Assessing Fidelity of Implementation (FOI) for School-Based Mindfulness and Yoga Interventions: A Systematic Review.
As school-based mindfulness and yoga programs gain popularity, the systematic study of fidelity of program implementation (FOI) is critical to provide a more robust understanding of the core components of mindfulness and yoga interventions, their potential to improve specified teacher and student outcomes, and our ability to implement these programs consistently and effectively. This paper reviews the current state of the science with respect to inclusion and reporting of FOI in peer-reviewed studies examining the effects of school-based mindfulness and/or yoga programs targeting students and/or teachers implemented in grades kindergarten through twelve (K-12) in North America. Electronic searches in PsychInfo and Web of Science from their inception through May 2014, in addition to hand searches of relevant review articles, identified 312 publications, 48 of which met inclusion criteria. Findings indicated a relative paucity of rigorous FOI. Fewer than 10% of studies outlined potential core program components or referenced a formal theory of action, and fewer than 20% assessed any aspect of FOI beyond participant dosage. The emerging nature of the evidence base provides a critical window of opportunity to grapple with key issues relevant to FOI of mindfulness-based and yoga programs, including identifying essential elements of these programs that should be faithfully implemented and how we might develop rigorous measures to accurately capture them. Consideration of these questions and suggested next steps are intended to help advance the emerging field of school-based mindfulness and yoga interventions.


Antinuclear antibodies giving the 'multiple nuclear dots' or the 'rim-like/membranous' patterns: diagnostic accuracy for primary biliary cirrhosis.
Serum antinuclear antibodies giving the 'multiple nuclear dots' or the 'rim-like/membranous' patterns are frequently detected by indirect immunofluorescence on HEp-2 cells in patients with primary biliary cirrhosis. To assess the accuracy of multiple nuclear dot and rim-like/membranous antinuclear antibodies for the diagnosis of primary biliary cirrhosis. Sera from 4371 consecutive patients referred to our laboratory were analysed under code for antinuclear antibodies testing by indirect immunofluorescence on HEp-2 cells. Review of the clinical records of the 4371 patients allowed identification of 101 patients with antimitochondrial antibody-positive primary biliary cirrhosis and 22 with antimitochondrial antibody-negative variant. Multiple nuclear dot and/or rim-like/membranous patterns were found in 59 (1.3%) of the 4371 patients: 31 antimitochondrial antibody-positive primary biliary cirrhosis, 17 antimitochondrial antibody-negative primary biliary cirrhosis and 11 non-primary biliary cirrhosis. The specificity for primary biliary cirrhosis of both the antinuclear antibodies pattern was 99%. Positive predictive value and likelihood ratio for a positive test were 86% (95% CI: 72.7-94) and 221 (95% CI: 91.7-544) for multiple nuclear dot, 79% (95% CI: 62.2-90.1) and 132 (95% CI: 56.8-312.7) for rim-like/membranous, respectively. Multiple nuclear dot and rim-like/membranous antinuclear antibodies are rare findings. Their positivity strongly suggests the diagnosis of primary biliary cirrhosis, irrespective of antimitochondrial antibody status. The high specificity for primary biliary cirrhosis makes them a useful diagnostic tool especially in antimitochondrial antibody-negative patients.


Wind-mediated horseweed (Conyza canadensis) gene flow: pollen emission, dispersion, and deposition.
Horseweed (Conyza canadensis) is a problem weed in crop production because of its evolved resistance to glyphosate and other herbicides. Although horseweed is mainly self-pollinating, glyphosate-resistant (GR) horseweed can pollinate glyphosate-susceptible (GS) horseweed. To the best of our knowledge, however, there are no available data on horseweed pollen production, dispersion, and deposition relative to gene flow and the evolution of resistance. To help fill this knowledge gap, a 43-day field study was performed in Champaign, Illinois, USA in 2013 to characterize horseweed atmospheric pollen emission, dispersion, and deposition. Pollen concentration and deposition, coupled with atmospheric data, were measured in a source field (180 m by 46 m) and its surrounding areas up to 1 km downwind horizontally and up to 100 m vertically. The source strength (emission rate) ranged from 0 to 140 pollen grains per plant per second (1170 to 2.1×10(6) per plant per day). For the life of the study, the estimated number of pollen grains generated from this source field was 10.5×10(10) (2.3×10(6) per plant). The release of horseweed pollen was not strongly correlated to meteorological data and may be mainly determined by horseweed physiology. Horseweed pollen reached heights of 80 to100 m, making long-distance transport possible. Normalized (by source data) pollen deposition with distance followed a negative-power exponential curve. Normalized pollen deposition was 2.5% even at 480 m downwind from the source edge. Correlation analysis showed that close to or inside the source field at lower heights (≤3 m) vertical transport was related to vertical wind speed, while horizontal pollen transport was related to horizontal wind speed. High relative humidity prevented pollen transport at greater heights (3-100 m) and longer distances (0-1000 m) from the source. This study can contribute to the understanding of how herbicide-resistance weeds or invasive plants affect ecology through wind-mediated pollination and invasion.


INSIGHTS FROM MACHINE-LEARNED DIET SUCCESS PREDICTION.
To support people trying to lose weight and stay healthy, more and more fitness apps have sprung up including the ability to track both calories intake and expenditure. Users of such apps are part of a wider "quantified self" movement and many opt-in to publicly share their logged data. In this paper, we use public food diaries of more than 4,000 long-term active MyFitnessPal users to study the characteristics of a (un-)successful diet. Concretely, we train a machine learning model to predict repeatedly being over or under self-set daily calories goals and then look at which features contribute to the model's prediction. Our findings include both expected results, such as the token "mcdonalds" or the category "dessert" being indicative for being over the calories goal, but also less obvious ones such as the difference between pork and poultry concerning dieting success, or the use of the "quick added calories" functionality being indicative of over-shooting calorie-wise. This study also hints at the feasibility of using such data for more in-depth data mining, e.g., looking at the interaction between consumed foods such as mixing protein- and carbohydrate-rich foods. To the best of our knowledge, this is the first systematic study of public food diaries.


The St Jude Medical Trifecta aortic pericardial valve: results from a global, multicenter, prospective clinical study.
The St Jude Medical Inc (St Paul, Minn) Trifecta valve is a novel aortic biological prosthesis that incorporates several design features, including a true supra-annular sewing cuff, a stent design that maximizes valve hemodynamics while minimizing leaflet stresses, and an ethanol-based anticalcification technology. This study establishes the safety and early clinical and hemodynamic performance of the Trifecta valve. The Trifecta bioprosthesis was implanted in 1014 eligible patients between 2007 and 2009 at 31 centers. The mean age of the population was 72.5 ± 9.0 years, of whom 650 (64.1%) were male and 364 (35.9%) were female. Eighty-two subjects (8.1%) had undergone previous open surgery. Indications for aortic valve replacement surgery included stenosis in 556 patients (54.8%), regurgitation in 61 patients (6.0%), and mixed pathology in 397 patients (39.2%). The overall follow-up included 844.3 late patient-years. Early (≤ 30 day) mortality occurred in 18 patients (1.8%), and there were 23 late (≥ 31 days) deaths yielding a linearized mortality rate of 2.72% per late patient-year. There were 27 early thromboembolic events, including 8 (0.8%) strokes, 17 (1.7%) reversible neurologic events, and 2 (0.2%) systemic embolic events. There were no instances of early valve thrombosis, endocarditis, or clinically significant hemolysis. There were 16 late thromboembolic events (linearized rate of 1.90% per year of follow-up), including 4 strokes and 12 reversible neurologic events. In total, there were 5 late valve explants, including 1 structural deterioration and 4 prosthetic valve endocarditis cases. Overall, freedom from valve explant was 99.4% at 2 years. At the time of discharge, average mean gradients ranged from 9.3 to 4.1 mm Hg and effective orifice area ranged from 1.58 to 2.50 cm(2) for valve sizes 19 to 29 mm, respectively. The St Jude Medical Trifecta valve is a unique pericardial bioprosthesis with design elements that provide excellent hemodynamic performance while providing ease of implantation. Long-term follow-up continues to confirm the promising results of this innovative bioprosthesis.


Structural Variation Detection with Read Pair Information: An Improved Null Hypothesis Reduces Bias.
Reads from paired-end and mate-pair libraries are often utilized to find structural variation in genomes, and one common approach is to use their fragment length for detection. After aligning read pairs to the reference, read pair distances are analyzed for statistically significant deviations. However, previously proposed methods are based on a simplified model of observed fragment lengths that does not agree with data. We show how this model limits statistical analysis of identifying variants and propose a new model by adapting a model we have previously introduced for contig scaffolding, which agrees with data. From this model, we derive an improved null hypothesis that when applied in the variant caller CLEVER, reduces the number of false positives and corrects a bias that contributes to more deletion calls than insertion calls. We advise developers of variant callers with statistical fragment length-based methods to adapt the concepts in our proposed model and null hypothesis.


Genetic determinants of HSP70 gene expression following heat shock.
The regulation of heat shock protein expression is of significant physiological and pathophysiological significance. Here we show that genetic diversity is an important determinant of heat shock protein 70 expression involving local, likely cis-acting, polymorphisms. We define DNA sequence variation for the highly homologous HSPA1A and HSPA1B genes in the major histocompatibility complex on chromosome 6p21 and establish quantitative and specific assays for determining transcript abundance. We show for lymphoblastoid cell lines established from individuals of African ancestry that following heat shock, expression of HSPA1B is associated with rs400547 (P 3.88 × 10(-8)) and linked single nucleotide polymorphisms (SNPs) located 62-93 kb telomeric to HSPA1B. This association was found to explain 31 and 29% of the variance in HSPA1B expression following heat shock or in resting cells, respectively. The associated SNPs show marked variation in minor allele frequency among populations, being more common in individuals of African ancestry, and are located in a region showing population-specific haplotypic block structure. The work illustrates how analysis of a heritable induced expression phenotype can be highly informative in defining functionally important genetic variation.


