Lived Lives at Fort Dunree: a rural Irish community perspective.
Background: Elevated suicide rates have alarmed policy makers and communities. In these circumstances, the value of understanding more about communities and their potential role in suicide intervention is becoming more apparent. This study involved evaluating feedback from individuals with and without previous suicidal thinking who participated in an arts-science rural community-based intervention project around suicide in County Donegal, Ireland ( Lived Lives at Fort Dunree). Methods: A combined quantitative and qualitative questionnaire was used to evaluate individual and community responses to the Lived Lives project. Results: Participants ( n = 83), with and without a mental health history and previous suicidal ideation, reported they believed Lived Lives could have potential to help suicide-bereaved families, people with mental illness and people with suicidal thinking. Qualitative results suggested its' suitability for specific groups affected by suicide. Discussion: The evaluation of the Lived Lives project indicated that supervised, "safe-space" community intervention projects around suicide have inherent value with positive impacts for bereaved individuals and communities, including those who have experienced suicidal feelings. Future research should explore the transferability of these findings to other communities, and at-risk groups.


Transfusion of plasma, platelets, and red blood cells in a 1:1:1 vs a 1:1:2 ratio and mortality in patients with severe trauma: the PROPPR randomized clinical trial.
Severely injured patients experiencing hemorrhagic shock often require massive transfusion. Earlier transfusion with higher blood product ratios (plasma, platelets, and red blood cells), defined as damage control resuscitation, has been associated with improved outcomes; however, there have been no large multicenter clinical trials. To determine the effectiveness and safety of transfusing patients with severe trauma and major bleeding using plasma, platelets, and red blood cells in a 1:1:1 ratio compared with a 1:1:2 ratio. Pragmatic, phase 3, multisite, randomized clinical trial of 680 severely injured patients who arrived at 1 of 12 level I trauma centers in North America directly from the scene and were predicted to require massive transfusion between August 2012 and December 2013. Blood product ratios of 1:1:1 (338 patients) vs 1:1:2 (342 patients) during active resuscitation in addition to all local standard-of-care interventions (uncontrolled). Primary outcomes were 24-hour and 30-day all-cause mortality. Prespecified ancillary outcomes included time to hemostasis, blood product volumes transfused, complications, incidence of surgical procedures, and functional status. No significant differences were detected in mortality at 24 hours (12.7% in 1:1:1 group vs 17.0% in 1:1:2 group; difference, -4.2% [95% CI, -9.6% to 1.1%]; P = .12) or at 30 days (22.4% vs 26.1%, respectively; difference, -3.7% [95% CI, -10.2% to 2.7%]; P = .26). Exsanguination, which was the predominant cause of death within the first 24 hours, was significantly decreased in the 1:1:1 group (9.2% vs 14.6% in 1:1:2 group; difference, -5.4% [95% CI, -10.4% to -0.5%]; P = .03). More patients in the 1:1:1 group achieved hemostasis than in the 1:1:2 group (86% vs 78%, respectively; P = .006). Despite the 1:1:1 group receiving more plasma (median of 7 U vs 5 U, P < .001) and platelets (12 U vs 6 U, P < .001) and similar amounts of red blood cells (9 U) over the first 24 hours, no differences between the 2 groups were found for the 23 prespecified complications, including acute respiratory distress syndrome, multiple organ failure, venous thromboembolism, sepsis, and transfusion-related complications. Among patients with severe trauma and major bleeding, early administration of plasma, platelets, and red blood cells in a 1:1:1 ratio compared with a 1:1:2 ratio did not result in significant differences in mortality at 24 hours or at 30 days. However, more patients in the 1:1:1 group achieved hemostasis and fewer experienced death due to exsanguination by 24 hours. Even though there was an increased use of plasma and platelets transfused in the 1:1:1 group, no other safety differences were identified between the 2 groups. clinicaltrials.gov Identifier: NCT01545232.


Identifying technology clusters based on automated patent landscaping.
We introduce a new general methodological approach for accurately and consistently retrieving a large set of patents related to specific technologies. We build upon the automated patent landscaping algorithm by incorporating a tractable amount of human supervision to improve the accuracy and consistency of our results. We demonstrate the efficacy of our approach by applying it to six novel and representative technologies: additive manufacturing, blockchain, computer vision, genome editing, hydrogen storage, and self-driving vehicles.


Improving quality in healthcare: start with the patient.
In the decade since the Institute of Medicine released To Err Is Human, patient harm from medical errors is still widespread. Healthcare has not undergone the transformative change that is needed to reduce medical errors and improve quality. This article discusses patient-centeredness as an organizing principle for transforming healthcare. We also describe important efforts that depict the shift from a provider-focused system to one that is more patient-centered. Finally, the article discusses challenges for the future and the importance of involving patients in the quest to deliver safe, quality care.


Comparative genomic analysis of monosporidial and monoteliosporic cultures for unraveling the complexity of molecular pathogenesis of Tilletia indica pathogen of wheat.
Tilletia indica (Ti) - a quarantined fungal pathogen of wheat and its pathogenesis is chiefly governed by pathogen effectors secreted inside the host plant. The de novo genome sequencing of several field isolates and stages available could be used for understanding the molecular pathogenesis. The presence of gaps and low coverage of assembled genomes poses a problem in accurate functional annotation of such functions. In the present study attempts were made to improve the Ti draft genome through reconciliation of globally available datasets of three highly virulent monoteliospore cultures of Ti field isolates. It has sequence depth of 107x and N50 scaffold size of 80,772 (more than 26 times as large as achieved in the draft assembly) with highest sequence contiguity, more accurate and nearly complete. Functional annotation revealed that Ti genome contains 9209 genes evolved with many expanded gene families and arranged mostly in a cluster. About 79% of Ti genes were orthologous to other basidiomycetes fungi, Around 7.93% proteins were having secretary signals and 6.66% were identified as highly virulent pathogenicity genes. Using improved Ti genome as a reference, the genomic variation was assessed with respect to repeats, SNPs/InDel, gene families and correct set of virulence associated genes during its life cycle. The comparative intra-species, inter-stage and inter-species genomic variation will have broader implications to understand the gene regulatory networks involved in growth, mating and virulence behaviour of Tilletia f. spp. and also for better appreciation of fungal biology and disease management.


Minimally Invasive Total Hip Arthroplasty in a Patient with Hereditary Multiple Exostoses: A Case Report.
Hip geometry abnormalities found in patients with hereditary multiple exostoses (HME) could promote premature hip joint degeneration which needs treatment. We report the case of a 45-year old male with right hip arthrosis who underwent two-incision minimally invasive (MIS-2) total hip arthroplasty (THA), with satisfactory outcome. This technique could be an alternative approach for performing THA in patients with hereditary multiple exostoses.


Assessment of bioavailability of selenium in different plant-soil systems by diffusive gradients in thin-films (DGT).
Uptake of selenium (Se) by plants largely depend on the availability of Se in soil. Soils and plants were sampled four times within 8 weeks of plant growth in pot experiments using four plant species. Sequential extraction and diffusive gradients in thin-films (DGT) method were employed to measure Se concentrations in potted soils in selenite- or selenate-amended soils. Results showed that DGT-measured Se concentrations (CDGT-Se) were generally several folds higher for selenate than selenite amended soils, which were obviously affected by the plant species and the duration of their growth. For example, the folds in soil planted with mustard were 1.49-3.47 and those in soils planted with purple cabbage and broccoli, which grew for 3 and 4 weeks after sowing, were 1.06-2.14 and only 0.15-0.62 after 6 weeks of growth. The selenate-amended soil planted with wheat showed an extremely high CDGT-Se compared with selenite-amended soil, except the last harvest. Furthermore, minimal changes in CDGT-Se and soluble Se(IV) were found in selenite-amended soils during plant growth, whereas significant changes were observed in selenate-amended soils (p < 0.05). Additionally, Se distribution in various fractions of soil remarkably changed; the soils planted with purple cabbage and broccoli showed the most obvious change followed by wheat and mustard. Soluble Se(VI) and exchangeable Se(VI) were likely the major sources of CDGT-Se in selenate-amended soils, and soluble Se(IV) was the possible source of CDGT-Se in selenite-amended soils. In selenate-amended soils, soluble Se(VI) and exchangeable Se(VI) were significantly correlated with Se concentrations in purple cabbage, broccoli, and mustard; in wheat, Se concentration was significantly correlated only with soluble Se(VI) but not with exchangeable Se. CDGT-Se eventually became positively correlated with Se concentrations accumulated by different plants, indicating that DGT is a feasible method in predicting plant uptake of selenate but not of selenite.


Rabeprazole: a review of its use in acid-related gastrointestinal disorders.
Rabeprazole is an inhibitor of the gastric proton pump. It causes dose-dependent inhibition of acid secretion and has a more rapid onset of action than omeprazole. Duodenal ulcers healed faster after treatment with rabeprazole 20 or 40 mg/day than placebo or ranitidine 150 mg 4 times daily and at a generally similar rate to omeprazole 20 mg/day in patients with duodenal ulcers; rabeprazole was similar or superior to these agents in relieving symptoms. Rabeprazole 20 and 40 mg/day healed gastric ulcers faster than placebo, and rabeprazole 20 mg/day healed ulcers at a similar healing rate, to omeprazole 20 mg/day in well controlled 6-week studies. Gastric ulcer symptom relief with rabeprazole was similar or superior to that provided by omeprazole or placebo. In 8-week studies in patients with gastro-oesophageal reflux disease (GERD), rabeprazole 10, 20 and 40 mg/day were more effective than placebo, rabeprazole 20 mg/day was more effective than ranitidine 150 mg twice daily, and rabeprazole 20 mg/day was similar in efficacy to omeprazole 20 mg/day. Symptom relief with rabeprazole in 8-week trials in patients with GERD was superior to that provided by placebo, and similar to ranitidine or omeprazole. Rabeprazole was similar to omeprazole and superior to placebo in both maintenance of healing and prevention of symptoms in patients with healed GERD in 1-year studies. One-week triple therapy with rabeprazole 20 mg twice daily plus 2 antibacterial agents achieved > or = 90% Helicobacter pylori eradication, but, as would be expected, a regimen of rabeprazole 20 mg twice daily plus 1 antibacterial agent was less successful. The drug was as effective as omeprazole and lansoprazole as part of triple therapy for H. pylori eradication. Rabeprazole successfully reduced acid output to target levels and prevented further pathological changes in 10 patients with Zollinger-Ellison syndrome. Usual dosages of rabeprazole are 20 mg/day for 4 weeks to treat duodenal ulcers, 6 weeks for gastric ulcers and 8 weeks for GERD, although some patients with duodenal ulcer may respond to a 10 mg/day dosage. For long term maintenance of GERD healing, 10 or 20 mg daily doses are adequate. Patients with hypersecretory states may need individualised dosages starting at 60 mg/day. The drug was well tolerated in clinical trials, with headache, rash, infection, diarrhoea and flu syndrome as the most common adverse events. In conclusion, rabeprazole appears to be a well tolerated proton pump inhibitor with a rapid onset of action and a low potential for drug interactions. The drug may be used to achieve healing and the relief of symptoms of duodenal ulcer, gastric ulcer and GERD, maintain GERD healing, and can form part of effective regimens to eradicate H. pylori.


