid recommendation method, we can achieve better performance in next-basket prediction. Experimental results on three real-world purchase datasets demonstrated the effectiveness of our approach as compared with the state-of-the-art methods.


Improving prostate cancer care collaboratively - a multidisciplinary, formal, consensus-based approach.
There are numerous standard treatment options for men diagnosed with localized prostate cancer. Multidisciplinary consultation before decision-making is a consensus- and quality-based objective in Ontario. With the goals of working together more collaboratively and to provide higher quality information for patients at the time of decision-making, a prostate cancer community partnership consensus (PCPC) panel was formed among six partnering centers in the Greater Toronto Area. Five iterative meetings were held among 40 prostate cancer specialists (32 urologists and 8 radiation oncologists) who participate in multidisciplinary clinics. The meetings defined the goals of the partnership as well as the topics and questions the group would address together. Answers to these questions were developed by formal consensus: >= 75% of participants had to agree with wording based on secret ballots to achieve consensus. All six groups wanted to participate to improve patient care/decision-making. Forty-one questions addressing 30 issues were derived from the literature and the group's collective experience. These issues were cross-tabbed against five management options: active surveillance, radical prostatectomy, low dose rate brachytherapy, high dose rate brachytherapy boost and external beam radiation. Answers common to all modalities were coalesced. Eighty-six issues were subjected to formal consensus. After three rounds of secret ballots, consensus was achieved for the answers to all issues. A formal consensus-based partnership between urology and radiation oncology to support newly diagnosed prostate cancer patients was feasible and resulted in a patient information guide which may improve decision-making.


Work-related stress, burnout, and related sociodemographic factors among nurses: Implications for administrators, research, and policy.
This study examined work-related stress and burnout symptoms with respect to related sociodemographic factors among nurses in Nigeria.A representative sample of nurses (N = 393) was randomly selected from hospitals in Southeast Nigeria to take part in this cross-sectional, correlational study from June to December 2017. Participants received questionnaires by mail, which measured work stress and burnout symptoms, respectively. Data collected were analyzed using bivariate correlations and multiple regression analyses.Among the sociodemographic factors investigated, sex was significantly correlated with work-related stress. The sociodemographic factors were not significantly associated with burnout symptoms. Stepwise multiple regression procedure produced a model that contained four sociodemographic factors and explained 4.5% of the variance in nurses' work stress scores and 0.8% of the variance in nurses' burnout scores. Age, work environment, and work experience did not make significant contributions to the prediction of work-related stress among the nurses. Finally, sex, age, work environment, and work experience did not make significant contributions to the prediction of burnout among the nurses.Nurses' sociodemographic factors, which included sex, age, work environment and work experience accounted for only a small proportion of variance in nurses' work stress and burnout in Southeast Nigeria. The study also furthers our awareness that sex is significantly linked to work-related stress among the nurses in Southeast Nigeria. Thus, the implications of the study for administrators, research, and policy were discussed.


Dermabrasion and Retinoic Acid in the Treatment of Pachyonychia Cogenita.
A typical case of pachyonychia congenita in a female is presented. Of the sixty cases of pachyonychia congenita reported in the literature, only one case is a female. Cases have been seen in families upto five generations. In our case five family members belonging to two generations manifested the disease. The hyperkeratotic plantar lesions were painful and incapacitating to the patients. With combined dermabrasion and topical retinoic acid the patients were made rapidly ambulatory. This new modality of treatment seemed gratifying in that the symptomatic relief to the patient was excellent.


Antifungal activity of the pygidial gland secretion of Laemostenus punctatus (Coleoptera: Carabidae) against cave-dwelling micromycetes.
The antifungal potential of the pygidial gland secretion of the troglophilic ground beetle Laemostenus punctatus from a cave in Southeastern Serbia against cave-dwelling micromycetes, isolated from the same habitat, has been investigated. Eleven collected samples were analyzed and 32 isolates of cave-dwelling fungi were documented. A total of 14 fungal species were identified as members of the genera Aspergillus, Penicillium, Alternaria, Cladosporium, Rhizopus, Trichoderma, Arthrinium, Aureobasidium, Epicoccum, Talaromyces, and Fusarium. Five isolates were selected for testing the antifungal activity of the pygidial gland secretion: Talaromyces duclauxi, Aspergillus brunneouniseriatus, Penicillium sp., Rhizopus stolonifer, and Trichoderma viride. The microdilution method has been applied to detect minimal inhibitory concentrations (MICs) and minimal fungicidal concentrations (MFCs). The most sensitive isolate was Penicillium sp., while the other isolates demonstrated a high level of resistance to the tested agent. L. punctatus has developed a special mechanism of producing specific compounds that act synergistically within the secretion mixture, which are responsible for the antifungal action against pathogens from the cave. The results open opportunities for further research in the field of ground beetle defense against pathogens, which could have an important application in human medicine, in addition to the environmental impact, primarily.


The Right to Food and the Planetary Boundaries framework.
The 'Right to Food' is a legal entitlement owed to all human beings established in international law more than half a century ago. Fulfilment of the right has been entrusted to states parties to the 1966 International Covenant on Economic, Social and Cultural Rights (ICESCR). However, in practice, the right is often breached because of hostility or indifference from individuals or institutions refusing access to provisions, or because of vicissitudes of nature. Adverse impacts due to human interference in natural processes are increasingly noticeable in the area of food production. These processes have been classified into nine distinct categories, all of which need be kept within certain margins, so-called 'Planetary Boundaries', which delineate a safe operating space for humanity. This paper discusses the impact each of these human-induced developments has on the provision of food as well as the other way round and what the consequences would be if the boundaries were exceeded. Yet there are means of keeping the worst consequences of most of these processes at bay. The paper explores some of these.


Evaluation of the Performance of Two Nomograms and Four Vault Prediction Formulas for Implantable Collamer Lens Size Selection.
To evaluate the performance of different nomograms and vault prediction formulas in predicting the optimal Implantable Collamer Lens (ICL; STAAR Surgical) size and vault. This retrospective study included 108 participants (214 eyes) who underwent ICL implantation. The efficacy of the manufacturer's nomogram, Parkhurst nomogram, NK formula, KS formula, Zhu formula, and ZZ formula was assessed by comparing the indicated ICL sizes to the postoperative vault measurements. Additionally, Bland-Altman plots and the Friedman test were used to assess the agreement and absolute error between the actual vault and predicted vault. The proportions of the ideal ICL category recommended by the manufacturer's nomogram, Parkhurst nomogram, NK formula, KS formula, Zhu formula, and ZZ formula were 50.5%, 45.3%, 46.7%, 42.5%, 50.0%, and 28.5%, respectively. The mean differences between the actual vault and the predicted vault using the NK, KS, Zhu, and ZZ formulas were 144.1 ± 261.1, -19.3 ± 179.6, 70.8 ± 284.2, and 182.6 ± 361.5 μm, respectively. The predicted ICL vault tended to overestimate the actual ICL vault, particularly when choosing a larger ICL size. The KS formula shows the smallest deviation in prediction error and is least affected by variation in ICL size. White-to-white distance from the Pentacam (Oculus Optikgeräte GmbH) coupled with the manufacturer's nomogram performed well for ICL size selection. Four vault prediction formulas tended to overestimate the actual ICL vault, particularly when selecting a larger ICL size. The KS formula appeared to have the least bias of the formulas. Simultaneously, vault prediction formulas need to be modified according to the ICL size. [J Refract Surg. 2023;39(7):456-461.].


The Value of Qualitative Description in Health Services and Policy Research.
Health services and policy (HSP) researchers have long used qualitative research methodologies to explore health system issues. However, the appropriateness of one approach, qualitative description, for HSP research is still often overlooked. In this article, I discuss the role that qualitative description can play in HSP research, and argue for its greater acceptance as a valid form of academic scholarship.


Taxane-Platin-Resistant Lung Cancers Co-develop Hypersensitivity to JumonjiC Demethylase Inhibitors.
Although non-small cell lung cancer (NSCLC) patients benefit from standard taxane-platin chemotherapy, many relapse, developing drug resistance. We established preclinical taxane-platin-chemoresistance models and identified a 35-gene resistance signature, which was associated with poor recurrence-free survival in neoadjuvant-treated NSCLC patients and included upregulation of the JumonjiC lysine demethylase KDM3B. In fact, multi-drug-resistant cells progressively increased the expression of many JumonjiC demethylases, had altered histone methylation, and, importantly, showed hypersensitivity to JumonjiC inhibitors in vitro and in vivo. Increasing taxane-platin resistance in progressive cell line series was accompanied by progressive sensitization to JIB-04 and GSK-J4. These JumonjiC inhibitors partly reversed deregulated transcriptional programs, prevented the emergence of drug-tolerant colonies from chemo-naive cells, and synergized with standard chemotherapy in vitro and in vivo. Our findings reveal JumonjiC inhibitors as promising therapies for targeting taxane-platin-chemoresistant NSCLCs.