Association between nutrient patterns and bone mineral density among ageing adults.
There is limited evidence on the link between the overall nutrients intake from diet and bone mineral density (BMD). We assessed the association between nutrient patterns and BMD among an ageing Australian population. Participants (n = 1135; males, 45.8%; median age, 62.0 years) with dietary and BMD data in the North West Adelaide Health Study (NWAHS) were included. Dietary intake was assessed using a food frequency questionnaire. BMD was measured using dual-energy X-ray absorptiometry. Nutrient patterns were identified by factor analysis. Linear regression analyses were conducted to assess the association between nutrient patterns and BMD (mg/cm2). Multiple imputation and sensitivity analyses were conducted to investigate the effect of missing data on the estimates. Three nutrient patterns (mixed-source [potassium, calcium, fibre, retinol and Vitamin B12], animal-sourced [cholesterol, protein, Vitamin B12 and fat] and plant-sourced [fibre, carotene, vitamin C and Lutein]) were identified. After adjusting for socio-demographic, lifestyle and behavioural characteristics, chronic conditions and energy intake, animal (β = -4.07; 95% confidence interval (CI): -11.89, 3.76) and plant-sourced (β = -0.99; 95% CI: -7.43, 5.45) patterns were not associated with BMD. However, we found that the mixed-source pattern was positively associated with BMD (β = 10.86; 95% CI: 1.91, 19.80). We did not find interactions between the pattern, other covariates and BMD. The multiple imputation and sensitivity analyses including missing data identified similar patterns of association between nutrient patterns and BMD. Whereas animal- and plant-sourced nutrient patterns are not associated with BMD, mixed-source pattern may have benefit in prevention of reduced BMD.


Characterization of Genomic Variants Associated with Resistance to Bedaquiline and Delamanid in Naive Mycobacterium tuberculosis Clinical Strains.
The role of mutations in genes associated with phenotypic resistance to bedaquiline (BDQ) and delamanid (DLM) in Mycobacterium tuberculosis complex (MTBc) strains is poorly characterized. A clear understanding of the genetic variants' role is crucial to guide the development of molecular-based drug susceptibility testing (DST). In this work, we analyzed all mutations in candidate genomic regions associated with BDQ- and DLM-resistant phenotypes using a whole-genome sequencing (WGS) data set from a collection of 4,795 MTBc clinical isolates from six countries with a high burden of tuberculosis (TB). From WGS analysis, we identified 61 and 163 unique mutations in genomic regions potentially involved in BDQ- and DLM-resistant phenotypes, respectively. Importantly, all strains were isolated from patients who likely have never been exposed to these medicines. To characterize the role of mutations, we calculated the free energy variation upon mutations in the available protein structures of Ddn (DLM), Fgd1 (DLM), and Rv0678 (BDQ) and performed MIC assays on a subset of MTBc strains carrying mutations to assess their phenotypic effect. The combination of structural and phenotypic data allowed for cataloguing the mutations clearly associated with resistance to BDQ (n = 4) and DLM (n = 35), only two of which were previously described, as well as about a hundred genetic variants without any correlation with resistance. Significantly, these results show that both BDQ and DLM resistance-related mutations are diverse and distributed across the entire region of each gene target, which is of critical importance for the development of comprehensive molecular diagnostic tools.


Towards Retrieving Force Feedback in Robotic-Assisted Surgery: A Supervised Neuro-Recurrent-Vision Approach.
Robotic-assisted minimally invasive surgeries have gained a lot of popularity over conventional procedures as they offer many benefits to both surgeons and patients. Nonetheless, they still suffer from some limitations that affect their outcome. One of them is the lack of force feedback which restricts the surgeon's sense of touch and might reduce precision during a procedure. To overcome this limitation, we propose a novel force estimation approach that combines a vision based solution with supervised learning to estimate the applied force and provide the surgeon with a suitable representation of it. The proposed solution starts with extracting the geometry of motion of the heart's surface by minimizing an energy functional to recover its 3D deformable structure. A deep network, based on a LSTM-RNN architecture, is then used to learn the relationship between the extracted visual-geometric information and the applied force, and to find accurate mapping between the two. Our proposed force estimation solution avoids the drawbacks usually associated with force sensing devices, such as biocompatibility and integration issues. We evaluate our approach on phantom and realistic tissues in which we report an average root-mean square error of 0.02 N.


The mechanisms of brush border Na+/H+ exchanger activation by corticosteroids.
Previously we showed that corticosterone and aldosterone increased proton fluxes in proximal tubule, by micropuncture and stationary microperfusion. Since the Na+/H+ exchanger is responsible for the main proximal proton secretion, we have now evaluated the effects aldosterone on Na+/H+ exchange activity in brush border vesicles. In order to evaluate the mechanism of action of glucocorticoids and mineralocorticoids, we studied the comparative effects of corticosterone and aldosterone on the abundance of NHE3 and NHE2 isoforms. We isolated renal brush border vesicles from rats by differential centrifugation in sham-operated, adrenalectomized, and adrenalectomized-aldosterone treated (ADX + aldosterone) animals. We measured the kinetics of H+ transport in response to increasing concentrations of Sodium Gluconate by fluorimetry using acridine orange. For Na+/H+ exchanger abundance we used Western blot analysis of brush border proteins in the above groups and in adrenalectomized-corticosterone treated rats. The Vmax in adrenalectomized animals was 22,162+/-1828 fluorescence units/min; in sham animals, 37,020+/-2722; and in ADX + aldosterone, 42,344+/-3044 (p<0.01 adrenalectomized vs others). No differences in Km were observed. Adrenalectomy decreased NHE3 abundance over Sham by 32% without modifying NHE2. Corticosterone-replacement enhanced NHE3 abundance by 76% and failed to increase NHE2. Aldosterone enhanced NHE2 abundance by 75% and did not increase NHE3. Mineralocorticoids enhance Na+/H+ exchange activity by increasing NHE2 abundance; glucocorticoids, by increasing NHE3 abundance.


No efficacy of subcutaneous methotrexate in active ankylosing spondylitis: a 16-week open-label trial.
To examine the potential therapeutic effect of methotrexate 20 mg given weekly as subcutaneous injections to 20 patients with ankylosing spondylitis refractory to non-steroidal antirheumatic drugs. 20 patients with ankylosing spondylitis, a mean Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score of 5.6 (range 4-9.3) and predominantly axial manifestations were treated with weekly 15 mg methotrexate subcutaneously for 4 weeks, which was then increased to 20 mg subcutaneously for the next 12 weeks. Clinical outcome assessments included, among others, BASDAI score physical function, spinal mobility, patients' and physicians' global assessment (visual analogue scale), peripheral joint assessment, quality of life (Short Form 36) and C reactive protein. The primary end point of the study was a 20% improvement on the ASsessments in Ankylosing Spondylitis (ASAS 20) scale. Using an intention-to-treat analysis, ASAS 20 was achieved in only 25% of patients. An ASAS 40 response was achieved in 10% of patients, and no patient reached an ASAS 70 response or the ASAS criteria for partial remission. For the mean BASDAI score, no change was observed between baseline and week 16 (baseline 5.6 v week 16, 5.6). No improvement was observed in any of the clinical parameters or C reactive protein, except a small but non-significant decrease in the number of swollen joints. In this open study, methotrexate did not show any benefit for axial manifestations in patients with active ankylosing spondylitis beyond the expected placebo response.


The Tangled Branches (Las Ramas Enredadas): sexual risk, substance abuse, and intimate partner violence among Hispanic men who have sex with men.
Hispanic men who have sex with men (MSM) experience a number of health disparities including high rates of HIV infection from high-risk sex, substance abuse, and intimate partner violence. Although some research is available to document the relationships of these health disparities in the literature, few studies have explored the intersection of these disparities and the factors that influence them. The purpose of this study was to explore the experiences that Hispanic MSM residing in South Florida have with high-risk sex, substance abuse, and intimate partner violence. Focus groups were conducted and analyzed using grounded theory methodology until data saturation was reached (n = 20). Two core categories with subcategories emerged from the data: The Roots of Risk (Los raices del riesgo) and The Tangled Branches (Las Ramas Enredadas). The results of the study provided some important clinical implications as well as directions for future research with Hispanic MSM.


Stat3 as a potential therapeutic target for rheumatoid arthritis.
Rheumatoid arthritis (RA) is a multi-factorial disease characterized by chronic inflammation and destruction of multiple joints. To date, various biologic treatments for RA such as anti-tumor necrosis factor alpha antibodies have been developed; however, mechanisms underlying RA development remain unclear and targeted therapy for this condition has not been established. Here, we provide evidence that signal transducer and activator of transcription 3 (Stat3) promotes inflammation and joint erosion in a mouse model of arthritis. Stat3 global KO mice show early embryonic lethality; thus, we generated viable Stat3 conditional knockout adult mice and found that they were significantly resistant to collagen-induced arthritis (CIA), the most common RA model, compared with controls. We then used an in vitro culture system to screen ninety-six existing drugs to select Stat3 inhibitors and selected five candidate inhibitors. Among them, three significantly inhibited development of arthritis and joint erosion in CIA wild-type mice. These findings suggest that Stat3 inhibitors may serve as promising drugs for RA therapy.