Relationships of land use mix with walking for transport: do land uses and geographical scale matter?
Physical activity and public health recommendations now emphasize the creation of activity-friendly neighborhoods. Mixed land use in a neighborhood is important in this regard, as it reflects the availability of destinations to which residents can walk or ride bicycles, and thus is likely to contribute to residents' active lifestyles that in turn will influence their overall health. Relationships between land use mix (LUM) and physical activity have not been apparent in some studies, which may be because geographical scale and the specificity of hypothesized environment-behavior associations are not taken into account. We compared the strength of association of four Geographic Information Systems-derived LUM measures with walking for transport and perceived proximity to destinations. We assessed physical activity behaviors of 2,506 adults in 154 Census Collection Districts (CCDs) in Adelaide, Australia, for which ''original'' LUM measures were calculated, and then refined by either: accounting for the geographic scale of measurement; including only the most-relevant land uses; or, both. The refined (but not the ''original'') LUM measures had significant associations with the frequency of walking for transport (p < 0.05) and area-corrected measures had significant associations with the duration of walking for transport. All LUM measures had significant associations with perceived proximity to destinations, but stronger associations were seen when using the refined measures compared with the original LUM. Identifying the LUM attributes most strongly associated with walking for transport is a priority and can inform environmental and policy initiatives that are needed to promote health-enhancing physical activity.


Efficacy of Artemisinin-Based Combination Treatments of Uncomplicated Falciparum Malaria in Under-Five-Year-Old Nigerian Children Ten Years Following Adoption as First-Line Antimalarials.
The efficacies of 3-day regimens of artemether-lumefantrine (AL), artesunate-amodiaquine (AA), and dihydroartemisinin-piperaquine (DHP) were evaluated in 910 children < 5 years old with uncomplicated malaria from six geographical areas of Nigeria. Parasite positivity 1 day and Kaplan-Meier estimated risk of persistent parasitemia 3 days after therapy initiation were both significantly higher, and geometric mean parasite reduction ratio 1 day after treatment initiation (PRRD1) was significantly lower in AL-treated children than in AA- and DHP-treated children. No history of fever, temperature > 38°C, enrollment parasitemia > 75,000 μL-1, and PRRD1 < 5,000 independently predicted persistent parasitemia 1 day after treatment initiation. Parasite clearance was significantly faster and risk of reappearance of asexual parasitemia after initial clearance was significantly lower in DHP-treated children. Overall, day 42 polymerase chain reaction-corrected efficacy was 98.3% (95% confidence interval [CI]: 96.1-100) and was similar for all treatments. In a non-compartment model, declines of parasitemias were monoexponential with mean terminal elimination half-life of 1.3 hours and unimodal frequency distribution of half-lives. All treatments were well tolerated. In summary, all three treatments evaluated remain efficacious treatments of uncomplicated malaria in young Nigerian children, but DHP appears more efficacious than AL or AA.


Human-IAPP disrupts the autophagy/lysosomal pathway in pancreatic β-cells: protective role of p62-positive cytoplasmic inclusions.
In type II diabetes (T2DM), there is a deficit in β-cells, increased β-cell apoptosis and formation of intracellular membrane-permeant oligomers of islet amyloid polypeptide (IAPP). Human-IAPP (h-IAPP) is an amyloidogenic protein co-expressed with insulin by β-cells. IAPP expression is increased with obesity, the major risk factor for T2DM. In this study we report that increased expression of human-IAPP led to impaired autophagy, due at least in part to the disruption of lysosome-dependent degradation. This action of IAPP to alter lysosomal clearance in vivo depends on its propensity to form toxic oligomers and is independent of the confounding effect of hyperglycemia. We report that the scaffold protein p62 that delivers polyubiquitinated proteins to autophagy may have a protective role against human-IAPP-induced apoptosis, apparently by sequestrating protein targets for degradation. Finally, we found that inhibition of lysosomal degradation increases vulnerability of β-cells to h-IAPP-induced toxicity and, conversely, stimulation of autophagy protects β-cells from h-IAPP-induced apoptosis. Collectively, these data imply an important role for the p62/autophagy/lysosomal degradation system in protection against toxic oligomer-induced apoptosis.


Calprotectin as a biomarker for rheumatoid arthritis: a systematic review.
Calprotectin (myeloid-related protein 8/14), a heterodimeric complex of calcium-binding proteins, is expressed in granulocytes and monocytes. Calprotectin levels are high in synovial tissue, particularly in activated cells adjacent to the cartilage-pannus junction. This systematic review evaluates the use of calprotectin as an indicator of disease activity, therapeutic response, and prognosis in rheumatoid arthritis (RA). Medline, Scopus, and the Cochrane Library (1970-2013) were searched for studies containing original data from patients with RA in whom calprotectin levels were measured in plasma/serum and/or synovial fluid (SF). We included studies examining associations between calprotectin levels and clinical and laboratory assessments, disease progression, and therapeutic response. There were no restrictions for sample size, disease duration, or length of followup. We evaluated 17 studies (1988-2013) with 1065 patients enrolled; 11 were cross-sectional and 8 had longitudinal designs with 2 studies reporting cross-sectional and longitudinal data. Systemic and SF levels of calprotectin were raised in RA. There was a wide range of levels and marked interstudy and intrastudy variability. Calprotectin levels were high in active disease and were particularly high in rheumatoid factor (RF)-positive patients. Levels fell with effective treatment. Longitudinal data showed that calprotectin was a significant and independent predictor of erosive progression and therapeutic responses, particularly in patients who received effective biological treatments. SF calprotectin levels are high, suggesting there is substantial local production by inflamed synovium. Blood calprotectin levels, though highly variable, are elevated in active RA and fall with effective therapy. High baseline calprotectin levels predict future erosive damage.


Differences in relationship conflict, attachment, and depression in treatment-seeking veterans with hazardous substance use, PTSD, or PTSD and hazardous substance use.
Veterans (N = 133) who were seeking treatment in either the Posttraumatic Stress Program or Substance Use Disorders Program at a Veterans Affairs Medical Center (VAMC) and, based on self-report of symptoms, met clinical norms for posttraumatic stress disorder (PTSD) or hazardous substance use (HSU) completed a survey related to relationship conflict behaviors, attachment styles, and depression severity. Participants were grouped into one of three categories on the basis of clinical norm criteria: PTSD only, HSU only, and PTSD + HSU. Participants completed the PTSD Checklist-Military, Experiences in Close Relationships Scale-Short Form, Center for Epidemiologic Studies-Depression scale, Alcohol Use Disorders Identification Test, Drug Use Disorders Identification Test, and Psychological Aggression and Physical Violence subscales of the Conflict Tactics Scale. Most participants were male and Caucasian. Significant differences were found between groups on depression, avoidant attachment, psychological aggression perpetration and victimization, and physical violence perpetration and victimization. Post hoc analyses revealed that the PTSD + HSU group had significantly higher levels of depression, avoidant attachment, and psychological aggression than the HSU only group. The PTSD + HSU group had significantly higher levels of physical violence than did the PTSD only group, but both groups had similar mean scores on all other variables. Potential treatment implications are discussed.


Understanding Gay Community Subcultures: Implications for HIV Prevention.
Gay and bisexual men (GBM) who participate in gay community subcultures have different profiles, including differing risk behaviors. We examined men's participation in gay community subcultures, and its association with risk behavior. In a cross-sectional survey, 849 GBM provided information about men in their personal networks. We devised measures of their participation in five subcultural groupings and explored their associations with sexual behavior. We identified five subcultural groupings: sexually adventurous; bear tribes; alternative queer; party scene; and sexually conservative. Higher scores on the sexually adventurous measure was associated with being older, having more gay friends, being HIV-positive, and being more sexually active. It was also independently associated with unprotected anal intercourse with casual partners (AOR 1.82; 95 % CI 1.20-2.76; p = 0.005). HIV prevention strategies need to account for the different subcultural groupings in which GBM participate. Measures of engagement with gay subcultures are useful indicators of differential rates of risk behavior and modes of participation in gay community life. Men in more sexually adventurous subcultures are more likely to engage in sexual risk behavior.


Human malaria parasites in continuous culture.
Plasmodium falciparum can now be maintained in continuous culture in human erythrocytes incubated at 38 degrees C in RPMI 1640 medium with human serum under an atmosphere with 7 percent carbon dioxide and low oxygen (1 or 5 percent). The original parasite material, derived from an infected Aotus trivirgatus monkey, was diluted more than 100 million times by the addition of human erythrocytes at 3- or 4-day intervals. The parasites continued to reproduce in their normal asexual cycle of approximately 48 hours but were no longer highly synchronous. The have remained infective to Aotus.


All-trans retinoic acid regulates CXCL16/SR-PSOX expression.
Several studies have shown the ability of retinoids to modulate inflammatory response. CXCL16/SR-PSOX is a novel protein functioning as a chemokine and a scavenger receptor. We investigated effects of all-trans retinoic acid (atRA) on CXCL16/SR-PSOX expression in several cell types. Real-time PCR showed that atRA increased CXCL16/SR-PSOX mRNA expression in THP-1 and endothelial cells, which corresponded to increased release of CXCL16 protein from the cells, measured by ELISA. In THP-1 cells this effect was reduced by retinoic acid receptor (RAR) antagonist, which indicates receptor-mediated inhibition. RAR-alpha and RAR-gamma agonists increased CXCL16 release, which suggests RAR-mediated effect of atRA, which is not selective for a particular RAR subtype. In smooth muscle cells, up-regulation of CXCL16 mRNA was observed only after 96 h of treatment, while protein expression did not change. These findings suggest that retinoid signaling might be a pathway modulating inflammatory response by regulating CXCL16 expression in a cell-specific manner.