Kinetic and equilibrium study on formic acid decomposition in relation to the water-gas-shift reaction.
Kinetics and equilibrium are studied on the hydrothermal decarbonylation and decarboxylation of formic acid, the intermediate of the water-gas-shift (WGS) reaction, in hot water at temperatures of 170-330 degrees C, to understand and control the hydrothermal WGS reaction. (1)H and (13)C NMR spectroscopy is applied to analyze as a function of time the quenched reaction mixtures in both the liquid and gas phases. Only the decarbonylation is catalyzed by HCl, and the reaction is first-order with respect to both [H(+)] and [HCOOH]. Consequently, the reaction without HCl is first and a half (1.5) order due to the unsuppressed ionization of formic acid. The HCl-accelerated decarbonylation path can thus be separated in time from the decarboxylation. The rate and equilibrium constants for the decarbonylation are determined separately by using the Henry constant (gas solubility data) for carbon monoxide in hot water. The rate constant for the decarbonylation is 1.5 x 10(-5), 2.0 x 10(-4), 3.7 x 10(-3), and 6.3 x 10(-2) mol(-1) kg s(-1), respectively, at 170, 200, 240, and 280 degrees C on the liquid branch of the saturation curve. The Arrhenius plot of the decarbonylation is linear and gives the activation energy as 146 +/- 3 kJ mol(-1). The equilibrium constant K(CO) = [CO]/[HCOOH] is 0.15, 0.33, 0.80, and 4.2, respectively, at 170, 200, 240, and 280 degrees C. The van't Hoff plot results in the enthalpy change of DeltaH = 58 +/- 6 kJ mol(-1). The decarboxylation rate is also measured at 240-330 degrees C in both acidic and basic conditions. The rate is weakly dependent on the solution pH and is of the order of 10(-4) mol kg(-1) s(-1) at 330 degrees C. Furthermore, the equilibrium constant K(CO2) = [CO(2)][H(2)]/[HCOOH] is estimated to be 1.0 x10(2) mol kg(-1) at 330 degrees C.


[Treatment of thoracolumbar tumors with total en bloc spondylectomy and the results of spinal stability reconstruction].
To investigate the therapeutic effect of total en bloc spondylectomy (TES) for thoracolumbar tumors and the results of spinal stability reconstruction. From January 2007 to June 2011 there were 18 patients with thoracolumbar tumors distributed in the thoracic vertebrae (n = 10) and lumbar vertebrae (n = 8). There were 7 haemangiomas, 5 giant cell tumors of bone, 1 malignant schwannoma, 1 solitary plasmocytoma, 1 neuroblastoma, 1 osteoblastoma, 1 metastatic malignant fibrous histiocytoma, and 1 metastasis of breast cancer. All the 18 patients were treated with improved TES under electrophysiological monitoring of spinal cord. Four patients were treated through one-stage combined anteroposterior approach and 14 patients through one-stage posterior approach. The anterior reconstructions included titanium mesh cages filled with bone or bone cement in 15 cases, titanium mesh cage with strengthened rings in 2 cases and artificial vertebral body replacement in 1 case. The posterior reconstruction included multiple segmental fixation with pedicle screw-rod system in 15 cases and short segmental fixation in 3 cases. Massive bone auto-graft was employed in 13 cases and fragmental bone graft in 5 cases. The total en bloc spondylectomy was performed successfully in 15 patients and unsuccessful in 3 whose spinal tumors were resected by piecemeal technique. In 15 patients with successfully performed TES, the duration of surgery was from 340 to 610 min (average, 450.7 min), the blood loss was from 3000 to 10 200 ml (average, 4850 ml), and the intraoperative blood transfusion was from 2800 to 9600 ml (average, 4200 ml). The operation-related complications comprised hemopneumothorax, intercostal nerve pain, stress ulcer and bleeding, and so on. One year after operation, the patients with neurological dysfunction recovered from grade A to grade D in one patient, and to grade E in the other 14 cases. The average visual analog scale (VAS) scores was 0.5. One patient with plasmacytoma and another one with L5 metastatic tumor suffered progression of the disease and were living with the diseases. The patient with metastatic malignant fibrous histiocytoma died of local recurrence and lung metastasis 16 months postoperatively. One patient with L4 neuroblastoma died of other reason and all the rest were free from relapse. The Cobb angle of upper and lower vertebral body adjacent to the involved vertebrae in sagittal plane was from -26.7° to 12.0° (average, -2.57°) just postoperatively and from -17.5° to 57.2° (average, 11.5°) at the last follow-up or before reoperation. There were 2 patients with screw-rod breakdown and 2 patients with internal fixation loosening. The measurement of titanium mesh cage subsided into adjacent vertebral bodies was average 7.5 mm. The revision surgery was performed in 3 patients, through combined anteroposterior approach in 2 and only posterior approach in 1 patient. TES significantly increases the therapeutic effect of spinal tumors, although accompanied with high difficulty and massive bleeding. In spinal stability reconstruction after total spondylectomy, it should be emphasized that posterior long segment fixation with pedicle screw-rod system, massive bone bridging graft and the application of thoracolumbosacral orthosis can achieve short-term firm fixation and long-term fusion-stabilization.


Identification of a novel target of SETD1A histone methyltransferase and the clinical significance in pancreatic cancer.
Although histone H3K4 methyltransferase SETD1A is overexpressed in various cancer types, the molecular mechanism underlying its overexpression and its target genes in pancreatic ductal adenocarcinoma (PDAC) remain unclarified. We conducted immunohistochemical staining for SETD1A in 105 human PDAC specimens to assess the relationship between SETD1A overexpression and clinicopathological features. The function and target genes of SETD1A were investigated using human pancreatic cancer cell lines. SETD1A expression was upregulated in 51.4% of patients with PDAC and was an independent prognostic factor associated with shorter disease-free survival after resection (p < 0.05). Knockdown and overexpression of SETD1A showed that SETD1A plays a crucial role in increasing the proliferation and motility of PDAC cells. SETD1A overexpression increased tumorigenicity. RNA sequencing of SETD1A-knockdown cells revealed downregulation of RUVBL1, an oncogenic protein ATP-dependent DNA helicase gene. ChIP analysis revealed that SETD1A binds to the RUVBL1 promoter region, resulting in increased H3K4me3 levels. Knockdown of RUVBL1 showed inhibition of cell proliferation, migration, and invasion of PDAC cells, which are similar biological effects to SETD1A knockdown. High expression of both SETD1A and RUVBL1 was an independent prognostic factor not only for disease-free survival but also for overall survival (p < 0.05). In conclusion, we identified RUVBL1 as a novel downstream target gene of the SETD1A-H3K4me3 pathway. Co-expression of SETD1A and RUVBL1 is an important factor for predicting the prognosis of patients with PDAC.


Tailoring haemostatic treatment to patient requirements - an update on monitoring haemostatic response using thrombelastography.
Currently, there is no single haemostasis laboratory test that has the capacity to accurately illustrate the clinical effects of procoagulant or anticoagulant interventions. Although the time course of thrombin generation in plasma and the endogenous thrombin potential (ETP) may be useful coagulation parameters, clotting involves components other than thrombin (e.g. platelets, fibrinogen). The continuous coagulation profiles of thrombelastography may provide a more accurate reflection of in vivo biology, covering initiation, development and final clot strength during whole blood clot formation. This method has helped to clarify the mechanism of action of whole blood clot formation, demonstrating the differences from clotting in plasma, and the importance of platelets and tissue factor titrations. It has also been used to investigate hypocoagulation (in haemophilia A, rare coagulation disorders, anticoagulant therapy and dilutional coagulopathy), hypercoagulation and the ex vivo testing of haemostatic interventions. Thrombelastography has been shown to reflect the clinical efficacy of activated prothrombin complex concentrate (aPCC) and recombinant activated factor VII (rFVIIa) in patients with haemophilia A with inhibitors and in patients with acquired haemophilia. Overall, tailoring laboratory assays to illustrate and correlate with clinical phenotypes is essential for effective coagulation monitoring. Applying an algorithm of preoperative, perioperative and postoperative tests, including thrombelastography, may enable physicians to achieve this.


SSA-MOA: a novel CTC isolation platform using selective size amplification (SSA) and a multi-obstacle architecture (MOA) filter.
Circulating tumor cells (CTCs) have gained increasing attention as physicians and scientists learn more about the role these extraordinarily rare cells play in metastatic cancer. In developing CTC technology, the critical criteria are high recovery rates and high purity. Current isolation methods suffer from an inherent trade-off between these two goals. Moreover, ensuring minimal cell stress and robust reproducibility is also important for the clinical application of CTCs. In this paper, we introduce a novel CTC isolation technology using selective size amplification (SSA) for target cells and a multi-obstacle architecture (MOA) filter to overcome this trade-off, improving both recovery rate and purity. We also demonstrate SSA-MOA's advantages in minimizing cell deformation during filter transit, resulting in more stable and robust CTC isolation. In this technique, polymer microbeads conjugated with anti-epithelial cell adhesion molecules (anti-EpCAM) were used to selectively size-amplify MCF-7 breast cancer cells, definitively differentiating from the white blood cells (WBCs) by avoiding the size overlap that compromises other size selection methods. 3 μm was determined to be the optimal microbead diameter, not only for size discrimination but also in maximizing CTC surface coverage. A multi-obstacle architecture filter was fabricated using silicon-on-glass (SOG) technology-a first such application of this fabrication technique-to create a precise microfilter structure with a high aspect ratio. The filter was designed to minimize cell deformation as simulation results predicted that cells captured via this MOA filter would experience 22% less moving force than with a single-obstacle architecture. This was verified by experiments, as we observed reliable cell capture and reduced cell deformation, with a 92% average recovery rate and 351 peripheral blood leukocytes (PBL) per millilitre (average). We expect the SSA-MOA platform to optimize CTC recovery rates, purity, and stability, increasing the sensitivity and reliability of such tests, thereby potentially expanding the utilization of CTC technologies in the clinic.


On static triplet structures in fluids with quantum behavior.
The problem of the equilibrium triplet structures in fluids with quantum behavior is discussed. Theoretical questions of interest to the real space structures are addressed by studying the three types of structures that can be determined via path integrals (instantaneous, centroid, and total thermalized-continuous linear response). The cases of liquid para-H2 and liquid neon on their crystallization lines are examined with path-integral Monte Carlo simulations, the focus being on the instantaneous and the centroid triplet functions (equilateral and isosceles configurations). To analyze the results further, two standard closures, Kirkwood superposition and Jackson-Feenberg convolution, are utilized. In addition, some pilot calculations with path integrals and closures of the instantaneous triplet structure factor of liquid para-H2 are also carried out for the equilateral components. Triplet structural regularities connected to the pair radial structures are identified, a remarkable usefulness of the closures employed is observed (e.g., triplet spatial functions for medium-long distances, triplet structure factors for medium k wave numbers), and physical insight into the role of pair correlations near quantum crystallization is gained.