Exposure of rural and urban populations in KwaZulu Natal, South Africa, to fumonisin B(1) in maize.
We surveyed households in rural and urban areas of KwaZulu Natal, South Africa, to assess the exposure of the inhabitants to fumonisin B(1) (FB(1)), a mycotoxin produced by Fusarium verticillioides. In southern African regions maize, used as a staple food by the population, is prone to F. verticillioides infection. Furthermore, high levels of FB(1) in maize have been associated with esophageal cancer in South Africa. We assessed exposure of the population to FB(1) at three levels, namely, by analyzing stored maize, plate-ready food, and feces. The positions of participating households in the rural area were recorded using geographic information systems (GIS) for ease and accuracy of follow-up. Of the 50 rural maize samples examined, 32% had levels of FB(1) ranging from 0.1-22.2 mg/kg, whereas 29% of the 28 cooked maize (phutu) samples contained FB(1) ranging from 0.1-0.4 mg/kg. The incidence and levels of FB(1) in feces were 33% and 0.5-39.0 mg/kg, respectively. Of the 49 urban maize samples analyzed 6.1% had a range of 0.2-0.5 mg/kg FB(1), whereas 3 of 44 fecal samples (6%) ranged between 0.6 and 16.2 mg/kg. No FB(1) was detected in urban phutu samples. Because these levels are lower than those published from regions in South Africa with high incidence of esophageal cancer, it may be concluded that the risk of esophageal cancer from FB(1) exposure is lower in the KwaZulu Natal region.


Further evidence for the role of fibrosis in the pathobiology of rhinophyma.
Recent evidence suggests that fibrosis may play an important role in the pathobiology of rhinophyma. The fibrogenic cytokine transforming growth factor (TGF)-beta2 has been reported to be up-regulated in rhinophyma tissue. Of the three common isoforms of TGF-beta, TGF-beta1 and TGF-beta2 are considered fibrogenic, whereas TGF-beta3 has antiscarring properties. To provide further evidence for the role of fibrosis in the pathobiology of rhinophyma, specimens from 8 patients with rhinophyma were compared with nine specimens of normal nasal skin. Immunohistochemistry was used to compare intensity levels of TGFbeta1 and TGFbeta3 proteins, and quantitative reverse transcription-polymerase chain reaction was used to determine messenger ribonucleic acid (mRNA) expression levels of TGFbeta1 and TGFbeta3. TGF-beta1 was elevated significantly in rhinophyma tissue (p < 0.001), whereas TGF-beta3 was no different in the rhinophyma specimens compared with normal nasal skin (p = 0.06). TGFbeta1 mRNA expression was five-fold higher in rhinophyma tissue compared with normal skin (p < 0.001). The mRNA expression of TGF-beta3 was the same for both pathological and normal tissue (p < 0.09). These data, together with previously published observations, present further evidence that fibrosis mediated by the fibrogenic cytokines TGFbeta1 and TGFbeta2 play a role in the pathobiology of rhinophyma and suggest a means of treatment by neutralizing or down-regulating these cytokines.


Cost effectiveness of cervical cancer screening for the elderly.
To analyze the costs and benefits of alternative cervical cancer screening schedules among elderly women. Population-based screening programs. A Markov model predicts the outcomes of periodic screening, diagnosis, and treatment for cervical cancer among women from 65 to 109 years of age. A hypothetical cohort of one million 65-year-old women; representative of the U.S. population. The costs and yields of screening. Triennial screening reduced mortality from cervical cancer among the elderly by 74% at a cost of $2254 per year of life saved. Annual screening increased costs to $7345 per year of life saved; less frequent schedules yielded lower costs but decreased savings in life. These results were most sensitive to the quality of the Papanicolaou smear and the characteristics of the women using the benefit. If the sensitivity of the Papanicolaou smear was reduced from a baseline estimate of 75% to 50% and the specificity was decreased to 87% from 95%, the cost effectiveness ratio increased by nearly $7000 per year of life saved. If triennial screening is targeted to women who have not had regular screening, the program will save money as well as years of life; however, screening women who have been screened regularly is considerably less efficient, increasing costs to $33,572 per year of life saved. The success of the new Medicare benefit depends substantially on physicians assuring that their elderly patients, particularly women without regular prior screening, obtain high quality Papanicolaou smears. The data also show that after a woman 65 years of age or older has a history of regular negative smears, screening is inefficient and can cease.


Systemic Lupus Erythematosus Accompanied by Psoriasis Induces IL-27-Producing Cells in Both Affected Areas of the Skin.
IL-27 is mainly produced by activated antigen-presenting cells (APCs), and has been reported in various Th1/Th17-mediated inflammatory diseases, including psoriasis, and even in Th2-complexed disease, such as systemic lupus erythematosus (SLE). We describe a 51-year-old Japanese man with SLE accompanied by psoriasis. Interestingly, immunohistochemical staining revealed the existence of IL-27-producing cells in biopsy specimens from both SLE and psoriasis. Our findings might suggest relationships between IL-27 and the pathogenesis of these inflammatory diseases.


Ambiguity and invariance: two fundamental challenges for visual processing.
The visual system is tasked with extracting stimulus content (e.g. the identity of an object) from the spatiotemporal light pattern falling on the retina. However, visual information can be ambiguous with regard to content (e.g. an object when viewed from far away), requiring the system to also consider contextual information. Additionally, visual information originating from the same content can differ (e.g. the same object viewed from different angles), requiring the system to extract content invariant to these differences. In this review, we explore these challenges from experimental and theoretical perspectives, and motivate the need to incorporate solutions for both ambiguity and invariance into hierarchical models of visual processing.


Seronegative generalised myasthenia gravis: clinical features, antibodies, and their targets.
Myasthenia gravis (MG) is a well-recognised disorder of neuromuscular transmission that can be diagnosed by the presence of antibodies to the acetylcholine receptor (AChR). However, some patients (about 15%) with generalised MG do not have detectable AChR antibodies. There is some evidence, however, that this "seronegative" MG is an antibody-mediated disorder. Plasma from patients with the disorder seems to contain various distinct humoral factors: IgG antibodies that reversibly inhibit AChR function; a non-IgG (possibly IgM) factor that indirectly inhibits AChR function; and an IgG antibody against the muscle-specific kinase (MuSK). The presence of antibodies against MuSK appears to define a subgroup of patients with seronegative MG who have predominantly localised, in many cases bulbar, muscle weaknesses (face, tongue, pharynx, etc) and reduced response to conventional immunosuppressive treatments. Moreover, muscle wasting may be present, which prevents complete response to these therapies.


The guanine-nucleotide exchange factor Vav is a crucial regulator of B cell receptor activation and B cell responses to nonrepetitive antigens.
The proto-oncogene product Vav is required for receptor clustering, proliferation, and differentiation of T cells, and Vav was identified as a substrate in the TCR and B cell receptor signaling pathway. The role of Vav in B cell responses to Ag challenge in vivo is not known. In this study, we show that Vav regulates B cell proliferation following in vitro activation of Ag receptors, but Vav has no apparent role in CD40-, IL-4-, or LPS-induced B cell activation. Increased degrees of Ag receptor cross-linking can partially reverse the proliferative defect in the anti-IgM response of vav-/- B cells. In vivo, vav-/- mice mounted protective antiviral IgM and IgG responses to infections with vesicular stomatitis virus and recombinant vaccinia virus expressing the vesicular stomatitis virus glycoprotein, which harbor repetitive surface epitopes that directly cross-link the Ag receptor and activate B cells in the absence of T cell help. vav-/- B cells also responded normally to the polyvalent, repetitive hapten Ag trinitrophenyl (TNP)-Ficoll that effectively cross-links B cell receptors. However, vav-/- mice failed to mount immune responses to the nonrepetitive, T cell-dependent hapten Ag (4-hydroxy-5-iodo-3-nitrophenyl)acetyl (NIP)-OVA. These results provide the first genetic evidence on the role of the guanine exchange factor Vav in immune responses to viral infections and antigenic challenge in vivo, and suggest that Vav adjusts the threshold for Ag receptor-mediated B cell activation depending on the nature of the Ag.


Comparative assessment of malaria rapid diagnostic tests (RDT) in Ibadan, Nigeria.
Deployment of sound diagnostic tests remains a crucial component of malaria management, prevention and control in Africa. We undertook a comparative assessment of sensitivity, specificity and efficiency of three popular brands of rapid diagnostic tests (RDT) available in Nigerian market alongside with traditional microscopy. 525 samples of patients that presented with acute uncomplicated malaria through clinical diagnosis were evaluated with the various tests. Total WBC count and haematocrit were also measured. Of the 525 samples, 300 (57.1%) were found positive by Giemsa microscopy. SD Bioline had a positivity rate of 49.5% (260/525), while the positivity rate for Acon was significantly lower (38.1%; 200/525) and Paracheck (28.6%; 150/525). The sensitivity, specificity and efficiency of the three RDTs were: SD Bioline (86.3%, 99.6%, 92%); Paracheck (50%, 97.7%, 70.4%) and Acon (66.7%, 100%, 80.9%), respectively. Pre-teens aged 6-12 yrs had the highest mean malaria parasite densities with 6,631.26 at p< 0.01. The dominant malaria species was Plasmodium falciparum with 280 (93.3%) cases. Co-infections of P. falciparum/vivax (15; 5.0%) and P. falciparum/malariae (5; 1.7%) were detected and confirmed with microscopy. Haematocrit values correlated inversely with parasite density (r = -0.744; p< 0.01). Microscopy still remains the reference standard for malaria diagnosis in limited resource settings in endemic areas. In furtherance to this, there is need for consistent monitoring of RDT product quality as part of the distribution process to end-users across Nigeria.