Early prediction of infected pancreatic necrosis secondary to necrotizing pancreatitis.
To assess the association between the clinical parameters within 48 hours of admission and the occurrence of infected pancreatic necrosis (IPN) during the late phase of necrotizing pancreatitis (NP).All patients were divided into 2 groups, the IPN and non-IPN groups. The clinical data were retrospectively analyzed. Univariate and multivariate logistic regression analyses were performed to evaluate the relationship between clinical parameters and IPN secondary to NP. The performance of each independent variable was plotted by the receiver-operating characteristic (ROC) curve. Consequently, the cut-off level of each independent variable with its sensitivity and specificity was calculated.A total of 215 patients were enrolled in our study. Among them, 87 (40.5%) patients developed IPNs after a median of 13.5 (9.5-23.0) days from admission. Multivariate analysis indicated that the level of hematocrit (HCT) from 40% to 50% (P=.012, odds ratio (OR) = 2.407), HCT over 50% (P < .009, OR = 6.794), blood urea nitrogen (BUN) (P = .040, OR = 1.894), C-reactive protein (CRP) (P = .043, OR = 1.837), and procalcitonin (PCT) (P = .002, OR = 2.559) were independent risk factors of IPN secondary to NP. The ROC cures revealed that the area under the ROC (AUC) of the maximum level of HCT, BUN, CRP, and PCT within 48 hours of admission was 0.687, 0.620, 0.630, and 0.674 respectively. Furthermore, the combination of these 4 individual parameters contributes to a more preferable AUC of 0.789 with a sensitivity of 67.8% and specificity of 77.3%.The maximum levels of PCT, CRP, HCT, and BUN within 48 hours of admission are independent factors of IPN and their combination might accurately predict the occurrence of IPN secondary to NP.


Predicting amyloid-beta pathology in the general population.
Reliable models to predict amyloid beta (Aβ) positivity in the general aging population are lacking but could become cost-efficient tools to identify individuals at risk of developing Alzheimer's disease. We developed Aβ prediction models in the clinical Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4) Study (n = 4,119) including a broad range of easily ascertainable predictors (demographics, cognition and daily functioning, health and lifestyle factors). Importantly, we determined the generalizability of our models in the population-based Rotterdam Study (n = 500). The best performing model in the A4 Study (area under the curve [AUC] = 0.73 [0.69-0.76]), including age, apolipoprotein E (APOE) ε4 genotype, family history of dementia, and subjective and objective measures of cognition, walking duration and sleep behavior, was validated in the independent Rotterdam Study with higher accuracy (AUC = 0.85 [0.81-0.89]). Yet, the improvement relative to a model including only age and APOE ε4 was marginal. Aβ prediction models including inexpensive and non-invasive measures were successfully applied to a general population-derived sample more representative of typical older non-demented adults.


Cerebral hemodynamics after hemorrhagic shock: effects of the type of resuscitation fluid.
Cerebral blood flow (CBF), cerebral oxygen delivery, and intracranial pressure were measured in 12 dogs subjected to hemorrhagic shock and then resuscitated with lactated Ringer's solution or 6% hetastarch. Hemorrhagic shock was produced by the rapid removal of blood to achieve a mean arterial pressure (MAP) of 40 mm Hg with BP maintained at that level for 30 min. Six animals were resuscitated with lactated Ringer's solution, 60 ml/kg iv, and six with 6% hetastarch, 20 ml/kg iv. Both solutions effectively restored systemic hemodynamic stability, increasing cardiac output and MAP. Intracranial pressure was significantly (p less than .05) lower after resuscitation in the hetastarch group, but CBF, which had decreased during shock, was not normalized by either fluid, and cerebral oxygen transport fell further with resuscitation secondary to a hemodilutional reduction of hemoglobin. Although 6% hetastarch may improve systemic hemodynamics and maintain a low intracranial pressure during resuscitation, it fails, as does lactated Ringer's solution, to restore cerebral oxygen transport to prehemorrhagic shock levels.


Effects of Nanoscale V-Shaped Pits on GaN-Based Light Emitting Diodes.
This paper reviews the formation of nanoscale V-shaped pits on GaN-based light emitting diodes (LEDs) grown by the metal organic chemical vapor deposition (MOCVD) system and studies the effect of V-shaped pits on quantum efficiency. Since V-pits could provide potential barriers around threading dislocations to lessen non-radiative recombinations in such a high defect environment. In our study, multiple InGaN/GaN quantum well samples with different emission wavelengths of 380, 420, 460, and 500 nm were grown, each with different nanoscale V-shaped pits of three diameters for 150, 200, and 250 nm, respectively. It was found that the multiple quantum well (MQW) sample with larger V-pits had a lower pit density, but a relatively larger total V-pits defected area. The optimum diameter of V-pits showing the highest quantum efficiency from the MQW sample depended on the emission wavelength. MQW samples with wavelengths of 380 and 500 nm exhibited the best internal quantum efficiency (IQE) performance at the smallest V-pits area; however, the best performance for MQW samples with wavelength around 420 and 460 nm occurred when large V-pit areas were presented. Photoluminescence (PL) peak shifts and Raman shifts can provide a relationship between quantum-confined Stark effect (QCSE) and IQE, as well as a comparison between strain and IQE. The results obtained in this phenomenological study shall provide a useful guide line in making high-performance GaN-based LEDs with wide emission spectra.


Automated Tortuosity Analysis of Nerve Fibers in Corneal Confocal Microscopy.
Precise characterization and analysis of corneal nerve fiber tortuosity are of great importance in facilitating examination and diagnosis of many eye-related diseases. In this paper we propose a fully automated method for image-level tortuosity estimation, comprising image enhancement, exponential curvature estimation, and tortuosity level classification. The image enhancement component is based on an extended Retinex model, which not only corrects imbalanced illumination and improves image contrast in an image, but also models noise explicitly to aid removal of imaging noise. Afterwards, we take advantage of exponential curvature estimation in the 3D space of positions and orientations to directly measure curvature based on the enhanced images, rather than relying on the explicit segmentation and skeletonization steps in a conventional pipeline usually with accumulated pre-processing errors. The proposed method has been applied over two corneal nerve microscopy datasets for the estimation of a tortuosity level for each image. The experimental results show that it performs better than several selected state-of-the-art methods. Furthermore, we have performed manual gradings at tortuosity level of four hundred and three corneal nerve microscopic images, and this dataset has been released for public access to facilitate other researchers in the community in carrying out further research on the same and related topics.


In pursuit of sisterhood: adult siblings as a resource for combined individual and family therapy.
Therapists traditionally view brothers and sisters as rivalrous and self-seeking. Under carefully arranged conditions, however, siblings can learn to cooperate with each other to resolve important conflicts in family relationships. This case documents a dramatic change in the relationship between a 29-year-old woman and her father, the outcome of a three-step therapeutic intervention in which sibling dynamics were selectively used by the psychotherapist. As part of her individual therapy, the therapist first aroused the woman's discontent with her status as the neglected "baby of the family." Next, a series of meetings were held with the woman and her three sisters that permitted resolution of their previous anger and misunderstandings, thus helping them to become a more cohesive group of sisters. The third step brought the sisters, now as allies both of the identified patient and of the therapist, into a constructive confrontation with the parents. This resulted in lasting personal change for the identified patient and improved relationships throughout the entire family.


Synergistic antitumor effect of a γ-secretase inhibitor PF-03084014 and sorafenib in hepatocellular carcinoma.
As a multi-kinase inhibitor, sorafenib is beneficial in around 30% of hepatocellular carcinoma (HCC) patients; however, HCC patients develop acquired drug resistance quickly. Clinical benefits of sorafenib, in combination with transarterial chemoembolization (TACE), radiotherapy, and other chemodrugs are limited. We investigated the efficacy and mechanisms of Notch signaling inhibition as adjuvant to sorafenib in HCC spheroid-derived in vitro and in vivo tumor models, using the γ-secretase inhibitor (GSI), PF-03084014. The combination of PF-03084014 plus sorafenib inhibited proliferation and self-renewal of HCC spheroids (stem-like cancer cells). PF-03084014 significantly enhanced antitumor activity of sorafenib; both agents at low dose reached synergistic tumor growth suppression of HCC spheroid-derived orthotopic tumors. The Notch1-Snail1 signaling pathway contributed to sorafenib resistance via increasing epithelial-mesenchymal transition (EMT) and EMT-mediated cancer stem cell (CSC) features, such as increased expression of Snail1, N-cadherin, ABCG2, and the stem cell related genes Nanog and Oct4, and decreased expression of E-cadherin. Anti-tumor activity of the combination therapy was associated with decreased expression of survival signals (Mek/Erk, PI3K/Akt) and reduced microvessel density. PF-03084014 plus sorafenib targets Notch1-Snail1 signaling to reverse EMT and EMT-mediated CSC stemness in the tumors. These synergistic effects provide a rationale to utilize GSIs, in combination with sorafenib, as a new therapeutic strategy for the treatment of HCC.


The effect of comorbidities and complications on the mortality of burned patients.
The World Health Organization has defined 'elderly' as 65 years or older. Age is a known major prognostic factor after burn injury. The objective of this study is to establish whether epidemiologic differences in the elderly contribute to higher mortality compared to younger patients. Patients admitted to the burn unit between 2011 and 2014 (229 patients) were included: 159 were under 65 years old and 70 (30.6%) were 65 or over. The elderly group had a higher mortality rate, 24.6% versus 8.2% (p=0.002). Patients over 65 presented more pre-existing co-morbidities (1.7 ± 1.1) than patients under 65 (1.1 ± 1.0), p<0.001, and COPD was significantly associated with higher mortality rate (p=0.014). Patients over and under 65 suffered similar TBSA, 15.7 versus 14.1, p=0.720. Regarding burn depth, deeper burns were significantly more prevalent in the over 65 group (17.1% vs. 5.0%, p=0.003). Patients over 65 developed more complications (0.9 ± 1.1) than the under 65s (0.5 ± 0.9), p=0.009, and sepsis was significantly associated with higher mortality rate (p=0.042). Over-65-year-old burn victims have a higher mortality risk than the under 65s. Elderly patients generally have more pre-existing comorbidities and develop more complications during hospital stay, which increase the mortality risk. Apparently, history of COPD or sepsis complication during hospital stay are independent risk factors for death in the elderly group. Although over-65-year-olds presented similar TBSA to the younger patients, the proportion of deep burns was higher, which suggests that burns might be more aggressive in the elderly.