Cryptography as information control.
In 1976, two researchers declared a revolution in cryptography: With the invention of public key encryption, cryptography could be used not only to share secret messages, but to secure and authenticate communications networks, and, eventually, to enable radically new kinds of social relationships facilitated by networked communication technology. This article explores a series of transformations in the meaning of cryptography in the 1960s and 1970s that led to the declaration of a revolution. Drawing on archival materials, the article considers how public key cryptography was the product of an emerging consensus among cryptographers of the importance of privacy in the wake of abuses of surveillance powers by government agencies. Shaped by a changing technological and political environment, it situates cryptography at the center of a focused effort to assert control over information in an era of sociopolitical upheaval, concluding that the invention of public key encryption both marked a change in the imaginary surrounding cryptography and offered a technical solution that foreclosed other approaches to addressing the problem of surveillance.


Calcified left ventricular aneurysm and non-atherosclerotic myocardial infarction in a child.
A 14-year-old boy, admitted with intractable chest pain, was found to have an enlarged heart and calcification in the apical region, with electrocardiographic features of massive inferolateral myocardial infarction. Left ventricular angiography revealed a large left ventricular aneurysm. He died following resection of the aneurysm and post mortem examination showed changes of a non-specific chronic myocarditis. A vasculitis involving small coronary arterioles was also found in the vicinity of the aneurysm, and the possibility of a rheumatic vasculitis was suggested by a transient episode of an erythema marginatum-like eruption. It is concluded that the association of infarction pattern on the electrocardiogram together with calcification of the heart in children is highly suggestive of a ventricular aneurysm secondary to a myocarditis or a vasculitis involving small, intramyocardial branches of the coronary arteries.


The potential of adeno-associated viral vectors for gene delivery to muscle tissue.
Muscle-directed gene therapy is rapidly gaining attention primarily because muscle is an easily accessible target tissue and is also associated with various severe genetic disorders. Localized and systemic delivery of recombinant adeno-associated virus (rAAV) vectors of several serotypes results in very efficient transduction of skeletal and cardiac muscles, which has been achieved in both small and large animals, as well as in humans. Muscle is the target tissue in gene therapy for many muscular dystrophy diseases, and may also be exploited as a biofactory to produce secretory factors for systemic disorders. Current limitations of using rAAVs for muscle gene transfer include vector size restriction, potential safety concerns such as off-target toxicity and the immunological barrier composing of pre-existing neutralizing antibodies and CD8(+) T-cell response against AAV capsid in humans. In this article, we will discuss basic AAV vector biology and its application in muscle-directed gene delivery, as well as potential strategies to overcome the aforementioned limitations of rAAV for further clinical application. Delivering therapeutic genes to large muscle mass in humans is arguably the most urgent unmet demand in treating diseases affecting muscle tissues throughout the whole body. Muscle-directed, rAAV-mediated gene transfer for expressing antibodies is a promising strategy to combat deadly infectious diseases. Developing strategies to circumvent the immune response following rAAV administration in humans will facilitate clinical application.


Hb Manitoba [α102(G9)Ser→Arg] in Pasifika: Tongan Case Report.
Hb Manitoba [α102(G9)Ser→Arg] results from an AGC>CGC or AGC>AGA substitution at codon 102 of the HBA1 or HBA2 genes. The variant is mildly unstable but carriers typically have normal clinical presentation and hematological profile. Hb Manitoba has not been reported in Pasifika of Tongan, Samoan or New Zealand (NZ) Māori descent before. The cases presented here support the findings from existing literature but include results from alternative methodology including capillary zone electrophoresis (CZE), which may slightly underestimate the true variant percentage. The subject of our case report, a Tongan male with microcytic indices, was shown to be heterozygous for Hb Manitoba III (HBA2: c.309C>A) coinherited with the -α3.7 (rightward) deletion.


Transformative Heterointerface Evolution and Plasmonic Tuning of Anisotropic Trimetallic Nanoparticles.
Multicomponent nanoparticles that incorporate multiple nanocrystal domains into a single particle represent an important class of material with highly tailorable structures and properties. The controlled synthesis of multicomponent NPs with 3 or more components in the desired structure, particularly anisotropic structure, and property is, however, challenging. Here, we developed a polymer and galvanic replacement reaction-based transformative heterointerface evolution (THE) method to form and tune gold-copper-silver multimetallic anisotropic nanoparticles (MAPs) with well-defined configurations, including structural order, particle and junction geometry, giving rise to extraordinarily high tunability in the structural design, synthesis and optical property of trimetallic plasmonic nanoantenna structures. MAPs can easily, flexibly integrate multiple surface plasmon resonance (SPR) peaks and incorporate various plasmonic field localization and enhancement within one structure. Importantly, a heteronanojunction in these MAPs can be finely controlled and hence tune the SPR properties of these structures, widely covering UV, visible and near-infrared range. The development of the THE method and new findings in synthesis and property tuning of multicomponent nanostructures pave ways to the fabrication of highly tailored multicomponent nanohybrids and realization of their applications in optics, energy, catalysis and biotechnology.


Recent experimental results of effects of perfluoroalkyl substances in laboratory animals - Relation to current regulations and guidance values.
The detection of perfluoroalkyl substances (PFAS) in surface and drinking water from various countries raised the attention to the presence of these chemicals in environmental probes and led to several regulatory actions to limit exposure in human beings. There was particular concern about perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS), due to their former wide-spread use. Recently, several institutions published revisions of former regulatory or recommended maximum concentrations in drinking water and food, which are markedly lower than the former values. The present short overview describes the current regulations for PFAS and compares them with the outcome of several experimental studies in laboratory animals at low-level exposure to PFOA and PFOS. In addition, regulations for short-chain PFAS are presented which, due to lack of toxicological information, are evaluated according to the concepts of Threshold of Toxicological Concern (TTC) or the Health-related Indication Values (HRIV).


Oral Escherichia coli expressing IL-35 meliorates experimental colitis in mice.
Ulcerative colitis (UC) is a type of inflammatory bowel disease (IBD) characterized by chronic inflammation of colon. It is commonly believed that the imbalance of immune system and overwhelming production of cytokines are involved in the pathogenesis of UC. Recent studies demonstrated that interleukin-35 (IL-35), a key player in the regulation of inflammation, has been identified as potential therapeutic target to treat UC. However, conventional intravenous administration is costly and inconvenient. The present study was designed to establish a novel IL-35 delivery system and investigate its therapeutic effects on dextran sulfate sodium (DSS)-induced experimental colitis in mice for the first time. An engineered Escherichia coli (E. coli/IL-35) expressing IL-35 was constructed. Adult male BALB/c mice randomly got the oral administration of E. coli/IL-35, empty plasmid-transformed E. coli (E. coli0) or PBS for treatment following ingestion of 3% DSS solution for 5 days. Normal mice were used as control group. Colonic and splenic tissues were collected on day 10 post-DSS-induction. Clinical signs, disease activity index (DAI), pathological and immunohistological changes, cytokine profiles and cell populations were evaluated. Intragastric administration of E. coli/IL-35 effectively protected the colitis mice from DSS assimilation including weight loss and colon shortening. Pathological analysis showed significantly lower DAI score and much less intra-colon infiltration of neutrophils and CD3+ cells in the IL-35 treated group. Moreover, E. coli/IL-35-treated mice demonstrated much less CD4+ IL-17A+ Th17 cells and a higher level of CD4+CD25+Foxp3+ Tregs in spleen and mesenteric lymph nodes, as well as increased colon and serum level of IL-10 and IL-35 and decreased levels of IL-6. Our study showed that E. coli/IL-35 as a novel oral IL-35 delivery system alleviated inflammatory damage of colonic tissue in the colitic mice. Genetic therapeutic strategies using engineered E. coli encoding immunoregulatory cytokines may provide a potential approach for the treatment of IBD.


Nano-delivery systems as a promising therapeutic potential for epilepsy: Current status and future perspectives.
Epilepsy is a common chronic neurological disorder caused by aberrant neuronal electrical activity. Antiseizure medications (ASMs) are the first line of treatment for people with epilepsy (PWE). However, their effectiveness may be limited by their inability to cross the blood-brain barrier (BBB), among many other potential underpinnings for drug resistance in epilepsy. Therefore, there is a need to overcome this issue and, hopefully, improve the effectiveness of ASMs. Recently, synthetic nanoparticle-based drug delivery systems have received attention for improving the effectiveness of ASMs due to their ability to cross the BBB. Furthermore, exosomes have emerged as a promising generation of drug delivery systems because of their potential benefits over synthetic nanoparticles. In this narrative review, we focus on various synthetic nanoparticles that have been studied to deliver ASMs. Furthermore, the benefits and limitations of each nano-delivery system have been discussed. Finally, we discuss exosomes as potentially promising delivery tools for treating epilepsy.