Functional expression of heterologous proteins in yeast: insights into Ca2+ signaling and Ca2+-transporting ATPases.
The baker's yeast Saccharomyces cerevisiae is a well-developed, versatile, and widely used model organism. It offers a compact and fully sequenced genome, tractable genetics, simple and inexpensive culturing conditions, and, importantly, a conservation of basic cellular machinery and signal transducing pathways with higher eukaryotes. In this review, we describe recent technical advances in the heterologous expression of proteins in yeast and illustrate their application to the study of the Ca(2+) homeostasis machinery, with particular emphasis on Ca(2+)-transporting ATPases. Putative Ca(2+)-ATPases in the newly sequenced genomes of organisms such as parasites, plants, and vertebrates have been investigated by functional complementation of an engineered yeast strain lacking endogenous Ca(2+) pumps. High-throughput screens of mutant phenotypes to identify side chains critical for ion transport and selectivity have facilitated structure-function analysis, and genomewide approaches may be used to dissect cellular pathways involved in Ca(2+) transport and trafficking. The utility of the yeast system is demonstrated by rapid advances in the study of the emerging family of Golgi/secretory pathway Ca(2+),Mn(2+)-ATPases (SPCA). Functional expression of human SPCA1 in yeast has provided insight into the physiology, novel biochemical characteristics, and subcellular localization of this pump. Haploinsufficiency of SPCA1 leads to Hailey-Hailey disease (HDD), a debilitating blistering disorder of the skin. Missense mutations, identified in patients with HHD, may be conveniently assessed in yeast for loss-of-function phenotypes associated with the disease.


Association of Epigenetic Metrics of Biological Age With Cortical Thickness.
Magnetic resonance imaging (MRI) studies of aging adults have shown substantial intersubject variability across various brain metrics, and some of this variability is likely attributable to chronological age being an imprecise measure of age-related change. Accurately quantifying one's biological age could allow better quantification of healthy and pathological changes in the aging brain. To investigate the association of DNA methylation (DNAm)-based biological age with cortical thickness and to assess whether biological age acceleration compared with chronological age captures unique variance in cortical thinning. This cross-sectional study used high-resolution structural brain MRI data collected from a sample of healthy aging adults who were participating in a larger ongoing neuroimaging study that began in May 2014. This population-based study accrued participants from the greater Omaha, Nebraska, metropolitan area. One hundred sixty healthy adults were contacted for the MRI component, 82 of whom participated in both DNAm and MRI study components. Data analysis was performed from March to June 2019. Vertexwise cortical thickness, DNAm-based biological age, and biological age acceleration compared with chronological age were measured. A pair of multivariable regression models were computed in which cortical thickness was regressed on DNAm-based biological age, controlling for sex in the first model and also controlling for chronological age in the second model. Seventy-nine adult participants (38 women; mean [SD] age, 43.82 [14.50] years; age range, 22-72 years) were included in all final analyses. Advancing biological age was correlated with cortical thinning across frontal, superior temporal, inferior parietal, and medial occipital regions. In addition, biological age acceleration relative to chronological age was associated with cortical thinning in orbitofrontal, superior and inferior temporal, somatosensory, parahippocampal, and fusiform regions. Specifically, for every 1 year of biological age acceleration, cortical thickness would be expected to decrease by 0.024 mm (95% CI, -0.04 to -0.01 mm) in the left orbitofrontal cortex (partial r, -0.34; P = .002), 0.014 mm (95% CI, -0.02 to -0.01 mm) in the left superior temporal gyrus (partial r, -0.36; P = .001), 0.015 mm (95% CI, -0.02 to -0.01 mm) in the left fusiform gyrus (partial r, -0.38; P = .001), 0.015 mm (95% CI, -0.02 to -0.01 mm) in the right fusiform gyrus (partial r, -0.43; P < .001), 0.019 mm (95% CI, -0.03 to -0.01 mm) in the right inferior temporal sulcus (partial r, -0.34; P = .002), and 0.011 mm (95% CI, -0.02 to -0.01 mm) in the right primary somatosensory cortex (partial r, -0.37; P = .001). To our knowledge, this is the first study to investigate vertexwise cortical thickness in relation to DNAm-based biological age, and the findings suggest that this metric of biological age may yield additional insight on healthy and pathological cortical aging compared with standard measures of chronological age alone.


Release of epithelium-derived PGE2 from canine trachea after antigen inhalation.
To investigate the role of prostaglandin (PG) E2 in allergen-induced hyperresponsiveness, dogs inhaled either the allergen Ascaris suum or vehicle (Sham). Twenty-four hours after inhalation, some animals exposed to allergen demonstrated an increased responsiveness to acetylcholine challenge in vivo (Hyp-Resp), whereas others did not (Non-Resp). Strips of tracheal smooth muscle, either epithelium intact or epithelium denuded, were suspended on stimulating electrodes, and a concentration-response curve to carbachol (10(-9) to 10(-5) M) was generated. Tissues received electrical field stimulation, and organ bath fluid was collected to determine PGE2 content. With the epithelium present, all three groups contracted similarly to 10(-5) M carbachol, whereas epithelium-denuded tissues from animals that inhaled allergen contracted more than tissues from Sham dogs. In response to electrical field stimulation, Hyp-Resp tissues contracted less than Sham tissues in the presence of epithelium and more than Sham tissues in the absence of epithelium. PGE2 release in the muscle bath was greater in Non-Resp tissues than in Sham or Hyp-Resp tissues when the epithelium was present. Removal of the epithelium greatly inhibited PGE2 release. We conclude that tracheal smooth muscle is hyperresponsive in vitro after in vivo allergen exposure only when the modulatory effect of the epithelium, largely through PGE2 release, is removed.


Early signals in the mitogenic response of Swiss 3T3 cells: a comparative study of purified PDGF homodimers.
Platelet-derived growth factor (PDGF) occurs as three dimeric isoforms, AA, BB, and AB. Two distinct receptor subunits, alpha and beta, have been identified which bind either all three isoforms of PDGF (alpha) or PDGF-BB only (beta). Here, we have compared the effect of purified PDGF homodimers on the early intracellular signaling events and mitogenesis in Swiss 3T3 cells, which possess equivalent numbers of the alpha and beta subunits. Both PDGF-AA and PDGF-BB stimulated receptor phosphorylation, inositol phosphate formation, activation of protein kinase C, calcium mobilization, EGF receptor transmodulation, sodium uptake, arachidonic acid release, cyclic AMP accumulation, and c-fos induction in a comparable, dose-dependent manner (half-maximal values for all these response were in the 2-10 ng/ml range for both homodimers). At high concentrations of PDGF (greater than 10 ng/ml), the BB homodimer effect on early membrane and cytosolic signals was 20-30% greater than PDGF-AA, reflecting the greater number of available binding sites for PDGF-BB. DNA synthesis studies indicated that PDGF-AA and PDGF-BB were potent mitogens for Swiss 3T3 cells, displaying identical dose-response effects. Moreover, the mitogenic activities of both homodimers were equally potentiated in the presence of insulin. These results indicate that both PDGF-AA and PDGF-BB stimulate the full complement of molecular responses required for the synergistic interactions mediating long-term mitogenesis. We conclude that alpha and beta receptor subunits do not differ in their ability to transduce PDGF-mediated signals leading to DNA synthesis in Swiss 3T3 cells.


Design Guidelines of a Computer-Based Intervention for Computer Vision Syndrome: Focus Group Study and Real-World Deployment.
Prolonged time of computer use increases the prevalence of ocular problems, including eye strain, tired eyes, irritation, redness, blurred vision, and double vision, which are collectively referred to as computer vision syndrome (CVS). Approximately 70% of computer users have vision-related problems. For these reasons, properly designed interventions for users with CVS are required. To design an effective screen intervention for preventing or improving CVS, we must understand the effective interfaces of computer-based interventions. In this study, we aimed to explore the interface elements of computer-based interventions for CVS to set design guidelines based on the pros and cons of each interface element. We conducted an iterative user study to achieve our research objective. First, we conducted a workshop to evaluate the overall interface elements that were included in previous systems for CVS (n=7). Through the workshop, participants evaluated existing interface elements. Based on the evaluation results, we eliminated the elements that negatively affect intervention outcomes. Second, we designed our prototype system LiquidEye that includes multiple interface options (n=11). Interface options included interface elements that were positively evaluated in the workshop study. Lastly, we deployed LiquidEye in the real world to see how the included elements affected the intervention outcomes. Participants used LiquidEye for 14 days, and during this period, we collected participants' daily logs (n=680). Additionally, we conducted prestudy and poststudy surveys, and poststudy interviews to explore how each interface element affects participation in the system. User data logs collected from the 14 days of deployment were analyzed with multiple regression analysis to explore the interface elements affecting user participation in the intervention (LiquidEye). Statistically significant elements were the instruction page of the eye resting strategy (P=.01), goal setting of the resting period (P=.009), compliment feedback after completing resting (P<.001), a mid-size popup window (P=.02), and CVS symptom-like effects (P=.004). Based on the study results, we suggested design implications to consider when designing computer-based interventions for CVS. The sophisticated design of the customization interface can make it possible for users to use the system more interactively, which can result in higher engagement in managing eye conditions. There are important technical challenges that still need to be addressed, but given the fact that this study was able to clarify the various factors related to computer-based interventions, the findings are expected to contribute greatly to the research of various computer-based intervention designs in the future.