Anti-VEGFR2 F(ab')2 drug conjugate promotes renal accumulation and glomerular repair in diabetic nephropathy.
Poor renal distribution of antibody-based drugs is the key factor contributing to low treatment efficiency for renal diseases and side effects. Here, we prepare F(ab')2 fragmented vascular endothelial growth factor receptor 2 antibody (anti-VEGFR2 (F(ab')2) to block VEGFR2 overactivation in diabetic nephropathy (DN). We find that the anti-VEGFR2 F(ab')2 has a higher accumulation in DN male mice kidneys than the intact VEGFR2 antibody, and simultaneously preserves the binding ability to VEGFR2. Furthermore, we develop an antibody fragment drug conjugate, anti-VEGFR2 F(ab')2-SS31, comprising the anti-VEGFR2 F(ab')2 fragment linked to the mitochondria-targeted antioxidant peptide SS31. We find that introduction of SS31 potentiates the efficacy of anti-VEGFR2 F(ab')2. These findings provide proof of concept for the premise that antibody fragment drug conjugate improves renal distribution and merits drug validation in renal disease therapy.


How urban and rural built environments influence the health attitudes and behaviors of people who use drugs.
Research suggests that the built environment is associated with drug use. However, there is limited scholarship focusing on specific features of the built environment that influence drug use behaviors, experiences, and patterns and how risk factors for drug use are placed in distinctive urban and rural settings. Applying Neely and Samura's conceptual theory that describes space as contested, fluid and historical, interactional and relational, and defined by inequality and difference, we assessed data from semi-structured qualitative interviews conducted between 2019 and 2020 with consumers at syringe exchange programs (SEPs) in an urban location (New York City) and a rural location (southern Illinois). We aimed to contextualize how drug use manifests in each space. In total, 65 individuals, including 59 people who use drugs (PWUD) and six professionals who worked with PWUD, were interviewed. Findings illustrate that, in both the urban and rural setting, the built environment regulates the drug use milieu by mediating social reproduction, namely the degree of agency PWUD exert to acquire and use drugs where they desire. Processes of "stigma zoning," defined as socio-spatial policing of boundaries of behavior deemed undesirable or deviant, impacted PWUD's socio-geographic mobility, social conditions, and resource access, and modulated PWUD's broader capacity and self-efficacy. Similar patterns of drug use, according to social and economic inequities chiefly related to housing instability, were further observed in both settings.


Crystal structure of pyruvate dehydrogenase kinase 3 bound to lipoyl domain 2 of human pyruvate dehydrogenase complex.
The human pyruvate dehydrogenase complex (PDC) is regulated by reversible phosphorylation by four isoforms of pyruvate dehydrogenase kinase (PDK). PDKs phosphorylate serine residues in the dehydrogenase (E1p) component of PDC, but their amino-acid sequences are unrelated to eukaryotic Ser/Thr/Tyr protein kinases. PDK3 binds to the inner lipoyl domains (L2) from the 60-meric transacetylase (E2p) core of PDC, with concomitant stimulated kinase activity. Here, we present crystal structures of the PDK3-L2 complex with and without bound ADP or ATP. These structures disclose that the C-terminal tail from one subunit of PDK3 dimer constitutes an integral part of the lipoyl-binding pocket in the N-terminal domain of the opposing subunit. The two swapped C-terminal tails promote conformational changes in active-site clefts of both PDK3 subunits, resulting in largely disordered ATP lids in the ADP-bound form. Our structural and biochemical data suggest that L2 binding stimulates PDK3 activity by disrupting the ATP lid, which otherwise traps ADP, to remove product inhibition exerted by this nucleotide. We hypothesize that this allosteric mechanism accounts, in part, for E2p-augmented PDK3 activity.


Comparisons of rotavirus polypeptides by limited proteolysis: close similarity of certain polypeptides of different strains.
The polypeptides of SA11 rotavirus produced in virus-infected cells were analyzed by limited proteolysis, using Staphylococcus aureus V8 protease. This clearly distinguished between all the known primary gene products of the virus and allowed relationships between other infected-cell proteins, and between infected-cell and virus structural proteins, to be ascertained. A comparison of the proteolysis cleavage patterns between SA11 rotavirus and the human rotavirus Wa was also performed which demonstrated a marked conservation in the digestion patterns among nonstructural and inner-shell structural proteins, but a marked variation in the digestion patterns among outer-shell structural proteins.


Bullying Victimization and Racial Discrimination Among Australian Children.
To compare the prevalence of bullying victimization and racial discrimination by ethnicity. We completed a cross-sectional analysis of 3956 children aged 12 to 13 years from wave 5 (2011-2012) of the nationally representative Longitudinal Study of Australian Children. Bullying victimization and racial discrimination were weakly associated and differently patterned by ethnicity. Children from visible minorities reported less bullying victimization but more racial discrimination than did their peers with Australian-born parents. Indigenous children reported the highest risk of bullying victimization and racial discrimination. Peer victimization and racial discrimination each require specific attention as unique childhood stressors. A focus on general bullying victimization alone may miss unique stress exposures experienced by children from stigmatized ethnic backgrounds.


Transverse myelopathy and radiculomyelopathy associated with pulmonary atypical Mycobacterium infections.
Myelopathy is a well recognised but rare association with Mycobacterium tuberculosis infection, but has not been described with atypical mycobacteria. We report two cases of disabling myelopathy in association with pulmonary infection by Mycobacterium kansasii and Mycobacterium malmoense; the myelopathy is presumed to be a para-infectious phenomenon.


Changing strategy in malaria control.
Residual-insecticide spraying methods may lead to the eradication of malaria from a country or from an area of it, and therefore to the possibility that the spraying campaign may eventually be discontinued. This is the final target to be aimed at in planning national malaria-control campaigns. As it is now known that some anopheline vector species may develop resistance to insecticides, a plea is made that control programmes should be planned to cover such large areas and with such criteria of efficiency as to eradicate malaria and to enable the campaign to be discontinued before resistance may have developed.


Trophic downgrading of an adaptable carnivore in an urbanising landscape.
Urbanisation critically alters wildlife habitat and resource distribution, leading to shifts in trophic dynamics. The loss of apex predators in human-transformed landscapes can result in changes in the ecological roles of the remaining mesocarnivores. Decreased top-down control together with increased bottom-up forcing through greater availability of anthropogenic foods can result in a predation paradox. Understanding these changes is important for conserving ecological function and biodiversity in rapidly urbanising systems. Here, we use stable isotope analysis to provide insight into longer term changes in trophic position, niche width and overlap of an elusive, medium-sized urban adapter, the caracal (Caracal caracal) in and around the city of Cape Town, South Africa. Using fur samples (n = 168) from individuals along a gradient of urbanisation we find that overall caracals have a broad isotopic dietary niche that reflects their large variation in resource use. When accounting for underlying environmental differences, the intensity of anthropogenic pressure, measured using the Human Footprint Index (HFI), explained variation in both food subsidy use (δ13C values) and trophic status (δ15N values). The significantly higher δ13C values (P < 0.01) and lower δ15N values (P < 0.001) of caracals in more urbanised areas suggest that predator subsidy consumption occurs via predictable, anthropogenic resource subsidies to synanthropic prey. These prey species are predominantly primary consumers, resulting in shifts in diet composition towards lower trophic levels. Further, caracals using areas with higher HFI had narrower isotope niches than those in less impacted areas, likely due to their hyperfocus on a few lower trophic level prey species. This pattern of niche contraction in urban areas is retained when accounting for caracal demographics, including sex and age. The removal of apex predators in human-transformed landscapes together with reliable resource availability, including abundant prey, may paradoxically limit the ecological influence of the remaining predators, and bring about a degree of predator trophic downgrading. The dampening of top-down control, and thus ecosystem regulation, likely points to widespread disruption of trophic dynamics in rapidly developing areas globally.


Multi-Instrument Characterization of Magnetospheric Cold Plasma Dynamics in the June 22, 2015 Geomagnetic Storm.
We present a comparison of magnetospheric plasma mass/electron density observations during an 11-day interval which includes the geomagnetic storm of June 22, 2015. For this study we used: Equatorial plasma mass density derived from geomagnetic field line resonances (FLRs) detected by Van Allen Probes and at the ground-based magnetometer networks EMMA and CARISMA; in situ electron density inferred by the Neural-network-based Upper hybrid Resonance Determination algorithm applied to plasma wave Van Allen Probes measurements. The combined observations at L ∼ 4, MLT ∼ 16 of the two longitudinally separated magnetometer networks show a temporal pattern very similar to that of the in situ observations: A density decrease by an order of magnitude about 1 day after the Dst minimum, a partial recovery a few hours later, and a new strong decrease soon after. The observations are consistent with the position of the measurement points with respect to the plasmasphere boundary as derived by a plasmapause test particle simulation. A comparison between plasma mass densities derived from ground and in situ FLR observations during favorable conjunctions shows a good agreement. We find however, for L < ∼3, the spacecraft measurements to be higher than the corresponding ground observations with increasing deviation with decreasing L, which might be related to the rapid outbound spacecraft motion in that region. A statistical analysis of the average ion mass using simultaneous spacecraft measurements of mass and electron density indicates values close to 1 amu in plasmasphere and higher values (∼2-3 amu) in plasmatrough.


Prevalence estimates of gestational diabetes mellitus in the United States, Pregnancy Risk Assessment Monitoring System (PRAMS), 2007-2010.
The true prevalence of gestational diabetes mellitus (GDM) is unknown. The objective of this study was 1) to provide the most current GDM prevalence reported on the birth certificate and the Pregnancy Risk Assessment Monitoring System (PRAMS) questionnaire and 2) to compare GDM prevalence from PRAMS across 2007-2008 and 2009-2010. We examined 2010 GDM prevalence reported on birth certificate or PRAMS questionnaire and concordance between the sources. We included 16 states that adopted the 2003 revised birth certificate. We also examined trends from 2007 through 2010 and included 21 states that participated in PRAMS for all 4 years. We combined GDM prevalence across 2-year intervals and conducted t tests to examine differences. Data were weighted to represent all women delivering live births in each state. GDM prevalence in 2010 was 4.6% as reported on the birth certificate, 8.7% as reported on the PRAMS questionnaire, and 9.2% as reported on either the birth certificate or questionnaire. The agreement between sources was 94.1% (percent positive agreement = 3.7%, percent negative agreement = 90.4%). There was no significant difference in GDM prevalence between 2007-2008 (8.1%) and 2009-2010 (8.5%, P = .15). Our results indicate that GDM prevalence is as high as 9.2% and is more likely to be reported on the PRAMS questionnaire than the birth certificate. We found no statistical difference in GDM prevalence between the 2 phases. Further studies are needed to understand discrepancies in reporting GDM by data source.