Bees exposed to climate change are more sensitive to pesticides.
Bee populations are exposed to multiple stressors, including land-use change, biological invasions, climate change, and pesticide exposure, that may interact synergistically. We analyze the combined effects of climate warming and sublethal insecticide exposure in the solitary bee Osmia cornuta. Previous Osmia studies show that warm wintering temperatures cause body weight loss, lipid consumption, and fat body depletion. Because the fat body plays a key role in xenobiotic detoxification, we expected that bees exposed to climate warming scenarios would be more sensitive to pesticides. We exposed O. cornuta females to three wintering treatments: current scenario (2007-2012 temperatures), near-future (2021-2050 projected temperatures), and distant-future (2051-2080). Upon emergence in spring, bees were orally exposed to three sublethal doses of an insecticide (Closer, a.i. sulfoxaflor; 0, 4.55 and 11.64 ng a.i./bee). We measured the combined effects of wintering and insecticide exposure on phototactic response, syrup consumption, and longevity. Wintering treatment by itself did not affect winter mortality, but body weight loss increased with increasing wintering temperatures. Similarly, wintering treatment by itself hardly influenced phototactic response or syrup consumption. However, bees wintered at the warmest temperatures had shorter longevity, a strong fecundity predictor in Osmia. Insecticide exposure, especially at the high dose, impaired the ability of bees to respond to light, and resulted in reduced syrup consumption and longevity. The combination of the warmest winter and the high insecticide dose resulted in a 70% longevity decrease. Smaller bees, resulting from smaller pollen-nectar provisions, had shorter longevity suggesting nutritional stress may further compromise fecundity in O. cornuta. Our results show a synergistic interaction between two major drivers of bee declines, and indicate that bees will become more sensitive to pesticides under the current global warming scenario. Our findings have important implications for pesticide regulation and underscore the need to consider multiple stressors to understand bee declines.


Emergency hemodialysis in the management of intoxication.
Management of intoxicated patients has many aspects in a wide spectrum, beginning with decontamination processes and basic supportive care. The most logical therapeutic approach is probably the specific antidotes, when available and/or applicable. On the other hand, many chemicals and drugs, can be removed from the body by means of hemodialysis or hemoperfusion while treating vital sign abnormalities and electrolyte and acid-base disturbances of the patient. In this paper, we describe 11 cases of intoxication, 6 with methyl alcohol, 3 with lithium, and 2 with salicylate, admitted to emergency department and treated with hemodialysis between January 1, 2002 and December 31, 2004. We review their medical charts and detailed demographic data, medical history, type of exposure, clinical and laboratory presentations, duration of hemodialysis performed, and the outcome.


Associations of Urinary Caffeine and Caffeine Metabolites With Arterial Stiffness in a Large Population-Based Study.
To assess the influence of caffeine on arterial stiffness by exploring the association of urinary excretion of caffeine and its related metabolites with pulse pressure (PP) and pulse wave velocity (PWV). Families were randomly selected from the general population of 3 Swiss cities from November 25, 2009, through April 4, 2013. Pulse pressure was defined as the difference between the systolic and diastolic blood pressures obtained by 24-hour ambulatory monitoring. Carotid-femoral PWV was determined by applanation tonometry. Urinary caffeine, paraxanthine, theophylline, and theobromine excretions were measured in 24-hour urine collections. Multivariate linear and logistic mixed models were used to explore the associations of quartiles of urinary caffeine and metabolite excretions with PP, high PP, and PWV. We included 863 participants with a mean ± SD age of 47.1±17.6 years, 24-hour PP of 41.9±9.2 mm Hg, and PWV of 8.0±2.3 m/s. Mean (SE) brachial PP decreased from 43.5 (0.5) to 40.5 (0.6) mm Hg from the lowest to the highest quartiles of 24-hour urinary caffeine excretion (P<.001). The odds ratio (95% CI) of high PP decreased linearly from 1.0 to 0.52 (0.31-0.89), 0.38 (0.22-0.65), and 0.31 (0.18-0.55) from the lowest to the highest quartile of 24-hour urinary caffeine excretion (P<.001). Mean (SE) PWV in the highest caffeine excretion quartile was significantly lower than in the lowest quartile (7.8 [0.1] vs 8.1 [0.1] m/s; P=.03). Similar associations were found for paraxanthine and theophylline, whereas no associations were found with theobromine. Urinary caffeine, paraxanthine, and theophylline excretions were associated with decreased parameters of arterial stiffness, suggesting a protective effect of caffeine intake beyond its blood pressure-lowering effect.


Intrasubject relationship between striatal 18F-FP-CIT uptake and cardiac 123I-MIBG uptake differs by motor subtype in early Parkinson disease.
Parkinson disease (PD) is a heterogeneous neurodegenerative disorder. Dopamine transporter imaging using 123I-2β-carbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl)-nortropane (FP-CIT) and noradrenergic cardiac imaging using 123I-meta-iodobenzylguanidine (MIBG) have been used in combination or separately to study PD patients. Published results regarding uptake of the 2 tracers in each motor subtype are fairly abundant and mostly in agreement. However, data on the intrasubject association between dopaminergic and noradrenergic systems in PD patients are relatively scant and vary. We aimed to assess the intrasubject relationship between striatal dopamine transporter density using a PET tracer and cardiac sympathetic innervation in tremor-dominant subtype (TD) and akinetic-rigid subtype (AR) of PD.This study has a cross-sectional design. Thirty-one patients with early PD (17 TD/14 AR) who underwent both 123I-MIBG cardiac scintigraphy and 18F-FP-CIT PET/CT were retrospectively selected. We assessed the relationship between heart-to-mediastinum ratio (H/M) of 123I-MIBG and specific (striatal)-to-nonspecific (cerebellar) dopamine transporter binding ratio (S/N) measured from 4 separate regions-of-interest (bilateral caudate nuclei and lentiform nuclei) of 18F-FP-CIT in each motor subtype.S/N of all 4 striatal regions were significantly lower in the AR subgroup than in the TD subgroup. H/M was not significantly different. There was a significant intrasubject correlation between H/M and S/N of the lentiform nucleus in AR-PD but no correlation between H/M and any of 4 S/N in TD-PD.Our data suggest a coupled degeneration of nigrostriatal dopaminergic and myocardial sympathetic denervation in AR subtype, but not in TD subtype, of early PD patients. These different results between the 2 motor subtypes likely reflects the heterogeneous pathophysiology of PD.


Recovery after exposure to high LET-radiation.
In many cellular systems the shape of survival curves is changed from a sigmoidal to a purely exponential type if the LET of the radiation is increased. This is often explained by the hypothesis that repair mechanisms are less effective or non-functional with lesions generated by densely ionizing radiation. The absence of split-dose sparing and/or recovery from potentially lethal damage is then taken as further support. A careful consideration has to take into account, however, that with particle exposure the pattern of energy deposition varies considerably within a cell population and that the actual distribution depends also on cell geometry. If one accepts the view that with low-LET radiations repair may be saturated at high dose, the survival curve shape characteristic of high LET may be explained by the assumption that in this case saturation may occur due to the energy deposited by one or few heavy charged particles. The absence of recovery would then be due to microdosimetric parameters rather than to the nature or pattern of the primary molecular lesions. This alternative can be tested quantitatively by comparative analysis of the survival behaviour of different cellular systems exposed to radiations of varying LET. Our experiments with yeast strains of different sensitivities show that recovery from potentially lethal damage can be demonstrated even after exposure to uranium ions. Quantitative analysis leads to the conclusion that the apparent reduction in the extent of recovery is mostly due to saturation at the cellular level rather than to non-reparability of the primary lesions or to destruction of the repair system.


What women want from local primary care services for unintended pregnancy in rural Australia: a qualitative study from rural New South Wales.
Under the generalist model of health care in rural Australia, general practitioners (GPs) are often the first point of contact for women seeking health services for unintended pregnancy, including pregnancy decision-making support and options advice, antenatal or abortion care. Rural women are more likely to experience unintended pregnancy in Australia, yet little is known about how well local rural primary healthcare services currently meet their needs. To address this gap, this qualitative study explores through in-depth semi-structured interviews, the experiences of 20 rural women managing an unintended pregnancy, and their expectations of, and satisfaction with, the quality of care they received. The Framework Method was used to organise data and conduct an inductive thematic analysis. Three themes related to management of unintended pregnancy in a rural primary care setting were identified: (1) women expect informed and efficient care once services are reached; (2) women desire greater choice and aftercare; and (3) comprehensive reproductive health should be part of rural primary care. Participants indicated an awareness of the limitations of the rural health system, yet a firm expectation that despite access delays, all of their reproductive health needs would be met. Choice, time efficiency, and aftercare were identified as gaps in the current primary care service experience. A desire for greater attention to rural reproductive health, including improved contraception, was also emphasised. Rural women with unintended pregnancy experienced gaps in service quality and described a lack of woman-centred care in their local rural health setting. This study offers insight into how rural primary care providers can better support women to make decisions about and reach their preferred services for unintended pregnancy.


Purification and Characterization of Geranylgeranyl Diphosphate Synthase from Methanobacterium thermoformicicum SF-4.
Geranylgeranyl diphosphate (GGPP) synthase [EC 184.108.40.206] was purified to homogeneity from Methanobacterium thermoformicicum SF-4. The enzyme was a dimeric protein consisting of two identical subunits (Mr = 39,000) and catalyzed prenyl transfer reactions using isopentenyl diphosphate (Km = 30.8 μM) and either dimethylallyl diphosphate (Km=16.8 μM), geranyl diphosphate (Km=12.6 μM), or farnesyl diphosphate (Km=14.7 μM) as allylic partners. During a sequential elongation, C5→C10→C15→C20' intermediates were accumulated with various ratios to the final product GGPP. In the presence of 0.8 M KCl, GGPP synthease activity was greatly enhanced, stabilized to heat treatment at 65°C for 30 min, and protected from inhibition by p-chloromercuribenzoic acid. No other prenyltransferase synthesizing C20 or shorter prenyl diphosphate was observed in M. thermoformicicum SF-4. These suggest that GGPP synthase alone is important in the biosynthetic pathways to squalene and membrane polar lipids at a chain elongation stage in this strain.


Primary pulmonary botryomycosis presenting with septic shock and acute lung injury.
Botryomycosis is a rare chronic suppurative bacterial infection involving mostly subcutaneous tissues and less frequently other organs. It can be diagnosed by histological examination and culture of the granules. Botryomycosis is mostly caused by Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa but the exact pathogenesis remains uncertain. Treatment often requires a combination of both surgical debridement and long-term antimicrobial therapy. The patient is a young woman known to have Down's syndrome. She had a dramatic presentation with septic shock and acute lung injury with persistence of pulmonary sepsis postoperatively. The importance of postoperative critical care is illustrated by this case in which a young patient underwent major surgery while septic and haemodynamically unstable. According to our research this is the first case of pulmonary botryomycosis reported in Down's syndrome and the first case which developed septic shock requiring vasoactive drugs and ventilation in the intensive care unit.