Effect of minimally invasive radical prostatectomy in older men.
Minimally invasive radical prostatectomy (MIRP) has been rapidly adopted over the last decade, however, little is known about outcomes in older patients. To examine the outcomes of MIRP vs. open radical prostatectomy (OPRP) stratified by age. We examined the Surveillance, End Results and Epidemiology-Medicare database between years 2004 and 2009 for men with nonmetastatic adenocarcinoma of the prostate. Our cohort (n = 12,092) was subdivided into 2 groups-MIRP vs. OPRP, and by patient age≥70 years (n = 6,660) vs. 66 to 69 years (n = 5,432). Multivariate analysis and multiple Cox proportional hazard models evaluated the influence of surgical approach and other variables on perioperative and postoperative complications in each age group. The use of MIRP increased over the 6-year time span (14.8%-73.3%;<70y) and 15.1%-69.8%;≥70y). OPRP was associated with a higher risk of blood transfusion and postoperative respiratory or genitourinary (GU) complications. Patients who underwent MIRP were more likely to have a diagnosis of erectile dysfunction or urinary incontinence compared to OPRP (56.9% vs. 42.2% and 53.9% vs. 43.2%, respectively; P<0.0001). Patients who underwent MIRP were less likely to have an anastomotic stricture or require additional cancer therapy. Men aged≥70 years, who underwent MIRP had higher rates of transfusion, GU complications, length of stay, incontinence, and anastomotic stricture rates compared with those of men aged 66 to 69 years. However, older men undergoing MIRP had 10% lower rates of erectile dysfunction compared with that of men aged 66 to 69 years of age. MIRP increased to>70% of all procedures performed in 2009. MIRP is associated with lower blood transfusion rates, postoperative respiratory or GU complications, anastomotic stricture diagnoses, and additional cancer therapies. This suggests that MIRP is a successful prostate cancer treatment for older patients.


Wisconsin Card Sorting Task-64 performance among HIV+ Black/African American and Latinx adults compared to normative samples and by sociocultural and health variables.
Many people living with HIV experience cognitive impairment, and HIV disproportionately affects racial/ethnic minority groups. Independent of HIV, racial/ethnic minority individuals perform worse than White individuals on cognitive tasks, even after accounting for education. Our goals were to (1) compare WCST-64 scores between HIV+ Black/African American (Black/AA) (n = 45) and Latinx (n = 41) urban-dwelling adults; (2) compare our total sample to the WCST-64 manual's normative (N) and clinical normative (CN) groups; and (3) explore relationships between WCST-64 performance and sociocultural/health variables. In our sample, employment (12%), mean annual income (<$10,000), and mean education (<12 years) were low, while mean medication adherence rates were high for both Black/AA (90%) and Latinx (87%). WCST-64 scores were similar between groups (p > .05). Percentages of "below average" and "mildly impaired" scores in our sample were higher than the N group, and similar to the CN group. Lifetime heroin use, dementia, and longer HIV illness duration were significantly associated with worse WCST-64 performance (ps < .05). The observed low scores in our asymptomatic sample are likely due to the intersectionality of sociocultural and medical burden, highlighting complexities in interpreting neuropsychological data in real-world HIV+ clinics. Executive deficits are linked to poorer outcomes, and routine cognitive screening may be clinically indicated.


Different Measures of Diet Diversity During Infancy and the Association with Childhood Food Allergy in a UK Birth Cohort Study.
Diet diversity (DD) during infancy may prevent food allergies (FA), possibly by exposing the gastrointestinal microbiota to diverse foods and nutrients. To investigate the association between 4 different measures of DD during infancy and development of FA over the first decade of life. A birth cohort born between 2001 and 2002 were followed prospectively, providing information on sociodemographic, environmental, and dietary exposures. Information on age of introduction of a range of foods and food allergens was collected during infancy. Children were assessed for FA at 1, 2, 3, and 10 years. DD was defined using 4 measures in the first year of life: the World Health Organization definition of minimum DD at 6 months, as food diversity (FD) and fruit and vegetable diversity (FVD) at 3, 6, and 9 months, and as food allergen diversity (FAD) at 3, 6, 9, and 12 months. A total of 969 pregnant women were recruited at 12-week gestation. A total of 900, 858, 891, and 827 offspring were assessed at 1, 2, 3, and 10 years. Univariate analysis showed that World Health Organization DD (P = .0047), FD (P = .0009), FAD (P = .0048), and FVD (P = .0174) at 6 months and FD (P = .0392), FAD (P = .0233), and FVD (.0163) at 9 months significantly reduced the odds of FA over the first decade of life. DD measures at 3 months were not associated with FA, but only 33% of the cohort had solid foods introduced by this age. Increased infant DD, as measured by 4 different methods, decreased the likelihood of developing FA.


Orally Administered D-Aspartate Depresses Rectal Temperature and Alters Plasma Triacylglycerol and Glucose Concentrations in Broiler Chicks.
L-Aspartate (L-Asp), D-aspartate (D-Asp) or their chemical conjugates plays important physiological roles in regulating food intake, plasma metabolites and thermoregulation in animals. However, there are very few studies available in layers and no reports have been found in broilers. Broilers are very important commercial birds for meat production, so effects of L- or D-Asp in broilers would provide new physiological insight of this strain. Therefore, the purpose of this study was to determine the effect of oral administration of L- or D-Asp on feed intake, rectal temperature and some plasma metabolites in broiler chicks. Broiler chicks (5 days old) were orally administered with different doses (0, 3.75, 7.5 and 15 mmol/kg body weight) of L- or D-Asp. At 120 min after administration of L- or D-Asp, the blood was immediately collected through the jugular vein. The rectal temperature of chicks was measured at 30, 60 and 120 min after administration using a digital thermometer with an accuracy of ±0.1°C, by inserting the thermistor probe in the rectum to a depth of 2 cm. A repeated-measures two-way ANOVA was applied for the analysis of feed intake and rectal temperature. Plasma metabolites were statistically analyzed by one-way ANOVA and regression equations. The study showed that oral administration of both L- and D-Asp did not alter feed intake. However, D-Asp, but not L-Asp, dose-dependently decreased the rectal temperature in chicks. It was also found that D-Asp increased plasma glucose and decreased triacylglycerol concentrations. The changes in plasma metabolites further indicate that D-Asp treatment modulates the energy metabolism in broiler chicks. In conclusion, D-Asp may be a beneficial nutrient not only for layers but also for broilers, since orally administered D-Asp lowered rectal temperature without reducing feed intake.


Increased central arterial stiffness explains baroreflex dysfunction in spinal cord injury.
After cervical spinal cord injury (SCI), orthostatic hypotension and intolerance commonly ensue. The cardiovagal baroreflex plays an important role in the acute regulation of blood pressure (BP) and is associated with the onset of presyncope. The cardiovagal baroreflex is dysfunctional after SCI; however, this may be influenced by either increased stiffening of the arteries containing the stretch-receptors (which has been shown in SCI) or a more downstream neural mechanism (i.e., solitary nucleus, sinoatrial node). Identifying where along this pathway baroreflex dysfunction occurs may highlight a potential therapeutic target. This study examined the relationship between spontaneous cardiovagal baroreflex sensitivity (BRS) and common carotid artery (CCA) stiffness in those with high level SCI before and after midodrine (alpha1-agonist) administration, as well as in able-bodied controls, to evaluate: (1) the role arterial stiffening plays mediating baroreflex function after SCI and (2) the effect of normalizing BP on these parameters. Three to five min recordings of beat-by-beat BP and heart rate, as well as 30 sec duration recordings of CCA diameter were used for analysis. All participants were tested supine and during upright-tilt. Arterial stiffness (β-stiffness index) was elevated in those with SCI when upright (+12%; p<0.05). Further, β-stiffness index was negatively related to reduced BRS in those with SCI when upright (R2=0.55; p<0.05), but not in able-bodied persons. Normalizing BP did not improve BRS or CCA stiffness. This study clearly shows that reduced BRS is closely related to increased arterial stiffness in the population with SCI.


Addressing hindfoot arthritis with concomitant tibial malunion or nonunion with retrograde tibiotalocalcaneal nailing: a novel treatment approach.
Tibial malunions and nonunions are associated with degenerative changes about the ankle. A comprehensive literature review revealed no articles discussing treatment options for patients with tibial shaft malunion and ipsilateral ankle arthritis. The aim of our study was to evaluate a series of patients in whom tibial osteotomy and retrograde tibiotalocalcaneal nailing were used to treat both tibial deformity and ankle osteoarthritis. Twenty-five patients underwent retrograde tibiotalocalcaneal nailing with concomitant realignment tibial osteotomy with takedown of the nonunion or malunion in a single procedure. All surgical procedures were performed by a single surgeon at a single institution. Baseline patient characteristics (age, sex, body mass index [BMI], preoperative diagnosis, and prior surgical procedures) were recorded. Data including visual analog scale (VAS) pain scores (0 to 10, with 0 indicating no pain and 10 indicating worst pain) and American Orthopaedic Foot & Ankle Society ankle-hindfoot (AOFAS-AH) scores were prospectively collected at the preoperative evaluation and the time of final follow-up, and patients were asked about their final satisfaction. Preoperative VAS scores averaged 8.3 (range, 7 to 10) of 10, which improved to an average of 2.8 (range, 0 to 6) at the time of final follow-up (p < 0.01). The preoperative AOFAS-AH scores averaged 43 (range, 18 to 62) of 100 and improved to 76 (range, 57 to 84) at the time of follow-up (p = 0.022). Twenty-one patients (84%) stated that they were extremely satisfied with the result of the procedure, three patients (12%) were satisfied, and one patient (4%) with a poor result was unsatisfied. Tibial malunion or nonunion with concomitant hindfoot arthritis can be addressed with a single-stage procedure consisting of tibial osteotomy and retrograde intramedullary nailing for correction of the angular deformity and hindfoot fusion. This procedure provides a viable alternative to multiplanar external fixation or a staged procedure addressing the nonunion or angular deformity and the hindfoot arthritis separately.