Neurotrophins enhance CaMKII activity and rescue amyloid-β-induced deficits in hippocampal synaptic plasticity.
Amyloid-β (Aβ) peptide-induced impairment of hippocampal synaptic plasticity is considered an underlying mechanism for memory loss in the early stages of Alzheimer's disease and its animal models. We previously reported inhibition of long-term potentiation (LTP) and miniature excitatory postsynaptic currents by oligomeric Aβ(1-42) at hippocampal synapses. While multiple cellular mechanisms could be involved in Aβ-induced synaptic dysfunction, blockade of activity-dependent autophosphorylation of Ca2+ and calmodulin-dependent protein kinase II (CaMKII) appeared to be a major component of Aβ action in our studies. The present study further tested this hypothesis and examined the therapeutic potential of trkB receptor-acting neurotrophins in rescuing Aβ-induced synaptic and signaling impairments. As expected, treatment of rat hippocampal slices with Aβ(1-42) significantly reduced LTP in the Schaffer collateral-CA1 pathway and dentate medial perforant path. LTP-associated CaMKII activation and AMPA receptor phosphorylation were blocked by Aβ(1-42) at the same concentration that inhibited LTP. Aβ-induced LTP impairment, however, was prevented when slices were co-treated with neurotrophin 4 (NT4). Western blotting and immunohistochemical analyses confirmed that treatment with NT4 or brain-derived neurotrophic factor, another trkB-acting neurotrophin, could oppose Aβ action, enhancing autophosphorylation of CaMKII, and AMPA receptor phosphorylation at a CaMKII-dependent site. These findings support the view that CaMKII is a key synaptic target of Aβ toxicity as well as a potential therapeutic site of neurotrophins for Alzheimer's disease.


Hierarchical Nacre Mimetics with Synergistic Mechanical Properties by Control of Molecular Interactions in Self-Healing Polymers.
Designing the reversible interactions of biopolymers remains a grand challenge for an integral mimicry of mechanically superior biological composites. Yet, they are the key to synergistic combinations of stiffness and toughness by providing sacrificial bonds with hidden length scales. To address this challenge, dynamic polymers were designed with low glass-transition temperature T(g) and bonded by quadruple hydrogen-bonding motifs, and subsequently assembled with high-aspect-ratio synthetic nanoclays to generate nacre-mimetic films. The high dynamics and self-healing of the polymers render transparent films with a near-perfectly aligned structure. Varying the polymer composition allows molecular control over the mechanical properties up to very stiff and very strong films (E≈45 GPa, σ(UTS)≈270 MPa). Stable crack propagation and multiple toughening mechanisms occur in situations of balanced dynamics, enabling synergistic combinations of stiffness and toughness. Excellent gas barrier properties complement the multifunctional property profile.


House dust mite avoidance measures for perennial allergic rhinitis.
This is an update of a Cochrane Review first published in The Cochrane Library in Issue 4, 2001 and previously updated in 2003 and 2007.It is estimated that in developed countries approximately 30% of the general population suffer from one or more allergic disorders, of which allergic rhinitis is particularly common. Perennial rhinitis is most often due to allergy to the house dust mite. In such patients house dust mite avoidance is logical, but there is considerable uncertainty regarding the efficacy and effectiveness of interventions designed to reduce dust mite exposure. To assess the benefit (and harm) of measures designed to reduce house dust mite exposure in the management of house dust mite sensitive allergic rhinitis. Our search included the Cochrane Ear, Nose and Throat Disorders Group Trials Register, the Cochrane Central Register of Controlled Trials Register (CENTRAL) (The Cochrane Library Issue 4, 2009), MEDLINE and EMBASE. The date of the last search was 31 December 2009. Randomised controlled trials, with or without blinding, in which house dust mite control measures have been evaluated in comparison with placebo or other dust mite avoidance measures, in patients with clinician-diagnosed allergic rhinitis and confirmed allergy to dust mite. Two authors independently screened titles and abstracts, graded methodological quality using the Cochrane approach and extracted data. Meta-analysis was neither possible nor appropriate due to heterogeneity of the patient groups studied. Nine trials involving 501 participants satisfied the inclusion criteria. Only two studies investigating the effectiveness of mite impermeable bedding covers were of good quality; the remaining seven studies were small and of poor quality. Two trials investigated the efficacy of acaricides, another two trials investigated the role of high-efficiency particulate air (HEPA) filters. One trial, using a factorial design, investigated the efficacy of both acaricide and house dust mite impermeable bedding covers in isolation and combination; the remaining four trials investigated the efficacy of bedroom environmental control programmes involving use of house dust mite impermeable bedding covers. Seven of the nine trials reported that, when compared with control, the interventions studied resulted in significant reductions in house dust mite load. Of the interventions studied to date, acaricides appear to be the most promising type of intervention, although the findings from these studies need to be interpreted with care because of their methodological limitations. House dust mite impermeable bedding as an isolated intervention is unlikely to offer clinical benefit. No serious adverse effects were reported from any of the interventions. Trials to date have on the whole been small and of poor methodological quality, making it difficult to offer any definitive recommendations on the role, if any, of house dust mite avoidance measures in the management of house dust mite sensitive perennial allergic rhinitis. The results of these studies suggest that use of acaricides and extensive bedroom-based environmental control programmes may be of some benefit in reducing rhinitis symptoms and, if considered appropriate, these should be the interventions of choice. Isolated use of house dust mite impermeable bedding is unlikely to prove effective.


Identification of mutations associated with peroxisome-to-mitochondrion mistargeting of alanine/glyoxylate aminotransferase in primary hyperoxaluria type 1.
We have previously shown that in some patients with primary hyperoxaluria type 1 (PH1), disease is associated with mistargeting of the normally peroxisomal enzyme alanine/glyoxylate aminotransferase (AGT) to mitochondria (Danpure, C.J., P.J. Cooper, P.J. Wise, and P.R. Jennings. J. Cell Biol. 108:1345-1352). We have synthesized, amplified, cloned, and sequenced AGT cDNA from a PH1 patient with mitochondrial AGT (mAGT). This identified three point mutations that cause amino acid substitutions in the predicted AGT protein sequence. Using PCR and allele-specific oligonucleotide hybridization, a range of PH1 patients and controls were screened for these mutations. This revealed that all eight PH1 patients with mAGT carried at least one allele with the same three mutations. Two were homozygous for this allele and six were heterozygous. In at least three of the heterozygotes, it appeared that only the mutant allele was expressed. All three mutations were absent from PH1 patients lacking mAGT. One mutation encoding a Gly----Arg substitution at residue 170 was not found in any of the control individuals. However, the other two mutations, encoding Pro----Leu and Ile----Met substitutions at residues 11 and 340, respectively, cosegregated in the normal population at an allelic frequency of 5-10%. In an individual homozygous for this allele (substitutions at residues 11 and 340) only a small proportion of AGT appeared to be rerouted to mitochondria. It is suggested that the substitution at residue 11 generates an amphiphilic alpha-helix with characteristics similar to recognized mitochondrial targeting sequences, the full functional expression of which is dependent upon coexpression of the substitution at residue 170, which may induce defective peroxisomal import.


Vasculitis in Systemic Autoinflammatory Diseases.
Autoinflammatory diseases (AID) are diseases of the innate immune system, characterized by recurrent episodes of localized or systemic inflammation. Vasculitis may accompany AID. The causes of the association of vasculitis with monogenic AID are still debated. Among the monogenic AID, Familial Mediterranean Fever (FMF) is the most common. IgA-related vasculitis (IgAV) and Polyarteritis Nodosa (PAN) involving small and/or medium-sized vessels have an increased frequency among FMF patients. There are also case reports revealing vasculitic features in Cryopyrin-Associated Periodic Fever Syndrome (CAPS), Tumor Necrosis Factor Receptor-Associated Periodic Syndrome (TRAPS), Mevalonate Kinase Deficiency (MKD), also known as Hyper IgD syndrome (HIDS), Deficiency of IL-1 Receptor Antagonist (DIRA) and Pyogenic Arthritis, Pyoderma gangrenosum, and Acne (PAPA) patients. Central nervous system vasculitis and vasculopathy have been reported in DIRA and PAPA patients whereas small vessel involvement affecting skin has been reported in CAPS, TRAPS, and MKD patients. Alternatively, vasculitis can also be a leading feature especially in the recently defined monogenic AID (Otulipenia, Deficiency of Adenosine Deaminase 2-DADA2, Haploinsufficiency of A20) and interferonopathies (STING-associated vasculopathy with onset in infancy-SAVI). DADA2 often presents as a PAN-like disease. In otulipenia, patients have painful subcutaneous nodules caused by septal panniculitis with small and medium vessel vasculitis. Haploinsufficiency of A20 (also called Familial Behcet-like Autoinflammatory Syndrome) results in a phenotype very similar to the variable vessel vasculitis of Behcet's disease with recurrent oral-genital ulcers, in addition to, skin rash, uveitis, and polyarthritis. SAVI is an autoinflammatory vasculopathy with increased Interferon (IFN) signature, causing severe skin lesions resulting in ulceration, necrosis, and in some cases, amputation. Behcet's Disease (BD) is a multifactorial polygenic AID characterized by recurrent attacks of oral-genital ulcers, skin lesions, uveitis and a unique vasculitis affecting both arteries and veins of all sizes. Many clinical features overlap with other autoinflammatory diseases and overexpression of proinflammatory cytokines is an important feature of the disease.


The ABCs of STIs: An Update on Sexually Transmitted Infections.
Sexually transmitted infections (STIs) are spread primarily through sexual contact and are a major cause of morbidity and mortality worldwide. Once identified, some STIs can be cured following appropriate therapy; for others, suppressive regimens and approaches to prevent ongoing transmission are important. The incidence of many common STIs is increasing in the US as well as worldwide, and hundreds of millions of people are currently infected. Laboratory testing plays a major role in the diagnosis and treatment of STIs, and clinical laboratorians should be familiar with the current guidelines and methods for testing. Accurate and sensitive methods to diagnose STIs are essential to direct appropriate antimicrobial therapy and interrupt the cycle of disease transmission. This review summarizes laboratory testing for common bacterial, viral, and parasitic causes of STIs. Disease manifestations reviewed include cervicitis and urethritis, genital ulcerative disease, human immunodeficiency virus, viral hepatitis, human papilloma virus, and vaginitis. Recent advancements in the recognition and management of STIs, including updates to diagnostic algorithms, advances in testing methods, and emerging challenges with antimicrobial resistance, are summarized. Diagnostic methods and therapeutic guidelines for STIs are rapidly evolving. In combination with changing epidemiology, the development of novel therapeutics, and advancements in diagnostic methods, this has resulted in changing practices in laboratory testing and, subsequently, management of disease. Molecular methods have facilitated personalized therapy and follow-up regimens targeted for individual types or strains of some STIs.