Application of multivariate analysis to the effects of additives on chemical and sensory quality of stored coffee brew.
The aim of this work was to obtain a black coffee brew to be consumed hot by extension of its shelf life, by addition of additives. Four pH-regulator agents (sodium and potassium carbonates and bicarbonates), one pH regulator and antioxidant (sodium citrate), three antioxidants [sodium ascorbate, ethylenediaminetetracetic acid (EDTA), and sodium sulfite], and lactoserum were tested by sensory analysis. Sodium carbonate and bicarbonate were selected for a study of the physicochemical (soluble and volatile compounds related to the sensory properties) and sensorial quality of coffee brew stored for 90 days at 4 degrees C. Although both additives extended the shelf life of the coffee brew up to 60 days, sodium carbonate was the chosen additive because it was the most useful in limiting the pH decrease and perception of sourness, which are some of the main factors involved in the rejection of stored coffee brews, and it better maintained the aroma and taste/flavor. Moreover, the application of multivariate analysis facilitated first the description of the global changes of the coffee brews with or without additives throughout the storage using principal component analysis and second the obtainment of a simple equation only with pH and caffeic acid parameters to discriminate the three types of coffee brews and simplify the analytical process, by means of the stepwise discriminant analysis.


Identification of an ITPase/XTPase in Escherichia coli by structural and biochemical analysis.
Inosine triphosphate (ITP) and xanthosine triphosphate (XTP) are formed upon deamination of ATP and GTP as a result of exposure to chemical mutagens and oxidative damage. Nucleic acid synthesis requires safeguard mechanisms to minimize undesired lethal incorporation of ITP and XTP. Here, we present the crystal structure of YjjX, a protein of hitherto unknown function. The three-dimensional fold of YjjX is similar to those of Mj0226 from Methanococcus janschii, which possesses nucleotidase activity, and of Maf from Bacillus subtilis, which can bind nucleotides. Biochemical analyses of YjjX revealed it to exhibit specific phosphatase activity for inosine and xanthosine triphosphates and have a possible interaction with elongation factor Tu. The enzymatic activity of YjjX as an inosine/xanthosine triphosphatase provides evidence for a plausible protection mechanism by clearing the noncanonical nucleotides from the cell during oxidative stress in E. coli.


Exploring the opportunities for alignment of regulatory postauthorization requirements and data required for performance-based managed entry agreements.
Performance-based managed entry agreements (PB-MEAs) might allow patient access to new medicines, but practical hurdles make competent authorities for pricing and reimbursement (CAPR) reluctant to implement PB-MEAs. We explored if the feasibility of PB-MEAs might improve by better aligning regulatory postauthorization requirements with the data generation of PB-MEAs and by active collaboration and data sharing. Reviewers from seven CAPRs provided structured assessments of the information available at the European Medicines Agency (EMA) Web site on regulatory postauthorization requirements for fifteen recently authorized products. The reviewers judged to what extent regulatory postauthorization studies could help implement PB-MEAs by addressing uncertainty gaps. Study domains assessed were: patient population, intervention, comparators, outcomes, time horizon, anticipated data quality, and anticipated robustness of analysis. Reviewers shared general comments about PB-MEAs for each product and on cooperation with other CAPRs. Reviewers rated regulatory postauthorization requirements at least partly helpful for most products and across domains except the comparator domain. One quarter of responses indicated that public information provided by the EMA was insufficient to support the implementation of PB-MEAs. Few PB-MEAs were in place for these products, but the potential for implementation of PB-MEAs or collaboration across CAPRs was seen as more favorable. Responses helped delineate a set of conditions where PB-MEAs may help reduce uncertainty. In conclusion, PB-MEAs are not a preferred option for CAPRs, but we identified conditions where PB-MEAs might be worth considering. The complexities of implementing PB-MEAs remain a hurdle, but collaboration across silos and more transparency on postauthorization studies could help overcome some barriers.


A novel blending method for dispensing powdered medicine.
We introduced the application of a planetary centrifugal mixer to dispensing powdered medicines to prevent from individual variation in the skills of pharmacists with a manual blending. The blending performance of the mixer was explored in terms of four operational variables, namely, operation speed (400-1000 rpm), operation time (10-60 s), charging rate in vessel (20-50%), and size of vessel (35, 58, 125, 550 mL), using colored lactose and crystalline lactose as the principle model medicine and diluent, respectively. The blending degree was assessed by image analysis, so the extent of uniformity was expressed as the relative standard deviation of the color difference signal Cb value of YCrCb color space. Application of the mixer to blending three commercial medicines with diluents was carried out. Sufficient blending was achieved at 10 s using a 20% charging rate and 35 mL vessel irrespective of operation speed. As the charging rate was increased, a higher operation speed was needed to obtain uniform blending. A larger sized vessel also required a higher operation speed. Uniform blending was achieved in all of the mixtures of colored lactose and crystalline lactose at the weight ratio of 1 : 9-9 : 1. In the application studies using Adona®, Anginal® and Neophylline® powder, the blending performance of the mixer was equivalent to that of the manual blending method, showing relative standard deviations of 2.2-3.3% and 1.8-3.8%, respectively. These results revealed that the planetary centrifugal mixer was suitable for blending powdered medicine.


Childhood wheezing, asthma, allergy, atopy, and lung function: different socioeconomic patterns for different phenotypes.
Identifying preventable exposures that lead to asthma and associated allergies has proved challenging, partly because of the difficulty in differentiating phenotypes that define homogeneous disease groups. Understanding the socioeconomic patterns of disease phenotypes can help distinguish which exposures are preventable. In the present study, we identified disease phenotypes that are susceptible to socioeconomic variation, and we determined which life-course exposures were associated with these inequalities in a contemporary birth cohort. Participants included children from the Avon Longitudinal Study of Parents and Children, a population-based birth cohort in England, who were born in 1991 and 1992 and attended the clinic at 7-8 years of age (n = 6,378). Disease phenotypes included asthma, atopy, wheezing, altered lung function, and bronchial reactivity phenotypes. Combining atopy with a diagnosis of asthma from a doctor captured the greatest socioeconomic variation, including opposing patterns between phenotype groups: Children with a low socioeconomic position (SEP) had more asthma alone (adjusted multinomial odds ratio = 1.50, 95% confidence interval: 1.21, 1.87) but less atopy alone (adjusted multinomial odds ratio = 0.80, 95% confidence interval: 0.66, 0.98) than did children with high SEP. Adjustment for maternal exposure to tobacco smoke during pregnancy and childhood exposure to tobacco smoke reduced the odds of asthma alone in children with a low SEP. Current inequalities among children who have asthma but not atopy can be prevented by eliminating exposure to tobacco smoke. Other disease phenotypes were not socially patterned or had SEP patterns that were not related to smoke exposure.


Prognosis of locally advanced rectal cancer can be predicted more accurately using pre- and post-chemoradiotherapy neutrophil-lymphocyte ratios in patients who received preoperative chemoradiotherapy.
The neutrophil-lymphocyte ratio (NLR) has been suggested as an inflammation-related factor, but also as an indicator of systemic anti-tumor immunity. We aimed to evaluate the prognostic value of the NLR and to propose a proper cut-off value in patients with locally advanced rectal cancer who received preoperative chemoradiation (CRT) followed by curative total mesorectal excision (TME). A total of 110 rectal cancer patients with clinical T3-4 or node-positive disease were retrospectively analyzed. The NLR value before preoperative CRT (pre-CRT NLR) and the NLR value between preoperative CRT and surgery (post-CRT NLR) were obtained. Using a maximally selected log-rank test, cut-off values were determined as 1.75 for the pre-CRT NLR and 5.14 for the post-CRT NLR. Patients were grouped as follows: group A, pre-CRT NLR ≤ 1.75 and post-CRT NLR ≤ 5.14 (n = 29); group B, pre-CRT NLR > 1.75 and post-CRT NLR ≤ 5.14, or pre-CRT NLR ≤ 1.75 and post-CRT NLR > 5.14 (n = 61); group C, pre-CRT NLR > 1.75 and post-CRT NLR > 5.14 (n = 20). The median follow-up time was 31.1 months. The 3-year disease-free survival (DFS) and overall survival (OS) rates showed significant differences between the NLR groups (3-year DFS rate: 92.7% vs. 73.0% vs. 47.3%, for group A, B, and C, respectively, p = 0.018; 3-year OS rate: 96.0% vs. 85.5% vs. 59.8%, p = 0.034). Multivariate analysis revealed that the NLR was an independent prognostic factor for DFS (p = 0.028). Both the pre-CRT NLR and the post-CRT NLR have a predictive value for the prognosis of patients with locally advanced rectal cancer treated with preoperative CRT followed by curative TME and adjuvant chemotherapy. A persistently elevated post-CRT NLR may be an indicator of an increased risk of distant metastasis.


A novel magnetic silica support for use in chromatographic and enzymatic bioprocessing.
A limited number of support matrices have so far been developed for use in magnetically stabilized fluidized bed (MSFB) applications. We have developed a versatile magnetic silica support which can be derivatized readily for both adsorption chromatography and enzyme immobilization by well-known techniques. A magnetic pellicular bead is prepared by electrostatically depositing alternating layers of colloidal silica and cationic polymer onto macroscopic nickel core particles. The polymer is then burned out and the silica partially sintered to yield a porous shell with 5-80 m(2)/g of surface area. This magnetic composite was tested as a support for immobilizing invertase. Sucrose was continuously converted to its component monosaccharides with nearly constant activity over the first 8 days and retention of 50% of initial activity after 25 days.