GPR30, the non-classical membrane G protein related estrogen receptor, is overexpressed in human seminoma and promotes seminoma cell proliferation.
Testicular germ cell tumours are the most frequent cancer of young men with an increasing incidence all over the world. Pathogenesis and reasons of this increase remain unknown but epidemiological and clinical data have suggested that fetal exposure to environmental endocrine disruptors (EEDs) with estrogenic effects, could participate to testicular germ cell carcinogenesis. However, these EEDs (like bisphenol A) are often weak ligands for classical nuclear estrogen receptors. Several research groups recently showed that the non classical membrane G-protein coupled estrogen receptor (GPER/GPR30) mediates the effects of estrogens and several xenoestrogens through rapid non genomic activation of signal transduction pathways in various human estrogen dependent cancer cells (breast, ovary, endometrium). The aim of this study was to demonstrate that GPER was overexpressed in testicular tumours and was able to trigger JKT-1 seminoma cell proliferation. We report here for the first time a complete morphological and functional characterization of GPER in normal and malignant human testicular germ cells. In normal adult human testes, GPER was expressed by somatic (Sertoli cells) and germ cells (spermatogonia and spermatocytes). GPER was exclusively overexpressed in seminomas, the most frequent testicular germ cell cancer, localized at the cell membrane and triggered a proliferative effect on JKT-1 cells in vitro, which was completely abolished by G15 (a GPER selective antagonist) and by siRNA invalidation. These results demonstrate that GPER is expressed by human normal adult testicular germ cells, specifically overexpressed in seminoma tumours and able to trigger seminoma cell proliferation in vitro. It should therefore be considered rather than classical ERs when xeno-estrogens or other endocrine disruptors are assessed in testicular germ cell cancers. It may also represent a prognosis marker and/or a therapeutic target for seminomas.


Three output port channel-drop filter based on photonic crystals.
We present a photonic-crystal (PC) channel-drop filter (CDF) design based on 3x3 PC ring resonators. The normalized transmission spectra for single-ring and dual-ring configurations have been investigated using two-dimensional finite-difference time-domain (FDTD) technique in a square-lattice dielectric-rod PC structure. First, we investigate a single ring and we show that backward and forward dropping is possible in the third communication window. Then we add another ring and waveguide to develop a new CDF. This filter consists of an input and three outputs. Our FDTD simulation yields more than 85% efficiency over each output port.


The Effect of Lingual Resistance Training Interventions on Adult Swallow Function: A Systematic Review.
Lingual resistance training has been proposed as an intervention to improve decreased tongue pressure strength and endurance in patients with dysphagia. However, little is known about the impact of lingual resistance training on swallow physiology. This systematic review scrutinizes the available evidence regarding the effects of lingual resistance training on swallowing function in studies using Videofluoroscopic Swallowing Studies (VFSS) with adults. Seven articles met the inclusion criteria and underwent detailed review for study quality, data extraction, and planned meta-analysis. Included studies applied this intervention to a stroke and brain injury patient populations or to healthy participants, applied different training protocols, and used a number of outcome measures, making it difficult to generalize results. Lingual resistance training protocols included anterior and posterior tongue strengthening, accuracy training, and effortful press against hard palate with varying treatment durations. VFSS protocols typically included a thin barium stimulus along with one other consistency to evaluate the effects of the intervention. Swallowing measures included swallow safety, efficiency, and temporal measures. Temporal measures significantly improved in one study, while safety improvements showed mixed results across studies. Reported improvements in swallowing efficiency were limited to reductions in thin liquid barium residue in two studies. Overall, the evidence regarding the impact of lingual resistance training for dysphagia is mixed. Meta-analysis was not possible due to differences in methods and outcome measurements across studies. Reporting all aspects of training and details regarding VFSS protocols is crucial for the reproducibility of these interventions. Future investigations should focus on completing robust analyses of swallowing kinematics and function following tongue pressure training to determine efficacy for swallowing function.


The role of noise and positive feedback in the onset of autosomal dominant diseases.
Autosomal dominant (AD) diseases result when a single mutant or non-functioning gene is present on an autosomal chromosome. These diseases often do not emerge at birth. There are presently two prevailing theories explaining the expression of AD diseases. One explanation originates from the Knudson two-hit theory of hereditary cancers, where loss of heterozygosity or occurrence of somatic mutations impairs the function of the wild-type copy. While these somatic second hits may be sufficient for stable disease states, it is often difficult to determine if their occurrence necessarily marks the initiation of disease progression. A more direct consequence of a heterozygous genetic background is haploinsufficiency, referring to a lack of sufficient gene function due to reduced wild-type gene copy number; however, haploinsufficiency can involve a variety of additional mechanisms, such as noise in gene expression or protein levels, injury and second hit mutations in other genes. In this study, we explore the possible contribution to the onset of autosomal dominant diseases from intrinsic factors, such as those determined by the structure of the molecular networks governing normal cellular physiology. First, simple models of single gene insufficiency using the positive feedback loops that may be derived from a three-component network were studied by computer simulation using Bionet software. The network structure is shown to affect the dynamics considerably; some networks are relatively stable even when large stochastic variations in are present, while others exhibit switch-like dynamics. In the latter cases, once the network switches over to the disease state it remains in that state permanently. Model pathways for two autosomal dominant diseases, AD polycystic kidney disease and mature onset diabetes of youth (MODY) were simulated and the results are compared to known disease characteristics. By identifying the intrinsic mechanisms involved in the onset of AD diseases, it may be possible to better assess risk factors as well as lead to potential new drug targets. To illustrate the applicability of this study of pathway dynamics, we simulated the primary pathways involved in two autosomal dominant diseases, Polycystic Kidney Disease (PKD) and mature onset diabetes of youth (MODY). Simulations demonstrate that some of the primary disease characteristics are consistent with the positive feedback-stochastic variation theory presented here. This has implications for new drug targets to control these diseases by blocking the positive feedback loop in the relevant pathways.


A design space of visualization tasks.
Knowledge about visualization tasks plays an important role in choosing or building suitable visual representations to pursue them. Yet, tasks are a multi-faceted concept and it is thus not surprising that the many existing task taxonomies and models all describe different aspects of tasks, depending on what these task descriptions aim to capture. This results in a clear need to bring these different aspects together under the common hood of a general design space of visualization tasks, which we propose in this paper. Our design space consists of five design dimensions that characterize the main aspects of tasks and that have so far been distributed across different task descriptions. We exemplify its concrete use by applying our design space in the domain of climate impact research. To this end, we propose interfaces to our design space for different user roles (developers, authors, and end users) that allow users of different levels of expertise to work with it.


Barrett's esophagus with high grade dysplasia: surgical results and long-term outcome--an update.
We updated our surgical results and long-term outcome for prophylactic esophagectomy in patients with Barrett's esophagus and high-grade dysplasia (HGD) and determined the incidence of occult adenocarcinoma. Sixty consecutive patients with HGD who underwent esophagectomy had pre- and postoperative pathology examined at our institution from 1982 to 2001. We reviewed medical records to determine patient characteristics, surgical approach, operative morbidity and mortality, pathology, and length of stay. Patients and/or referring physicians were contacted to determine long-term outcome. Fifty-three men (88%) and 7 women (12%) were followed up for a median of 4.6 years. Transhiatal esophagectomy was performed in the majority of patients (82%). There was one operative death (1.7%) and 15 complications (29%). Median length of stay was 9 days. In 18 patients (30%), invasive adenocarcinoma was detected in the resected specimen. When examined by time periods, 43% (13/30) of patients were diagnosed with occult cancer from 1982-1994, whereas 17% (5/30) harbored occult malignancy from 1994-2001. All patients with adenocarcinoma in the recent interval had stage I disease, as opposed to only 61.5% of patients from the earlier study. Operative mortality declined from 3.3% to 0% over the two intervals as did mean length of stay from 14 days to 10 days. Five-year survival was excellent at 88%. Age and amount of preoperative weight loss were preoperative predictors of survival, whereas major postoperative complications and stage were postoperative predictors of outcome. Barrett's esophagus with high-grade dysplasia continues to be an indication for prophylactic esophagectomy. Overall prevalence of occult adenocarcinoma remains high. We have demonstrated a declining incidence of occult cancer and treatment of earlier stage adenocarcinoma when found in this population of patients treated with esophagectomy.


Barriers and enablers of breast-feeding protection and support after the 2017 earthquakes in Mexico.
To study the barriers and enablers of breast-feeding protection and support after the 2017 earthquakes in Mexico. A qualitative study using a phenomenological approach to analyse data collected from in-depth interviews, virtual ethnography and documentary analysis of newspapers. Data were collected after the September 2017 earthquakes in Mexico (from 8 September 2017 to 15 May 2018). The participants included key informants (n 13) from different sectors. Postings retrieved from forty-two Facebook and forty-seven Twitter accounts and a WhatsApp group informed the virtual ethnography analysis. Newspaper material covering the 2017 earthquakes in Mexico (seven newspapers) was retrieved for the documentary analysis. Interviews with key informants revealed a lack of knowledge, unclear institutional protocols during emergencies and lack of enforcement of existing international frameworks. The virtual ethnography uncovered a strong call for donations in the immediate aftermath of the earthquakes, and generalized donations of formula revealed a tense relationship between actions taken by breast-feeding experts and the negative reactions from the government and citizens. This analysis highlights the relevance of pre-existing networks of experts in protecting and supporting breast-feeding. From the newspaper documentary analysis, similar themes emerged. This study identified key barriers and enablers in the protection and support of breast-feeding during the 2017 earthquakes in Mexico. Relevant actors should embrace the lessons highlighted in this study because countries such as Mexico are likely to experience other emergencies in the near future.