Temperature stress tolerance of conifer seedlings after exposure to UV-B radiation.
Ground-level UV-B radiation has increased globally due to a thinning stratospheric ozone layer. We estimated the effects of increased UV-B on 10 conifer species grown in chambers in greenhouses with supplemental UV-B. Species were selected from a wide range of geographic locations. Plant material of two ages (germinants, first growing season; seedlings, second season) were exposed to three levels of UV-B from ambient (at Victoria, B.C., Canada) to three times ambient (12 kJ m(-2) d(-1)) for up to four months. Frost hardiness and heat tolerance of shoots were estimated from changes in chlorophyll fluorescence after exposure to test temperatures. There were no significant differences among seed sources from different elevations in their response to temperature stresses. When UV-B increased above the ambient level, three species (interior Douglas-fir, Engelmann spruce, and interior lodgepole pine) increased in frost hardiness and four (grand fir, interior spruce, yellow-cedar, and western redcedar) decreased. Two species (western redcedar and western hemlock) increased in heat tolerance when UV-B increased to the 12 kJ level. The main differences in stress tolerance were between the triple ambient and the other two treatments, not between ambient and double ambient, suggesting that any changes in UV-B would have to be large to elicit physiological changes in conifer seedlings.


A Golgi-based KDELR-dependent signalling pathway controls extracellular matrix degradation.
We recently identified an endomembrane-based signalling cascade that is activated by the KDEL receptor (KDELR) on the Golgi complex. At the Golgi, the KDELR acts as a traffic sensor (presumably via binding to chaperones that leave the ER) and triggers signalling pathways that balance membrane fluxes between ER and Golgi. One such pathway relies on Gq and Src. Here, we examine if KDELR might control other cellular modules through this pathway. Given the central role of Src in extracellular matrix (ECM) degradation, we investigated the impact of the KDELR-Src pathway on the ability of cancer cells to degrade the ECM. We find that activation of the KDELR controls ECM degradation by increasing the number of the degradative structures known as invadopodia. The KDELR induces Src activation at the invadopodia and leads to phosphorylation of the Src substrates cortactin and ASAP1, which are required for basal and KDELR-stimulated ECM degradation. This study furthers our understanding of the regulatory circuitry underlying invadopodia-dependent ECM degradation, a key phase in metastases formation and invasive growth.


Early childhood stress is associated with elevated antibody levels to herpes simplex virus type 1.
It is well known that children need solicitous parenting and a nurturing rearing environment to ensure their normal behavioral development. Early adversity often negatively impacts emotional and mental well-being, but it is less clearly established how much the maturation and regulation of physiological systems is also compromised. The following research investigated the effect of 2 different types of adverse childhood experiences, early deprivation through institutionalization and physical abuse, on a previously unexplored outcome: the containment of herpes simplex virus (HSV). The presence of HSV-specific antibody in salivary specimens was determined in 155 adolescents, including 41 postinstitutionalized, 34 physically-abused, and 80 demographically-similar control youth. Across 4 school and home days, HSV antibody was higher in both postinstitutionalized and physically-abused adolescents when compared with control participants. Because the prevalence of HSV infection was similar across the groups, the elevated antibody was likely indicative of viral recrudescence from latency. Total secretory Ig-A secretion was associated with HSV, but did not account for the group differences in HSV-specific antibody. These findings are likely caused by a failure of cellular immune processes to limit viral reactivation, indicating a persistent effect of early rearing on immune functioning. The fact that antibody profiles were still altered years after adoption into a more benevolent setting with supportive families suggests these results were not caused by contemporaneous factors, but rather reflect a lingering influence of earlier life experiences.


Effect of leukotriene C4 on electromechanical activity and Ca2+ uptake in taenia coli.
The actions of leukotriene C4 (LTC4) on electromechanical activity and 45Ca2+ uptake in guinea pig taenia coli were investigated. The contractile action of LTC4 was abolished by the removal of extracellular Ca2+. LTC4 concentrations eliciting a maximal contraction in normal medium produced no response in preparations depolarized with KCl. In single sucrose gap studies, LTC4 increased both the frequency of electrical spiking and tension. These effects were blocked by the dihydropyridine Ca2+-channel antagonist PY 108-068 and by the leukotriene receptor antagonist FPL 55712. In double sucrose gap experiments, LTC4 caused a small depolarization without measurable change in membrane conductivity; increased spontaneous electrical activity was again accompanied by an increase in tension. LTC4 caused a detectable increase in 45Ca2+ uptake only at extracellular Ca2+ concentrations less than 1 mM, and this was again inhibited by PY 108-068 or FPL 55712. It is concluded that the contractile effects of LTC4 in guinea pig taenia coli occur as a consequence of its ability to open voltage-sensitive Ca2+ channels, an effect that may occur independently of membrane depolarization.


Biophysical and biochemical characterization of a liposarcoma-derived recombinant MnSOD protein acting as an anticancer agent.
A recombinant MnSOD (rMnSOD) synthesized by specific cDNA clones derived from a liposarcoma cell line was shown to have the same sequence as the wild-type MnSOD expressed in the human myeloid leukaemia cell line U937, except for the presence of the leader peptide at the N-terminus. These results were fully confirmed by the molecular mass of rMnSOD as evaluated by ES/MS analysis (26662.7 Da) and the nucleotide sequence of the MnSOD cDNA. The role of the leader peptide in rMnSOD was investigated using a fluorescent and/or (68)Gallium-labelled synthetic peptide. The labelled peptide permeated MCF-7 cells and uptake could be inhibited in the presence of an excess of oestrogen. In vivo it was taken up by the tumour, suggesting that the molecule can be used for both therapy and diagnosis. The in vitro and in vivo pharmacology tests confirmed that rMnSOD is only oncotoxic for tumour cells expressing oestrogen receptors. Pharmacokinetic studies in animals performed with (125)I- and (131)I-labelled proteins confirmed that, when administered systemically, rMnSOD selectively reached the tumour, where its presence was unambiguously demonstrated by scintigraphic and PET scans. PCR analysis revealed that Bax gene expression was increased and the Bcl2 gene was down regulated in MCF7 cells treated with rMnSOD, which suggests that the protein induces a pro-apoptotic mechanism.


Parental experiences of children's disabilities and special education in the United States and Japan: implications for school social work.
Cultural beliefs about disability and related systems of special education affect the experience of children with disabilities and their parents. This article reviews research on the perceptions and experiences of parents who have preschool or elementary school-age children with disabilities in the United States and Japan. Parents' experiences affect their children's development--for example, through caregiving and advocacy for appropriate services. Existing research suggests that U.S. and Japanese parents report similar difficulties, including difficulties establishing relationships with professionals providing services for their children, but that they have different expectations regarding these relationships. Japanese parents are more likely to emphasize the importance of emotional connections, such as empathy, with professionals and to express feelings of stigma, whereas U.S. parents are more likely to assert that their children are entitled to receive appropriate educational resources. These experiences reflect structural differences in U.S. and Japanese special education services. Parents' perceptions also have the potential to recreate cultural beliefs and eventually modify service delivery systems to reflect those beliefs. Discussion of U.S. and Japanese concepts of disability suggests ways in which services in both countries may be strengthened. The Japanese case suggests ways of strengthening empathy and trust, and the U.S. case provides a positive model of inclusion.


Active site flexibility revealed in crystal structures of Parabacteroides merdae β-glucuronidase from the human gut microbiome.
β-Glucuronidase (GUS) enzymes in the gastrointestinal tract are involved in maintaining mammalian-microbial symbiosis and can play key roles in drug efficacy and toxicity. Parabacteroides merdae GUS was identified as an abundant mini-Loop 2 (mL2) type GUS enzyme in the Human Microbiome Project gut metagenomic database. Here, we report the crystal structure of P. merdae GUS and highlight the differences between this enzyme and extant structures of gut microbial GUS proteins. We find that P. merdae GUS exhibits a distinct tetrameric quaternary structure and that the mL2 motif traces a unique path within the active site, which also includes two arginines distinctive to this GUS. We observe two states of the P. merdae GUS active site; a loop repositions itself by more than 50 Å to place a functionally-relevant residue into the enzyme's catalytic site. Finally, we find that P. merdae GUS is able to bind to homo and heteropolymers of the polysaccharide alginic acid. Together, these data broaden our understanding of the structural and functional diversity in the GUS family of enzymes present in the human gut microbiome and point to specialization as an important feature of microbial GUS orthologs.


Dual S-100-AE1/3 Immunohistochemistry to Detect Perineural Invasion in Nonmelanoma Skin Cancers.
Background. Perineural invasion (PNI) is an adverse prognostic histologic finding and increases the risk of local recurrence and metastasis. Objective. We aimed to determine if dual immunohistochemical (IHC) staining with S-100 and AE1/3 would increase the detection of PNI on nonmelanoma skin cancers (NMSCs). Methods. We collected 45 specimens of NMSCs in which there was clinical suspicion for PNI. Two dermatopathologists independently reviewed the tumors for the unequivocal presence of PNI. Results. Unequivocal PNI was present on 10 of the 45 tumors by H&E staining and on 15 of the 45 tumors by IHC staining. Large nerves (>0.1 mm) were involved in 3 of 10 H&E-stained cases and 3 of 15 IHC-stained cases, with 2 of the 4 cases demonstrating large nerve involvement with both staining methods. Of the 8 cases of PNI detected only on IHC, 7 were small nerves (≤0.1 mm). Limitations. All cases were selected because they were clinically suspicious for PNI, and this may be considered selection bias. Conclusions. PNI detection may be increased using dual S-100 and AE1/3 staining, but the majority of additional cases detected were small nerves. The clinical significance, given the small size of the involved nerves, is unclear.