Generalized seizures associated with the use of muromonab-CD3 in two patients after kidney transplantation.
To report two cases of seizures associated with the use of muromonab-CD3. Two uremic cadaveric kidney transplant recipients had developed generalized seizures following administration of muromonab-CD3 within the first 2 days after transplantation. Seizures were treated successfully with intravenous phenytoin, and muromonab-CD3 administration was discontinued. The overall frequency of seizures during muromonab-CD3 administration is 6%. Uremia in patients in the early posttransplant period appears to predispose them to seizures. Seizures that happened to our two uremic patients after transplant suggest that they had been induced by muromonab-CD3 administration. The mechanism of how this could have induced seizures is unknown. Prophylactic muromonab-CD3 should be used carefully in uremic kidney transplant recipients following surgery. If therapy with muromonab-CD3 is necessary early hemodialysis should be considered in an effort to lower the risk of seizures.


Anti-RSV prophylaxis efficacy for infants and young children with cystic fibrosis in Ireland.
There is limited evidence supporting the routine use of palivizumab in paediatric cystic fibrosis (CF) patients to reduce respiratory syncytial virus (RSV) infection and related hospitalisation. Despite this, anti-RSV prophylaxis is increasingly common. This is the first report from Ireland regarding palivizumab outcomes for children with CF, under 2 years old, despite the greatest prevalence of CF globally. An audit was performed at a tertiary hospital in Ireland's mid-West to document all children with CF, <24 months old, who received palivizumab over a five year period and comparision made with all eligible children for the prior five year period who had not received the product (also CF patients). Palivizumab was administered to both cohorts in their first year of life. Hospitalisation rates were compared using Fisher's exact test. Incidence of RSV and Pseudomonas aeruginosa infection was recorded. A total of 19 patients who received palivizumab were included in the study; comparision was made with a retrospective control group of 30 patients. Prophylactic palivizumab did not prevent hospitalisation for 10/19 patients, 3 of whom were affected by RSV. This was significantly greater than in the control group, where no hospitalisations were recorded (p < 0.0001). P. aeruginosa was isolated in one case from the study cohort, while no P. aeruginosa was detected in the control group. This study, the first of its kind from Ireland where CF prevalence is highest, does not provide unequivocal support for prophylactic use of palivizumab in CF patients under 2 years. Despite being derived from a small sample size, based on these data and complementary clinical observation, we have discontinued such prophylaxis. However, should reported incidence of RSV-related hospitalisation increase, there is scientific plausibility for appropriately powered, randomised, controlled trials of palivizumab.


Phenotypic and genotypic characterization of enterotoxigenic Escherichia coli serotype O8:KX105 and O8:K"2829" strains isolated from piglets with diarrhea.
Twelve pathogenic and seven nonpathogenic enterotoxigenic Escherichia coli strains which were previously identified as belonging to serogroup O8:KX105 (A. Broes, J. M. Fairbrother, S. Larivière, M. Jacques, and W. M. Johnson, Infect. Immun. 56:241-246, 1988) were further examined for their phenotypic and genotypic properties. Only the 12 pathogenic strains were confirmed to possess the capsular antigen KX105. The seven nonpathogenic strains did not possess this antigen and thus were incorrectly assigned to have capsular antigen KX105. All seven nonpathogenic strains apparently possessed a previously unrecognized capsular antigen which has been designated K"2829". Studies with antisera prepared against F1 (type 1) fimbriae from three E. coli strains suggested that at least three antigenic subtypes of F1 fimbriae were represented among the O8:KX105 strains examined. By using serotyping, biotyping, and outer membrane protein profile analyses, the O8:KX105 strains were divided into at least two distinct clusters, whereas the O8:K"2829" strains were grouped into a single unique cluster. Most of the strains of the same cluster were further differentiated by testing for antibiotic resistance and colicin production and resistance and by analysis of plasmid content. With the exception of one strain which lost its enterotoxicity during storage, all of the O8:KX105 strains hybridized with the gene probes for the heat-labile (LT) and heat-stable (STb) enterotoxins. For each O8:KX105 strain, a single plasmid ranging in size from 61 to 77 megadaltons carried the LT and STb genes. All of the enterotoxigenic O8: KX105 strains fermented sorbose, whereas the nonenterotoxigenic strain did not. All of the O8:K "2829" strains hybridized with the STb probe only. For each O8:K "2829" strain, the STb genes were located on a single plasmid of 61 or 22 megadaltons. None of the strains demonstrated homology with the genes encoding the F4 (K88), F5 (K99), F6 (987P), and F41 fimbrial antigens and STaP and STaH.


Milk Donor Blood Screening for HIV, Syphilis and Hepatitis B Markers in a Brazilian Human Milk Bank: Prevalence Time-trends Over the 2005- 2015 Period.
Human milk banking has been promoted to provide donated breast milk for at-risk children whose mothers cannot breastfeed them but this effort was hindered by the advent of HIV epidemic. To estimate the seroprevalence of HIV, syphilis and hepatitis B in the blood of human milk donors registered in a major maternity hospital in the northern region of the Santa Catarina State, Brazil. A retrospective study included serological tests for HIV, syphilis and hepatitis B screening of milk donor candidates in the 2005-2015 period. The 95% confidence intervals were calculated using the Poisson distribution. For HIV, the prevalence per 100.000 pregnant women was 155, 170 and zero over the three periods analyzed (2005-2009, 2010-2012 and 2013-2015), respectively. Syphilis prevalence per 100,000 pregnant women was 509, 460 and 1749 in the three periods analyzed. For the HBsAg marker of recent hepatitis B infection, the prevalence on the same scale was 254, 231 and 299, respectively, while the anti-HBc prevalence, a marker of lifetime risk for hepatitis B infection, was 7339 in the 2010-2012 period and 3874 in the 2013-2015 period. High prevalence of HIV, syphilis and hepatitis B was found for the 2005-2015 period among breastfeeding mothers who offered to donate their exceeding milk to a human milk bank in Brazil. Despite apparent elimination of the HIV by the end of the period, the decline was not statistically significant. There was no significant change in the acute hepatitis B prevalence over time but the increased syphilis prevalence in the most recent period was statistically significant.


Is DNA ploidy related to smoking?
In the oral cavity, genomic instability is caused by long-term exposure to carcinogens. The aim of this study was to evaluate the relationship between smoking and DNA ploidy. Cytological material was obtained from patients participating in the Outpatient Smoking Treatment Program of the Heart Institute (INCOR-HCFMUSP), and of the Discipline of Oral Medicine (ICT-UNESP). The inclusion criteria for all groups were the absence of a history of malignant tumors, absence of clinical signs of changes in the selected area, and alcohol consumption of less than 3 units per week. Group 1:30 smokers before smoking cessation treatment; Group 2:30 non-smokers; Group 3:30 ex-smokers abstinent for at least 1 year. Cytological smears were collected from the floor of the mouth and border of the tongue and stained by Feulgen. Aneuploidy was evaluated using the ACIS® III system. The Kruskal-Wallis test showed no statistically significant difference (P = .4383) between the groups studied. No association between tobacco consumption and aneuploidy was observed in group 1 (P = 1) or group 2 (P = .68; Fisher's exact test). Smoking was not associated with changes in DNA content or the incidence of aneuploidy in normal oral mucosa.


Mediating effects of social support between antenatal depression and fear of childbirth among nulliparous woman.
Although gestation and childbirth are progressive physical processes for most pregnant women, there are both physical and great psychosocial challenges throughout the process, which increase the sensitivity and vulnerability of women. Even for women with low-risk pregnancies, it is common to experience degrees of fear, especially for primipara women when faced with childbirth. During their first pregnancy, women may have no relevant health knowledge or experience with delivery and have difficulty identifying prenatal depression and other existing mental health factors; a fear of childbirth (FOC) may engender adverse outcomes for mothers and babies. Social support is a very important influential factor for prenatal depression. This study adopted a descriptive cross-sectional design. The participant cohort involved 609 primipara women (≥18 years old) who had received routine prenatal care and visited a tertiary care hospital in Xi'an. The participants completed structured questionnaires, including the 10-item Edinburgh Postnatal Depression Scale (EPDS), 12-item Multidimensional Scale of Perceived Social Support (MSPSS), and 33-item Wijma Delivery Expectancy/Experience Questionnaire (W-DEQ), alongside contribution of information regarding their demographic characteristics. Descriptive and correlation analyses were adopted to verify the correlations among these variables. Multiple regression models were examined by the SPSS PROCESS procedure with bootstrapping to confirm the significance of the mediation effect. The widespread prevalence of FOC in healthy pregnant women was 22.3% (WDEQ score ≥85). The mean scores of depression, social support, as well as FOC scores of participants were 9.50 (5.19), 70.91 (9.25), and 70.43 (20.88), respectively. Remarkable correlations were identified between pregnancy depressive symptoms, social support, and FOC. Results presented an indirect effect, indicating that the impacts of antenatal depression on FOC were mediated by social support. Perceived social support played a mediating role between antenatal depression and FOC among healthy primipara women. Techniques and suggestions for boosting social support may be expected to have a positive impact on the depressive symptoms of pregnant women with FOC.


[Intraperitoneal chemotherapy in gastric cancer patients with peritoneal dissemination].
Peritoneal dissemination is one of the non-curative factors in gastric cancer and colon cancer. Although many treatments have been conducted for peritoneal dissemination, no standard chemotherapy has yet been established. For sometime we had used continuous hyperthermic peritoneal perfusion (CHPP)for peritoneal dissemination in gastric cancer and colon cancer. CHPP has a marked survival benefit for scirrhous type gastric cancer patients without liver metastasis. Patients with prophylactic CHPP have significantly better prognoses than those without prophylactic CHPP, and therapeutic CHPP has a survival benefit for gastric cancer patients with slight to moderate peritoneal dissemination (P 1-2). But CHPP has no significant prognostic benefit for gastric cancer patients with severe peritoneal dissemination (P 3). Therefore, a new cancer treatment is needed for those patients. On the other hand, many kinds of anticancer agents, including cisplatin, via intraperitoneal (ip) administration have been tried thus far for peritoneal dissemination therapy. Especially, intraperitoneal taxane anticancer agent is very effective for the treatment and local control of severe peritoneal dissemination in gastric cancer. A phase I/II study of taxane anticancer agents via ip administration should be tried in gastric cancer patients with peritoneal dissemination.