The coexistence of symbiosis and pathogenicity-determining genes in Rhizobium rhizogenes strains enables them to induce nodules and tumors or hairy roots in plants.
Bacteria belonging to the family Rhizobiaceae may establish beneficial or harmful relationships with plants. The legume endosymbionts contain nod and nif genes responsible for nodule formation and nitrogen fixation, respectively, whereas the pathogenic strains carry vir genes responsible for the formation of tumors or hairy roots. The symbiotic and pathogenic strains currently belong to different species of the genus Rhizobium and, until now, no strains able to establish symbiosis with legumes and also to induce tumors or hairy roots in plants have been reported. Here, we report for the first time the occurrence of two rhizobial strains (163C and ATCC11325T) belonging to Rhizobium rhizogenes able to induce hairy roots or tumors in plants and also to nodulate Phaseolus vulgaris under natural environmental conditions. Symbiotic plasmids (pSym) containing nod and nif genes and pTi- or pRi-type plasmids containing vir genes were found in these strains. The nodD and nifH genes of the strains from this study are phylogenetically related to those of Sinorhizobium strains nodulating P. vulgaris. The virA and virB4 genes from strain 163C are phylogenetically related to those of R. tumefaciens C58, whereas the same genes from strain ATCC 11325T are related to those of hairy root-inducing strains. These findings may be of high relevance for the better understanding of plant-microbe interactions and knowledge of rhizobial phylogenetic history.


Decreased incidence of severe ovarian hyperstimulation syndrome in high risk in-vitro fertilization patients receiving intravenous albumin: a prospective study.
The administration of human serum albumin has been reported to prevent severe ovarian hyperstimulation syndrome (OHSS) while undergoing ovarian stimulation protocols for in-vitro fertilization (IVF). This prospective, randomized study investigated the effectiveness of a single dose of human serum albumin (20 g) administered i.v. immediately after oocyte retrieval. Women enrolled in the IVF programme were treated with long gonadotrophin-releasing hormone agonist, triptorelin, and an individually-adjusted human menopausal gonadotrophin protocol. The criteria for inclusion in the study were young age, non-obesity, oestradiol concentration > 9200 pmol/l on the day of human chorionic gonadotrophin administration and > 20 follicles > 14 mm diameter as observed by transvaginal sonography. The treatment group (n = 22) received albumin while the control group (n = 18) did not. Patients were followed-up using ultrasound every 3 days. There was a significantly higher number of severe OHSS cases in the control group (n = 4) than in the treatment group (n = 0) (P = 0.035). Where the data base was restricted to patients with an oestradiol concentration > 15,000 pmol/l, the difference between control and treatment groups was highly significant (P = 0.008). These findings support the use of i.v. albumin in preventing severe OHSS during IVF treatment.


The Swedish snus and the Sudanese toombak: are they different?
In Sweden, snuff (locally known as snus), was introduced since the year 1637. Presently, Sweden has the highest per capita consumption and sale figures of snuff in the world, and the habit is becoming increasingly popular. Snus is manufactured into a dry form used in the nasal cavity and a moist form used in the oral cavity. Snus manufactured for oral use is a moist ground tobacco of Dark Kentucky or Virginia species mixed with an aqueous solution of water and other blending ingredients. This form of snuff is found in two types: (1) loose and (2) portion-bag-packed. These are the most widely used. The loose moist form (1-2 g a quid) is the most popular type consumed by 73% of the males, followed by the portion-bag-packed form (0.5-1 g a quid), consumed by 13% of the males, while 14% of the males are mixed users. The majority of snus users place the quid in the vestibular area of the upper lip, and the prevalence among persons 15 years of age or older in 15.9% among males and 0.2% among females. The pH of snus has declined from a previous range of 8-9 to a range of 7.8-8.5, moisture content ranges 35-60% and nicotine content is in the order of 5-11 mg/g dry wt tobacco-specific N-nitrosamines (TSNAs) in micrograms (N'-nitrosonornicotine: NNN 5-9; 4-(methyl-nitrosamino)-1-(3-pyridyl)-1-butanone: NNK 1-2; N'-nitrosoanatabine: NAT 2-5). In the Sudan, snuff, locally known as toombak, was introduced approximately 400 years ago. It is always processed into a loose moist form, and its use is widespread in the country. Tobacco used for manufacture of toombak is of the species Nicotiana rustica, and the fermented ground powder is mixed with an aqueous solution of sodium bicarbonate. The resultant product is moist, with a strong aroma, highly addictive and its use is widespread particularly among males. Its pH range is 8-11, moisture content ranges 6-60% and nicotine content is from 8 to 102 mg/g dry wt, and TSNAs contents in micrograms (NNN 420-1 550; NNK 620-7 870; NAT 20-290). Snus and toombak dippers develop a clinically and histologically characteristic lesion at the site of dipping. Probably due to control of the TSNAs in snus, this type of snuff is associated with a lower risk of cancer of the oral cavity (relative risk: RR 5-6-fold), whereas the risk for cancer of the oral cavity among toombak users was high (RR 7.3-73.0-fold). In conclusion, the two snuff products significantly differ in many aspects. Most notable differences are tobacco species, fermentation and ageing, nicotine and TSNAs content, pH, expression of the p53 tumour suppressor gene, and keratin types 13, 14, and 19. It was, therefore, the object of the present study to highlight the oral health hazards of toombak, and to compare it with snus regarding the aforementioned differences.


Sleep-related sympathovagal imbalance in SHR.
The role of the autonomic nervous system in spontaneous hypertension during each stage of the sleep-wake cycle remains unclear. The present study attempted to evaluate the differences in cardiac autonomic modulations among spontaneously hypertensive rats (SHR), normotensive Wistar-Kyoto rats (WKY), and Sprague-Dawley rats (SD) across sleep-wake cycles. Continuous power spectral analysis of electroencephalogram, electromyogram, and heart rate variability was performed in unanesthetized free moving rats during daytime sleep. Frequency-domain analysis of the stationary R-R intervals (RR) was performed to quantify the high-frequency power (HF), low-frequency power (LF)-to-HF ratio (LF/HF), and normalized LF (LF%) of heart rate variability. WKY and SD had similar mean arterial pressure, which is significantly lower than that of SHR during active waking, quiet sleep, and paradoxical sleep. Compared with WKY and SD, SHR had lower HF but similar RR, LF/HF, and LF% during active waking. During quiet sleep, SHR developed higher LF/HF and LF% in addition to lower HF. SHR ultimately exhibited significantly lower RR accompanied with higher LF/HF and LF% and lower HF during paradoxical sleep compared with WKY. We concluded that significant cardiac sympathovagal imbalance with an increased sympathetic modulation occurred in SHR during sleep, although it was less evident during waking.


Reliable Sensory Processing in Mouse Visual Cortex through Cooperative Interactions between Somatostatin and Parvalbumin Interneurons.
Intrinsic neuronal variability significantly limits information encoding in the primary visual cortex (V1). However, under certain conditions, neurons can respond reliably with highly precise responses to the same visual stimuli from trial to trial. This suggests that there exists intrinsic neural circuit mechanisms that dynamically modulate the intertrial variability of visual cortical neurons. Here, we sought to elucidate the role of different inhibitory interneurons (INs) in reliable coding in mouse V1. To study the interactions between somatostatin-expressing interneurons (SST-INs) and parvalbumin-expressing interneurons (PV-INs), we used a dual-color calcium imaging technique that allowed us to simultaneously monitor these two neural ensembles while awake mice, of both sexes, passively viewed natural movies. SST neurons were more active during epochs of reliable pyramidal neuron firing, whereas PV neurons were more active during epochs of unreliable firing. SST neuron activity lagged that of PV neurons, consistent with a feedback inhibitory SST→PV circuit. To dissect the role of this circuit in pyramidal neuron activity, we used temporally limited optogenetic activation and inactivation of SST and PV interneurons during periods of reliable and unreliable pyramidal cell firing. Transient firing of SST neurons increased pyramidal neuron reliability by actively suppressing PV neurons, a proposal that was supported by a rate-based model of V1 neurons. These results identify a cooperative functional role for the SST→PV circuit in modulating the reliability of pyramidal neuron activity.SIGNIFICANCE STATEMENT Cortical neurons often respond to identical sensory stimuli with large variability. However, under certain conditions, the same neurons can also respond highly reliably. The circuit mechanisms that contribute to this modulation remain unknown. Here, we used novel dual-wavelength calcium imaging and temporally selective optical perturbation to identify an inhibitory neural circuit in visual cortex that can modulate the reliability of pyramidal neurons to naturalistic visual stimuli. Our results, supported by computational models, suggest that somatostatin interneurons increase pyramidal neuron reliability by suppressing parvalbumin interneurons via the inhibitory SST→PV circuit. These findings reveal a novel role of the SST→PV circuit in modulating the fidelity of neural coding critical for visual perception.


Screening therapeutic EMT blocking agents in a three-dimensional microenvironment.
Epithelial-mesenchymal transition (EMT) plays a critical role in the early stages of dissemination of carcinoma leading to metastatic tumors, which are responsible for over 90% of all cancer-related deaths. Current therapeutic regimens, however, have been ineffective in the cure of metastatic cancer, thus an urgent need exists to revisit existing protocols and to improve the efficacy of newly developed therapeutics. Strategies based on preventing EMT could potentially contribute to improving the outcome of advanced stage cancers. To achieve this goal new assays are needed to identify targeted drugs capable of interfering with EMT or to revert the mesenchymal-like phenotype of carcinoma to an epithelial-like state. Current assays are limited to examining the dispersion of carcinoma cells in isolation in conventional 2-dimensional (2D) microwell systems, an approach that fails to account for the 3-dimensional (3D) environment of the tumor or the essential interactions that occur with other nearby cell types in the tumor microenvironment. Here we present a microfluidic system that integrates tumor cell spheroids in a 3D hydrogel scaffold, in close co-culture with an endothelial monolayer. Drug candidates inhibiting receptor activation or signal transduction pathways implicated in EMT have been tested using dispersion of A549 lung adenocarcinoma cell spheroids as a metric of effectiveness. We demonstrate significant differences in response to drugs between 2D and 3D, and between monoculture and co-culture.