Risk-benefit assessment of treatment of epileptic women of childbearing age with valproic acid.
Valproic acid (VPA) is a widely used anti-epileptic drug (AED) of demonstrated efficacy. However, its teratogenic effects have resulted in many regulatory agencies recommending that it should not be administered to women of childbearing age unless they are taking contraceptives. The aim of this study was to determine the willingness of candidate patients to change their treatment and to monitor the evolution of their attitude. We identified patients aged between 15 and 45 years old who had been diagnosed with epilepsy and were being treated with VPA. A shared decision-making visit was arranged, during which variables related to their epilepsy were recorded. The patients were informed about the teratogenic effects of VPA and the risks/benefits of a change in treatment. The patient, or legal guardian, then freely chose the course of treatment that they wished to follow. On a follow-up visit, six months later, seizure control and tolerance to the chosen treatment were recorded. The variables related to each patient's willingness to their change treatment were analysed. A total of 60 patients, with a median age of 32.7 years, were included in the study. Of these, 25 (41.7%) suffered some form of intellectual disability. Only one (1.7%) had poor seizure control. After the initial visit, 41 patients (68%) opted to continue with the VPA treatment, six opted to stop receiving VPA, and 13 decided to switch to another AED. The median age of the patients who opted to change treatment was significantly lower than that of those who opted to continue with the VPA treatment (29.1 vs. 34.4, p = 0.024). The absence of intellectual disability (p = 0.047) and a length of treatment of less than five years (0.016) were both significantly associated with the decision to change treatment. Of the 19 patients who changed treatment, nine (47%) returned to the initial treatment with VPA. Despite being informed of the teratogenic risk associated with VPA, a significant number of patients and legal guardians opted to continue with this treatment; the reasons given for this were the low possibility of pregnancy and the risk of breakthrough seizures. In almost half the cases studied, the pharmacological alternatives to VPA were poorly tolerated and did not provide a good level of seizure control.


Natural allelic variation in a modulator of auxin homeostasis improves grain yield and nitrogen use efficiency in rice.
The external application of nitrogen (N) fertilizers is an important practice for increasing crop production. However, the excessive use of fertilizers significantly increases production costs and causes environmental problems, making the improvement of crop N-use efficiency (NUE) crucial for sustainable agriculture in the future. Here we show that the rice (Oryza sativa) NUE quantitative trait locus DULL NITROGEN RESPONSE1 (qDNR1), which is involved in auxin homeostasis, reflects the differences in nitrate (NO3-) uptake, N assimilation, and yield enhancement between indica and japonica rice varieties. Rice plants carrying the DNR1indica allele exhibit reduced N-responsive transcription and protein abundance of DNR1. This, in turn, promotes auxin biosynthesis, thereby inducing AUXIN RESPONSE FACTOR-mediated activation of NO3- transporter and N-metabolism genes, resulting in improved NUE and grain yield. We also show that a loss-of-function mutation at the DNR1 locus is associated with increased N uptake and assimilation, resulting in improved rice yield under moderate levels of N fertilizer input. Therefore, modulating the DNR1-mediated auxin response represents a promising strategy for achieving environmentally sustainable improvements in rice yield.


Characterization of Lactococcus lactis phage 949 and comparison with other lactococcal phages.
The virulent Lactococcus lactis phage 949 was isolated in 1975 from cheese whey in New Zealand. This phage is a member of the Siphoviridae family and of a rare lactococcal phage group that bears its name (949 group). It has an icosahedral capsid (79-nm diameter) and a very long noncontractile tail (length, 500 nm; width, 12 nm). It infected 7 of 59 tested L. lactis strains, a somewhat expanded host range for a rare lactococcal phage. The abortive phage infection defense mechanisms AbiQ and AbiT strongly inhibited the multiplication of phage 949, but AbiK and AbiV did not. Its double-stranded DNA (dsDNA) genome of 114,768 bp is, to date, the largest among lactococcal phages. Its GC content was calculated at 32.7%, which is the lowest reported for a lactococcal phage. Its 154 open reading frames (ORFs) share limited identity with database sequences. In addition, terminal redundancy was observed as well as the presence of six tRNAs, one group I intron, and putative recombinases. SDS-PAGE coupled with mass spectrometry identified 13 structural proteins. The genomes of the members of the 10 currently known L. lactis phage groups were used to construct a proteomic tree. Each L. lactis phage group separated into distinct genetic clusters, validating the current classification scheme. Of note, members of the polythetic P335 groups were clearly separated into subgroups.


Cyclic nucleotides suppress tumor necrosis factor alpha-mediated apoptosis by inhibiting caspase activation and cytochrome c release in primary hepatocytes via a mechanism independent of Akt activation.
Cyclic nucleotides have been previously shown to modulate cell death processes in many cell types; however, the mechanisms by which cyclic nucleotides regulate apoptosis are unclear. In this study, we demonstrated that cAMP as well as cGMP analogs suppressed tumor necrosis factor alpha (TNFalpha) plus actinomycin D (ActD)-induced apoptosis in a dose-dependent manner in cultured primary hepatocytes. Furthermore, forskolin, which increases intracellular cAMP levels, also effectively suppressed TNFalpha+ActD-induced apoptosis. Activation of multiple caspases was suppressed in cells exposed to TNFalpha+ActD in the presence of cAMP or cGMP analogs. TNFalpha+ActD-induced cytochrome c release from mitochondria was also inhibited by cAMP or cGMP, reinforcing our conclusion that cyclic nucleotides interfere with the early signaling events of TNFalpha-mediated apoptosis. We evaluated the possibility that cAMP and cGMP inhibit apoptosis by activating the serine/threonine kinase Akt, which is known to promote cell survival. Both cAMP- and cGMP-elevating agents led to marked increases in Akt activation that was inhibited by the phosphatidylinositol 3'-kinase inhibitors, LY294002 and wortmannin. However, complete inhibition of cyclic nucleotide-induced Akt activation had little effect on cyclic nucleotide-mediated cell survival, indicating the existence of other survival pathways. Interestingly, the specific inhibitor of protein kinase A (PKA), KT5720, blocked cGMP-mediated protection but only partially prevented the anti-apoptotic effect of cAMP, indicating that both PKA-dependent and -independent mechanisms are involved in cAMP-mediated suppression of apoptosis signaling. Our data suggest that multiple survival signaling pathways coexist in cells and that cyclic nucleotides delay apoptosis by interfering with apoptosis signaling by both PKA-dependent and -independent mechanisms.


Neurexins.
The neurexin family of cell adhesion proteins consists of three members in vertebrates and has homologs in several invertebrate species. In mammals, each neurexin gene encodes an α-neurexin in which the extracellular portion is long, and a β-neurexin in which the extracellular portion is short. As a result of alternative splicing, both major isoforms can be transcribed in many variants, contributing to distinct structural domains and variability. Neurexins act predominantly at the presynaptic terminal in neurons and play essential roles in neurotransmission and differentiation of synapses. Some of these functions require the formation of trans-synaptic complexes with postsynaptic proteins such as neuroligins, LRRTM proteins or cerebellin. In addition, rare mutations and copy-number variations of human neurexin genes have been linked to autism and schizophrenia, indicating that impairments of synaptic function sustained by neurexins and their binding partners maybe relevant to the pathomechanism of these debilitating diseases.


Quality of life in patients with neurofibromatosis type 1: a nationwide database study in Japan from 2015 to 2019.
This study examined the association between dermatological, neurological, and bone manifestations of neurofibromatosis type 1 (NF1) and quality of life (QoL) in patients with NF1 using a nationwide database of all patients who newly claimed for medical expense subsidies in Japan from 2015 to 2019. The Japanese Ministry of Health, Labour and Welfare provided the "National Database of Designated Intractable Diseases of Japan" containing clinical and personal records ("Medical Certificates of Designated Intractable Diseases") of all patients with NF1 following approval of the study protocol. To examine the association between the severity of symptoms and QoL, multinominal logistic regression analyses were performed, adjusted for potential confounders. The final study population consisted of 1,487 patients (775 females and 712 males; mean (standard deviation) age, 45.4 (17.9) years). More than 50% and nearly 45% of participants were recorded as having moderate or severe "pain/discomfort" and "anxiety/depression," respectively. The severity of neurological symptoms was significantly associated with all components of QoL, whereas the severity of dermatological symptoms was significantly associated with only moderate or severe subjective and mental health-related components of QoL, and the severity of bone lesions was associated with only moderate or severe physical health-related components of QoL. Subjective and mental health-related components of QoL tended to be deteriorated more than physical health-related components of QoL in younger and female patients. Severities of neurological and dermatological symptoms were significantly associated with subjective and mental health-related components of QoL, while the severity of bone symptoms was associated with only moderate and severe deterioration of physical health-related components of QoL.


The influence of DL-methionine on the metabolism of S-adenosylethionine in rats chronically treated with DL-ethionine.
The concentration of S-adenosylethionine in the liver of ethionine-fed rats was increased gradually during the process of carcinogenesis. This increase may have been due to the decreased capacity of the treated rats to acetylate ethionine sulfoxide. Ethionine sulfoxide is considered as the main reserve pool of ethionine for the synthesis of S-adenosylethionine. When the ethionine diet was supplemented by DL-methionine (0.3 to 0.9%), the increase in the concentration of S-adenosylethionine during the period of observation (28 to 150 days) was lower and the acetylation of ethionine sulfoxide was significantly higher. The concentration of the total S-adenosyl compounds in the liver of rats on a diet supplemented with DL-methionine was increased over the concentration of S-adenosylethionine in rats fed ethionine alone, and the S-adenosylethionine portion of this fraction was only about 30% lower. The supplementation of the diet with methionine restored the diurnal oscillation of adenosine 5'-triphosphate in the liver, which had been absent in rats ingesting only ethionine.


DRESS syndrome induced by imatinib.
Drug rash with eosinophilia and systemic symptoms (DRESS syndrome) is a severe, potentially life-threatening drug-induced hypersensitivity reaction characterized by cutaneous eruptions, fever, diffuse lymphadenopathy, along with eosinophilia and elevated liver enzymes. The severity and potential organ damage associated with DRESS mandates withdrawing the offending drug and provide a suitable replacement. We report a 55-year-old man who developed prolonged fever, generalized maculopapular rash and facial edema after 3 weeks of starting imatinib for chronic myeloid leukemia (CML). A diagnosis of DRESS was confirmed by eosinophilia and skin biopsy findings, along with a consistent RegiSCAR score. Imatinib was stopped and he was initiated on low-dose steroids, which led to complete resolution of rash and eosinophilia. A rechallenge with imatinib was positive, and he was switched to dasatinib for further therapy, following which he attained an optimal molecular response. DRESS following imatinib has only been reported in eight patients so far. In this report we summarize the current evidence for managing DRESS and its impact on the treatment of CML.