A Complex Combination Therapy for a Complex Disease-Neuroimaging Evidence for the Effect of Music Therapy in Schizophrenia.
Schizophrenia is a disease characterized by clinical polymorphism: a combination of diverse syndromes defined by differences in structure, course and outcome. The etiology and pathogenesis of this mental disorder is still not completely understood, in spite of the achievements in the fields of neuroscience, genetics, neuroimaging and others. Different treatment strategies have been developed for patients with schizophrenia, but the search for new pharmacological agents continues with the mission of achieving a more effective control over the disease manifestations (positive and negative symptoms), improvement of the patients' social functioning and quality of life. The accumulated clinical experience has revealed that drug treatment and the inclusion in various rehabilitation programs and social skills training shows promising results in these patients. In recent years a plethora of evidence has been compiled regarding the role of music therapy as a possible alternative in the combination treatment of patients with mental disorders, schizophrenia included. Thus, the purpose of this review is to present the reader with a more detailed and science-based account of the beneficial effect of music therapy on the general wellbeing of patients diagnosed with schizophrenia. To fulfill our goal, we will focus mainly on the evidence provided by modern neuroimaging research.


Distinct core thalamocortical pathways to central and dorsal primary auditory cortex.
The cat primary auditory cortex (AI) is usually assumed to form one continuous functional region. However, the dorsal and central parts of the AI iso-frequency domain contain neurons that have distinct response properties to acoustic stimuli. In this study, we asked whether neurons projecting to dorsal versus central regions of AI originate in different parts of the medial geniculate body (MGB). Spike rate responses to variations in the sound level and frequency of pure tones were used to measure characteristic frequency (CF) and frequency resolution. These were mapped with high spatial density in order to place retrograde tracers into matching frequency regions of the central narrow-band region (cNB) and dorsal AI. Labeled neurons projecting to these two parts of AI were concentrated in the middle and rostral thirds of the MGB, respectively. There was little evidence that differences in dorsal and central AI function could be due to convergent input from cells outside the ventral division of the MGB (MGBv). Instead, inputs arising from different locations along the caudal-to-rostral dimension of MGBv represent potential sources of response differences between central and dorsal sub-regions of AI.


Lignans and secoiridoids from the root bark of Chionanthus virginicus L.: isolation, identification and HPLC analysis.
Five lignans, phillyrin (1), pinoresinol-beta-D-glucoside (2), pinoresinol di-beta-D-glucoside (3), phillyrin-2-O-beta-D-glucoside (6), phillyrin-6-O-beta-D-glucoside (7), and three secoiridoids, oleuropein (4), ligustroside (5) and angustifolioside B (8), have been isolated from the root bark of Chionanthus virginicus L. (Oleaceae), a raw material used in the commercial preparation of homeopathy tinctures. Compound 6 is a new lignan, and compounds 2, 3, 4, 5, 7 and 8 are described for the first time in the title plant. The structures of these compounds were elucidated by spectroscopic methods (NMR and HPLC-MS). An isocratic HPLC method for the rapid characterisation and quantification of the major constituents, 1 and 4, of the root bark is described and validated.


A prospective randomized trial comparing image quality, study interpretability, and radiation dose of narrow acquisition window with widened acquisition window protocols in prospectively ECG-triggered coronary computed tomography angiography.
Prospectively triggered coronary computed tomography angiography (CTA) is commonly performed with a widened acquisition window to provide flexibility in image reconstruction. We conducted a randomized controlled trial to determine whether the use of a narrow acquisition window in prospectively triggered coronary CTA would allow lower radiation dose while preserving image quality and interpretability. Prospective 2-center 2- platform randomized trial that evaluated 205 consecutive patients 96 with widened acquisition (WA) and 109 narrow acquisition (NA) referred for coronary CTA in sinus rhythm and heart rate <65 beats/min. Patients scanned with WA had phases reconstructed at 5% intervals, and each phase was assigned an individual study ID. Images were reviewed with individual phase reconstructions interpreted randomly by 2 level 3 readers with a third for consensus. Images were evaluated with a 5-point Likert scale on a per-vessel basis (best score on any phase). Scores were then dichotomized into diagnostic (score 3-5) compared with nondiagnostic (score 1-2). Readers also reported obstructive coronary artery disease on a per-patient basis. Agreement for the diagnosis of obstructive disease and per-artery interpretability was performed. Signal and noise measurements were also performed. No difference in demographics between groups (P = NS). The signal-to-noise ratio was comparable 12.99 ± 3.4 NA and 12.53 ± 4.13 for the WA (P = 0.45). The median effective dose was 1.78 mSv for NA compared with 3.26 mSv for WA (P < 0.001). Image quality, diagnostic interpretability, interreader agreement, and downstream testing were not significantly different between the 2 groups (P= NS for all). Coronary CTA with NA resulted in a 47% lower radiation dose without significant difference in study interpretability or image quality or increased downstream resource use or testing.


The effects of ionizing radiation on DNA synthesis in eukaryotic cells.
To review observations of the effects of ionizing radiation on DNA synthesis in eukaryotes. Available information broadly falls into two categories: descriptions of the phenomenon, including dose response data and analysis; and, more recently, investigations utilizing genetic approaches. The down-regulation of DNA replication in the presence of radiation-induced DNA damage appears to be an active cellular response, termed the S-phase damage-sensing (SDS) checkpoint control (Larner et al. 1997). Observations on a variety of eukaryotes, including man, suggest that the regulatory controls involved are highly conserved and may additionally function in G1 and G2 checkpoint controls. Budding yeast, fission yeast and human homologues are identified. The SDS checkpoint control appears to be comprised of a complex of checkpoint proteins that respond to the stalled replication complex. The replication complex is thought to signal down-regulation of the mitotic kinase, ensuring that the cell does not enter mitosis while S phase is delayed. Concomitantly, the checkpoint complex is believed to transmit a signal via two key checkpoint proteins (Rad3 and Cds1 in the fission yeast), in order to arrest further DNA synthesis initiation.


Cavin-1 deficiency modifies myocardial and coronary function, stretch responses and ischaemic tolerance: roles of NOS over-activity.
Caveolae and associated cavin and caveolins may govern myocardial function, together with responses to mechanical and ischaemic stresses. Abnormalities in these proteins are also implicated in different cardiovascular disorders. However, specific roles of the cavin-1 protein in cardiac and coronary responses to mechanical/metabolic perturbation remain unclear. We characterised cardiovascular impacts of cavin-1 deficiency, comparing myocardial and coronary phenotypes and responses to stretch and ischaemia-reperfusion in hearts from cavin-1 +/+ and cavin-1 -/- mice. Caveolae and caveolins 1 and 3 were depleted in cavin-1 -/- hearts. Cardiac ejection properties in situ were modestly reduced in cavin-1 -/- mice. While peak contractile performance in ex vivo myocardium from cavin-1 -/- and cavin-1 +/+ mice was comparable, intrinsic beating rate, diastolic stiffness and Frank-Starling behaviour (stretch-dependent diastolic and systolic forces) were exaggerated in cavin-1 -/- hearts. Increases in stretch-dependent forces were countered by NOS inhibition (100 µM L-NAME), which exposed negative inotropy in cavin-1 -/- hearts, and were mimicked by 100 µM nitroprusside. In contrast, chronotropic differences appeared largely NOS-independent. Cavin-1 deletion also induced NOS-dependent coronary dilatation, ≥3-fold prolongation of reactive hyperaemic responses, and exaggerated pressure-dependence of coronary flow. Stretch-dependent efflux of lactate dehydrogenase and cardiac troponin I was increased and induction of brain natriuretic peptide and c-Fos inhibited in cavin-1 -/- hearts, while ERK1/2 phospho-activation was preserved. Post-ischaemic dysfunction and damage was also exaggerated in cavin-1 -/- hearts. Diverse effects of cavin-1 deletion reveal important roles in both NOS-dependent and -independent control of cardiac and coronary functions, together with governing sarcolemmal fragility and myocardial responses to stretch and ischaemia.


Characterization and kinetics of 45 kDa chitosanase from Bacillus sp. P16.
An extracellular 45 kDa endochitosanase was purified and characterized from the culture supernatant of Bacillus sp. P16. The purified enzyme showed an optimum pH of 5.5 and optimum temperature of 60 degrees C, and was stable between pH 4.5-10.0 and under 50 degrees C. The Km and Vmax were measured with a chitosan of a D.A. of 20.2% as 0.52 mg/ml and 7.71 x 10(-6) mol/sec/mg protein, respectively. The enzyme did not degrade chitin, cellulose, or starch. The chitosanase digested partially N-acetylated chitosans, with maximum activity for 15-30% and lesser activity for 0-15% acetylated chitosan. The chitosanase rapidly reduced the viscosity of chitosan solutions at a very early stage of reaction, suggesting the endotype of cleavage in polymeric chitosan chains. The chitosanase hydrolyzed (GlcN)7 in an endo-splitting manner producing a mixture of (GlcN)(2-5). Time course studies showed a decrease in the rate of substrate degradation from (GlcN)7 to (GlcN)6 to (GlcN)5, as indicated by the apparent first order rate constants, k1 values, of 4.98 x 10(-4), 2.3 x 10(-4), and 9.3 x 10(-6) sec(-1), respectively. The enzyme hardly catalyzed degradation of chitooligomers smaller than the pentamer.


Aqueous-Processed Inorganic Thin-Film Solar Cells Based on CdSe(x)Te(1-x) Nanocrystals: The Impact of Composition on Photovoltaic Performance.
Aqueous processed nanocrystal (NC) solar cells are attractive due to their environmental friendliness and cost effectiveness. Controlling the bandgap of absorbing layers is critical for achieving high efficiency for single and multijunction solar cells. Herein, we tune the bandgap of CdTe through the incorporation of Se via aqueous process. The photovoltaic performance of aqueous CdSexTe1-x NCs is systematically investigated, and the impacts of charge generation, transport, and injection on device performance for different compositions are deeply discussed. We discover that the performance degrades with the increasing Se content from CdTe to CdSe. This is mainly ascribed to the lower conduction band (CB) of CdSexTe1-x with higher Se content, which reduces the driving force for electron injection into TiO2. Finally, the performance is improved by mixing CdSexTe1-x NCs with conjugated polymer poly(p-phenylenevinylene) (PPV), and power conversion efficiency (PCE) of 3.35% is achieved based on ternary NCs. This work may provide some information to further optimize the aqueous-processed NC and hybrid solar cells.


Heterogenomic recombinants from compatible nocardiae.
Recombinants obtained from matings of Nocardia erythropolis x N. canicruria were tested for their genetic stability by comparing phenotypes from direct selection with the same population after unselected growth. Contraselective loci were employed in various combinations in order that all of the mapped characters might be subjected to unselected analysis. Some recombinant class types appeared as stable haploids, whereas others behaved as heterozygous diploids, segregating out new phenotypes. All regions of the parental genomes were found to be involved in segregation, implying that the entire mapped region can become merozygotic under standard mating conditions. On the basis of segregating phenotypes, the genetic potentials of these compatible nocardiae were ascertained as follows: the formation of a diploid with subsequent segregation of parental or haploid recombinant genomes or both; persistence of the diploid through many generations; continuing reassortment of genetic information by multiple matings between parental or recombinant organisms; and, very probably, second-round recombinations within the diploid. A considerable difference in the nuclear division time between the parental organisms was postulated to have significant effects on the nature of the unselected segregants.


Ethical, social, and cultural issues related to clinical genetic testing and counseling in low- and middle-income countries: protocol for a systematic review.
There has been little focus in the literature on how to build genetic testing and counseling services in low- and middle-income countries in a responsible, ethical, and culturally appropriate manner. It is unclear to what extent this area is being explored and what form further research should take. The proposed knowledge synthesis aims to fill this gap in knowledge and mine the existing data to determine the breadth of work in this area and identify ethical, social, and cultural issues that have emerged. An integrated knowledge translation approach will be undertaken by engaging knowledge users throughout the review to ensure relevance to their practice. Electronic databases encompassing various disciplines, such as healthcare, social sciences, and public health, will be searched. Studies that address clinical genetic testing and/or counseling and ethical, social, and/or cultural issues of these genetic services, and are performed in low- and middle-income countries as defined by World Bank will be considered for inclusion. Two independent reviewers will be involved in a two-stage literature screening process, data extraction, and quality appraisal. Studies included in the review will be analyzed by thematic analysis. A narrative synthesis guided by the social ecological model will be used to summarize findings. This systematic review will provide a foundation of evidence regarding ethical, social, and cultural issues related to clinical genetic testing and counseling in low- and middle-income countries. Using the social ecological model as a conceptual framework will facilitate the understanding of broader influences of the sociocultural context on an individual's experience with clinical genetic testing and counseling, thereby informing interdisciplinary sectors in future recommendations for practice and policy. PROSPERO CRD42016042894.


Thermal and viscoelastic properties of kappa/iota-hybrid carrageenan gels obtained from the Portuguese seaweed Mastocarpus stellatus.
The potential use of the underexploited Portuguese seaweed Mastocarpus stellatus as a source of natural thickening and gelling agents for food applications has been investigated. The alkaline pretreatment duration and extraction parameters (pH, temperature, and extraction duration) of seaweeds have been systematically varied in order to produce kappa/iota-hybrid carrageenans exhibiting a wide range of chemical properties. The mechanical spectra and the setting and melting temperatures of gels obtained by cooling 1.5 wt % extracted biopolymers solutions in 0.05 mol/dm3 KCl were measured by means of small amplitude oscillatory shear experiments. Gels showing elastic storage moduli ranging from 250 to 2750 Pa with no water syneresis could be obtained, and the relationships between the thermal properties and elasticity of the gels were evidenced. Gels mechanical properties are shown to correlate well with polysaccharides chemical parameters such as the degree of sulfate groups, the molecular weight distribution, and the relative content in iota-carrageenan monomers as determined by FTIR spectroscopy.


Loss of thermal refugia near equatorial range limits.
This study examines the importance of thermal refugia along the majority of the geographical range of a key intertidal species (Patella vulgata Linnaeus, 1758) on the Atlantic coast of Europe. We asked whether differences between sun-exposed and shaded microhabitats were responsible for differences in physiological stress and ecological performance and examined the availability of refugia near equatorial range limits. Thermal differences between sun-exposed and shaded microhabitats are consistently associated with differences in physiological performance, and the frequency of occurrence of high temperatures is most probably limiting the maximum population densities supported at any given place. Topographical complexity provides thermal refugia throughout most of the distribution range, although towards the equatorial edges the magnitude of the amelioration provided by shaded microhabitats is largely reduced. Importantly, the limiting effects of temperature, rather than being related to latitude, seem to be tightly associated with microsite variability, which therefore is likely to have profound effects on the way local populations (and consequently species) respond to climatic changes.


Non-surgical treatment of variceal haemorrhage.
Bleeding from gastro-oesophageal varices is a serious medical emergency associated with high morbidity and mortality. Recent advances in treatment include the use of safer vasoactive agents, endoscopic injection of cyanoacrylate, endoscopic variceal ligation and radiological porto-systemic shunt. This article will discuss these new therapies and suggest an integrated approach to the management of variceal haemorrhage.


Disseminated Histoplasmosis in Early Human Immunodeficiency Virus Infection.
Early human immunodeficiency virus (HIV) infection leads to transient immunosuppression followed by a quasi-homeostatic state with slow progression towards AIDS. Histoplasmosis has never been reported in early HIV. We present a case of disseminated histoplasmosis with documented recent seroconversion and review the literature regarding other opportunistic infections in early HIV.


[Inhibitory effect of soman on stress induced hyperthermia in rats and the influence of central and peripheral cholinergic antagonists].
To determine the effect of soman on stress induced hyperthermia and the influence of central and peripheral cholinergic antagonists. Effects of subcutaneous injection of soman, scopolamine, methylscopolamine and pyridostigmine on stress-induced hyperthermia were observed in rats by radio telemetry in an open-field environment. Plasma cholinesterase (ChE) activity was measured by a spectrophotometry. (1) Core temperature of the control group increased by 0.96 degrees C when exposed to open-field, whereas core temperature only increased by 0.55 degrees C in soman treated animals. Scopolamine, a central cholinergic antagonist, nearly abolished inhibitory effects of soman on core temperature when exposed to open-field. Methylscopolamine, a peripheral cholinergic antagonist, coadministered with soman reduced significantly the hyperthermic response to open-field exposure compared with rats dosed with soman. (2) Pyridostigmine, a peripheral anti-ChE agent that caused a 52% decrease in plasma ChE activity led to a significant enhancement of the hyperthermic response to open-field exposure. Methyl scopolamine nearly abolished the effects of pyridostigmine on stress-induced hyperthermia response. Inhibitory effect of soman on the open field hyperthermia suggested that soman treatment hampered the ability of the rat to develop a normal hyperthermic response when placed in the open-field environment. Its inhibitory effects were mediated primarily through a central muscarinic pathway. In addition, peripheral cholinergic nerve was involved in the control of stress hyperthermic response.


Targeted high throughput sequencing in hereditary ataxia and spastic paraplegia.
Hereditary ataxia and spastic paraplegia are heterogeneous monogenic neurodegenerative disorders. To date, a large number of individuals with such disorders remain undiagnosed. Here, we have assessed molecular diagnosis by gene panel sequencing in 105 early and late-onset hereditary ataxia and spastic paraplegia probands, in whom extensive previous investigations had failed to identify the genetic cause of disease. Pathogenic and likely-pathogenic variants were identified in 20 probands (19%) and variants of uncertain significance in ten probands (10%). Together these accounted for 30 probands (29%) and involved 18 different genes. Among several interesting findings, dominantly inherited KIF1A variants, p.(Val8Met) and p.(Ile27Thr) segregated in two independent families, both presenting with a pure spastic paraplegia phenotype. Two homozygous missense variants, p.(Gly4230Ser) and p.(Leu4221Val) were found in SACS in one consanguineous family, presenting with spastic ataxia and isolated cerebellar atrophy. The average disease duration in probands with pathogenic and likely-pathogenic variants was 31 years, ranging from 4 to 51 years. In conclusion, this study confirmed and expanded the clinical phenotypes associated with known disease genes. The results demonstrate that gene panel sequencing and similar sequencing approaches can serve as efficient diagnostic tools for different heterogeneous disorders. Early use of such strategies may help to reduce both costs and time of the diagnostic process.


An analysis of 70 years of morphine classical conditioning: implications for clinical treatment of narcotic addition.
A review of all morphine classical conditioning studies performed since Pavlov reveals significant shifts in methodological and conceptual thinking during the past 7 decades. These shifts have tended to obscure the fact that a great deal of basic data are still needed before morphine classical conditioning can be understood. These data are needed to help clarify the relationship between drug conditioning and drug addiction. Recent evidence, for example, suggests that once morphine autonomic conditional reactions are established, they are highly resistant to extinction. The inclusion of these types of data in any conceptualization of drug dependency would appear to be of help in the formulation of new clinical approaches to this problem.