T Regulatory Cell Induced Foxp3 Binds the IL2, IFNγ, and TNFα Promoters in Virus-Specific CD8+ T Cells from Feline Immunodeficiency Virus Infected Cats.
Polyfunctional CD8+ T cells play a critical role in controlling viremia during AIDS lentiviral infections. However, for most HIV-infected individuals, virus-specific CD8+ T cells exhibit loss of polyfunctionality, including loss of IL2, TNFα, and IFNγ. Using the feline immunodeficiency virus (FIV) model for AIDS lentiviral persistence, our laboratory has demonstrated that FIV-activated Treg cells target CD8+ T cells, leading to a reduction in IL2 and IFNγ production. Furthermore, we have demonstrated that Treg cells induce expression of the repressive transcription factor, Foxp3, in CD8+ T cells. Based upon these findings, we asked if Treg-induced Foxp3 could bind to the IL2, TNFα, and IFNγ promoter regions in virus-specific CD8+ T cells. Following coculture with autologous Treg cells, we demonstrated decreased mRNA levels of IL2 and IFNγ at weeks 4 and 8 postinfection and decreased TNFα at week 4 postinfection in virus-specific CD8+ T cells. We also clearly demonstrated Treg cell-induced Foxp3 expression in virus-specific CD8+ T cells at weeks 1, 4, and 8 postinfection. Finally, we documented Foxp3 binding to the IL2, TNFα, and IFNγ promoters at 8 weeks and 6 months postinfection in virus-specific CD8+ T cells following Treg cell coculture. In summary, the results here clearly demonstrate that Foxp3 inhibits IL2, TNFα, and IFNγ transcription by binding to their promoter regions in lentivirus-specific CD8+ T cells. We believe this is the first description of this process during the course of AIDS lentiviral infection.


Using zebrafish to study the function of nephronophthisis and related ciliopathy genes.
Zebrafish are a valuable vertebrate model in which to study development and characterize genes involved in cystic kidney disease. Zebrafish embryos and larvae are transparent, allowing non-invasive imaging during their rapid development, which takes place over the first 72 hours post fertilisation. Gene-specific knockdown of nephronophthisis-associated genes leads to ciliary phenotypes which can be assessed in various developmental structures. Here we describe in detail the methods used for imaging cilia within Kupffer's vesicle to assess nephronophthisis and related ciliopathy phenotypes.


[Complete transposition of the major vessels].
The study of 16 hearts with complete transposition of the main vessels shows that there is no correlation between the degree of subaortic cone and the forward displacement of the aorta. The anterior part of the interventricular septum is placed on the same plane with its posterior part. The conic part of the septum occupied antero-posterior position, which is explained by the absence of inversion of conus septum. The antero-posterior position of the main vessels is apparently due to a slight counterclockwise rotation of the truncus.


Chemoradiation in the management of esophageal cancer.
The combination of chemotherapy, fluorouracil and cisplatin, and radiation has improved outcome for patients with esophageal cancer. A randomized controlled trial confirmed a long-term survival benefit when this chemotherapy was added to radiotherapy for squamous cell carcinoma, but the approach has not been definitively assessed in patients with adenocarcinoma. Preoperative chemoradiotherapy has been tested in numerous phase II studies and underpowered or flawed phase III studies. Nevertheless, collectively, the evidence strongly suggests that preoperative chemoradiotherapy improves outcome, and thus, this strategy has become a standard treatment option. Attempts to improve outcome by intensifying conventional cytotoxic drugs or increasing the radiation dose have not been successful. Camptothecin and taxane-based regimens combined with radiation have altered the toxicity profile, but substantial improvement in survival outcomes has yet to be demonstrated. Future improvements will likely require the incorporation of targeted agents that add minimally to existing toxicity, the use of molecular predictors of response to individualize selection of the chemotherapeutic regimen, and early identification of responders such that therapy might be altered dynamically.


Assessment of infants with peripherally inserted central catheters: Part 1. Detecting the most frequently occurring complications.
Inserting, maintaining, and monitoring vascular access are integral components of neonatal care. Advances in vascular access technology have led to the insertion of peripherally inserted central catheters (PICC) to provide stable venous access for early and aggressive parenteral nutrition. Medications that are irritating or damaging, or those with a high osmolality or a nonphysiologic pH, can also be safely administered into the central venous system. The need for repeated peripheral intravenous attempts, as well as the associated pain and physiologic instability, are virtually eliminated once a PICC line is placed. Complications related to PICCs may occur at any phase of therapy: during insertion, while indwelling, or after discontinuing the line. The risk factors associated with PICCs are distinctly different from peripheral intravenous lines because of their long dwell time, central placement, and potential to migrate. Part 1 of Focus on the Physical offers a review of the relevant anatomy of the vascular system and a discussion of the appropriate sites for catheter tip placement. Guidelines for a systematic physical assessment, along with recommendations for standardized PICC documentation, are provided. A review of the signs and symptoms of more frequently occurring complications, such as catheter occlusion and bloodstream infections, is presented to enhance awareness of PICC-specific complications in the neonate and to expedite early detection and treatment. Part 2 of this series will focus on systematic assessment for less common complications such as catheter migration, dislodgement, breakage, and thrombosis, as well as the life-threatening complications of pleural and pericardial effusion.


Acoustic diffraction by deformed edges of finite length: theory and experiment.
The acoustic diffraction by deformed edges of finite length is described analytically and in the frequency domain through use of an approximate line-integral formulation. The formulation is based on the diffraction per unit length of an infinitely long straight edge, which inherently limits the accuracy of the approach. The line integral is written in terms of the diffraction by a generalized edge, in that the "edge" can be a single edge or multiple closely spaced edges. Predictions based on an exact solution to the impenetrable infinite knife edge are used to estimate diffraction by the edge of a thin disk and compared with calculations based on the T-matrix approach. Predictions are then made for the more complex geometry involving an impenetrable thick disk. These latter predictions are based on an approximate formula for double-edge diffraction [Chu et al., J. Acoust. Soc. Am. 122, 3177 (2007)] and are compared with laboratory data involving individual elastic (aluminum) disks spanning a range of diameters and submerged in water. The results of this study show this approximate line-integral approach to be versatile and applicable over a range of conditions.


Metabolism and disposition of the metabotropic glutamate receptor 5 antagonist (mGluR5) mavoglurant (AFQ056) in healthy subjects.
The disposition and biotransformation of (14)C-radiolabeled mavoglurant were investigated in four healthy male subjects after a single oral dose of 200 mg. Blood, plasma, urine, and feces collected over 7 days were analyzed for total radioactivity, mavoglurant was quantified in plasma by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS), and metabolite profiles were generated in plasma and excreta by high-performance liquid chromatography (HPLC) and radioactivity detection. The chemical structures of mavoglurant metabolites were characterized by LC-MS/MS, wet-chemical and enzymatic methods, NMR spectroscopy, and comparison with reference compounds. Mavoglurant was safe and well tolerated in this study population. Mavoglurant absorption was ≥50% of dose reaching mean plasma Cmax values of 140 ng/ml (mavoglurant) and 855 ng-eq/ml (total radioactivity) at 2.5 and 3.6 hours, respectively. Thereafter, mavoglurant and total radioactivity concentrations declined with mean apparent half-lives of 12 and 18 hours, respectively. The elimination of mavoglurant occurred predominantly by oxidative metabolism involving primarily 1) oxidation of the tolyl-methyl group to a benzyl-alcohol metabolite (M7) and subsequently to a benzoic acid metabolite (M6), and 2) oxidation of the phenyl-ring leading to a hydroxylated metabolite (M3). The subjects were mainly exposed to mavoglurant and seven main metabolites, which combined accounted for 60% of (14)C-AUC0-72 h (area under the concentration-time curve from time 0 to infinity). The primary steps of mavoglurant metabolism observed in vivo could partially be reproduced in vitro in incubations with human liver microsomes and recombinant cytochrome P450 enzymes. After 7 days, the mean balance of total radioactivity excretion was almost complete (95.3% of dose) with 36.7% recovered in urine and 58.6% in feces.


Complexation-induced resolution enhancement of 3D-printed hydrogel constructs.
Three-dimensional (3D) hydrogel printing enables production of volumetric architectures containing desired structures using programmed automation processes. Our study reports a unique method of resolution enhancement purely relying on post-printing treatment of hydrogel constructs. By immersing a 3D-printed patterned hydrogel consisting of a hydrophilic polyionic polymer network in a solution of polyions of the opposite net charge, shrinking can rapidly occur resulting in various degrees of reduced dimensions comparing to the original pattern. This phenomenon, caused by complex coacervation and water expulsion, enables us to reduce linear dimensions of printed constructs while maintaining cytocompatible conditions in a cell type-dependent manner. We anticipate our shrinking printing technology to find widespread applications in promoting the current 3D printing capacities for generating higher-resolution hydrogel-based structures without necessarily having to involve complex hardware upgrades or other printing parameter alterations.


Determination of anabolic steroids in dried blood using microsampling and gas chromatography-tandem mass spectrometry: Application to a testosterone gel administration study.
Anabolic androgenic steroids (AAS) have been the most commonly abused substances taken by not only professional sportsmen but also recreational bodybuilders. The detection of micro-dose testosterone (T) misuse is particularly challenging as it possesses pseudo-endogenous origin and is sometimes impossible to be identified in urine samples. Dried blood (DB) obtained by finger pricking has been proven to be an alternative matrix for better correlating to physiological responses. Moreover, the introduction of the volumetric absorptive microsampling (VAMS) technology allows overcoming some major limitations of spotting blood onto a filter paper card. In this work, a fast and sensitive GC-MS/MS method was developed and validated for the quantification of AAS in DB collected by means of VAMS. T and the eight top abused synthetic AAS, namely nandrolone, boldenone, mesterolone, drostanolone, metenolone, metandienone, oxandrolone, and dehydrochloromethyl T were selected as the target analytes. The method based on VAMS exhibited good precision, accuracy as well as stability, and superior extraction recoveries over the punched DB spots reported in the literature. The chromatographic separation was achieved within 6.4 min and the detection limit is as little as 50 fg (i.e. able to detect 0.10 ng mL-1 in 20 μL of DB). Confirmed by forty real blood samples, the Deming regression and Bland-Altman analysis revealed that the VAMS DB could be employed for quantifying blood T level in agreement with using the serum specimen. The feasibility of the method was then successfully proven by the analysis of samples collected from a three-arm T administration trial. Our results highlighted that DB total T was a sensitive indicator for identifying transdermal micro-dosing of T. In the groups of receiving T gel administration, T concentrations could rise up to ten times higher than the baseline at 9 h after the application. As a future step, this approach is being expanded to a large cohort screening of bodybuilders at gym and ultimately may allow universal applications on monitoring sports drug misuse.