Ghrelin O Acyl Transferase (GOAT) as a Novel Metabolic Regulatory Enzyme.
Obesity and Type 2 Diabetes Mellitus (T2DM) presents a growing threat to the global health. Evidences highlight an important role of ghrelin as a key regulator of glucose metabolism. The physiological functions of ghrelin are mediated by enzyme ghrelin-O-acyltransferase (GOAT) which is capable of generating the active form of this metabolic hormone. However, its exact mechanism of action and influence on energy balance and glucose metabolism is yet to be explored. To review the physiological role of GOAT in the regulation of energy balance and glucose metabolism and explore the potential therapeutic avenues of modulators of GOAT to counter the progression of obesity and T2DM. Publications were sought through electronic searches. The bibliographies of all papers, book, chapters and editorials were scanned and hand searches were also conducted for journals, and conference proceedings. GOAT peptide modulates the insulin secretion as well as insulin sensitivity. Modulators of GOAT signaling like inhibitors of GOAT increases insulin secretion, enhance peripheral insulin sensitivity and thus counters obesity and T2DM. Modulators of GOAT can be a probable therapy for modifying food intake and for countering obesity and T2DM.


Cortistatin, an antiinflammatory peptide with therapeutic action in inflammatory bowel disease.
Cortistatin is a recently discovered cyclic neuropeptide related to somatostatin that has emerged as a potential endogenous antiinflammatory factor based on its production by, and binding to, immune cells. Crohn's disease is a chronic debilitating disease characterized by severe T helper 1 (Th1)-driven inflammation of the gastrointestinal tract. The aim of this study is to investigate the therapeutic effect of cortistatin in a murine model of colitis. Cortistatin treatment significantly ameliorated the clinical and histopathologic severity of the inflammatory colitis, abrogating body weight loss, diarrhea, and inflammation and increased the survival rate of the colitic mice. The therapeutic effect was associated with down-regulation of inflammatory and Th1-driven autoimmune response, including the regulation of a wide spectrum of inflammatory mediators. In addition, a partial involvement of regulatory IL-10-secreting T cells in this therapeutic effect was demonstrated. Importantly, cortistatin treatment was therapeutically effective in established colitis and avoided the recurrence of the disease. This work identifies cortistatin as an antiinflammatory factor with the capacity to deactivate the intestinal inflammatory response and restore mucosal immune tolerance at multiple levels. Consequently, cortistatin represents a multistep therapeutic approach for the treatment of Crohn's disease and other Th1-mediated inflammatory diseases.


[The clinical value of fluorescence cystoscopy in the detection of superficial transitional epithelial cell carcinoma of the bladder].
The prognosis of superficial bladder cancer in terms of local recurrence and transformation into invasive cancer is related to the multiplicity of tumor sites and the concomitant presence of "flat" tumours, such as dysplasia and carcinoma in situ. This study of 51 patients emphasizes the value of fluorescence cystoscopy in the early detection of superficial transitional cell carcinomas. This method is based on induction of fluorescence in carcinomatous sites which selectively accumulate an endogenous photosensitizer, protoporphyrin IX, in response to intravesical administration of its precursor, 5-aminolevulinic acid. The sensitivity of the method in the present series was close to 93%. Fluorescence cystoscopy is a simple and reliable method to map the bladder mucosa looking for areas of dysplasia and carcinoma in situ.


The retinitis pigmentosa protein RP2 interacts with polycystin 2 and regulates cilia-mediated vertebrate development.
Ciliopathies represent a growing group of human genetic diseases whose etiology lies in defects in ciliogenesis or ciliary function. Given the established entity of renal-retinal ciliopathies, we have been examining the role of cilia-localized proteins mutated in retinitis pigmentosa (RP) in regulating renal ciliogenesis or cilia-dependent signaling cascades. Specifically, this study examines the role of the RP2 gene product with an emphasis on renal and vertebrate development. We demonstrate that in renal epithelia, RP2 localizes to the primary cilium through dual acylation of the amino-terminus. We also show that RP2 forms a calcium-sensitive complex with the autosomal dominant polycystic kidney disease protein polycystin 2. Ablation of RP2 by shRNA promotes swelling of the cilia tip that may be a result of aberrant trafficking of polycystin 2 and other ciliary proteins. Morpholino-mediated repression of RP2 expression in zebrafish results in multiple developmental defects that have been previously associated with ciliary dysfunction, such as hydrocephalus, kidney cysts and situs inversus. Finally, we demonstrate that, in addition to our observed physical interaction between RP2 and polycystin 2, dual morpholino-mediated knockdown of polycystin 2 and RP2 results in enhanced situs inversus, indicating that these two genes also regulate a common developmental process. This work suggests that RP2 may be an important regulator of ciliary function through its association with polycystin 2 and provides evidence of a further link between retinal and renal cilia function.


Production and early preservation of lipid biomarkers in iron hot springs.
The bicarbonate-buffered anoxic vent waters at Chocolate Pots hot springs in Yellowstone National Park are 51-54°C, pH 5.5-6.0, and are very high in dissolved Fe(II) at 5.8-5.9 mg/L. The aqueous Fe(II) is oxidized by a combination of biotic and abiotic mechanisms and precipitated as primary siliceous nanophase iron oxyhydroxides (ferrihydrite). Four distinct prokaryotic photosynthetic microbial mat types grow on top of these iron deposits. Lipids were used to characterize the community composition of the microbial mats, link source organisms to geologically significant biomarkers, and investigate how iron mineralization degrades the lipid signature of the community. The phospholipid and glycolipid fatty acid profiles of the highest-temperature mats indicate that they are dominated by cyanobacteria and green nonsulfur filamentous anoxygenic phototrophs (FAPs). Diagnostic lipid biomarkers of the cyanobacteria include midchain branched mono- and dimethylalkanes and, most notably, 2-methylbacteriohopanepolyol. Diagnostic lipid biomarkers of the FAPs (Chloroflexus and Roseiflexus spp.) include wax esters and a long-chain tri-unsaturated alkene. Surprisingly, the lipid biomarkers resisted the earliest stages of microbial degradation and diagenesis to survive in the iron oxides beneath the mats. Understanding the potential of particular sedimentary environments to capture and preserve fossil biosignatures is of vital importance in the selection of the best landing sites for future astrobiological missions to Mars. This study explores the nature of organic degradation processes in moderately thermal Fe(II)-rich groundwater springs--environmental conditions that have been previously identified as highly relevant for Mars exploration.


Are women with major depression in pregnancy identifiable in population health data?
Although record linkage of routinely collected health datasets is a valuable research resource, most datasets are established for administrative purposes and not for health outcomes research. In order for meaningful results to be extrapolated to specific populations, the limitations of the data and linkage methodology need to be investigated and clarified. It is the objective of this study to investigate the differences in ascertainment which may arise between a hospital admission dataset and a dispensing claims dataset, using major depression in pregnancy as an example. The safe use of antidepressants in pregnancy is an ongoing issue for clinicians with around 10% of pregnant women suffer from depression. As the birth admission will be the first admission to hospital during their pregnancy for most women, their use of antidepressants, or their depressive condition, may not be revealed to the attending hospital clinicians. This may result in adverse outcomes for the mother and infant. Population-based de-identified data were provided from the Western Australian Data Linkage System linking the administrative health records of women with a delivery to related records from the Midwives' Notification System, the Hospital Morbidity Data System and the national Pharmaceutical Benefits Scheme dataset. The women with depression during their pregnancy were ascertained in two ways: women with dispensing records relating to dispensed antidepressant medicines with an WHO ATC code to the 3rd level, pharmacological subgroup, 'N06A Antidepressants'; and, women with any hospital admission during pregnancy, including the birth admission, if a comorbidity was recorded relating to depression. From 2002 to 2005, there were 96698 births in WA. At least one antidepressant was dispensed to 4485 (4.6%) pregnant women. There were 3010 (3.1%) women with a comorbidity related to depression recorded on their delivery admission, or other admission to hospital during pregnancy. There were a total of 7495 pregnancies identified by either set of records. Using data linkage, we determined that these records represented 6596 individual pregnancies. Only 899 pregnancies were found in both groups (13.6% of all cases). 80% of women dispensed an antidepressant did not have depression recorded as a comorbidity on their hospital records. A simple capture-recapture calculation suggests the prevalence of depression in this population of pregnant women to be around 16%. No single data source is likely to provide a complete health profile for an individual. For women with depression in pregnancy and dispensed antidepressants, the hospital admission data do not adequately capture all cases.


Liposomal Bupivacaine Use in Transversus Abdominis Plane Blocks Reduces Pain and Postoperative Intravenous Opioid Requirement After Colorectal Surgery.
Enhanced recovery protocols frequently use multimodal postoperative analgesia to improve postoperative outcomes in patients undergoing colorectal surgery. The purpose of this study was to evaluate liposomal bupivacaine use in transversus abdominis plane blocks on postoperative pain scores and opioid use after colorectal surgery. This was a retrospective cohort study comparing outcomes between patients receiving nonliposomal anesthetic (n = 104) and liposomal bupivacaine (n = 303) blocks. The study was conducted at a single tertiary care center. Patients included those identified within an institutional database as inpatients undergoing colorectal procedures between 2013 and 2015 who underwent transversus abdominis plane block for perioperative analgesia. The study measured postoperative pain scores and opioid requirements. Patients receiving liposomal bupivacaine had significantly lower pain scores for the first 24 to 36 postoperative hours. Pain scores were similar after 36 hours. The use of intravenous opioids among the liposomal bupivacaine group decreased by more than one third during the hospitalization (99.1 vs 64.5 mg; p = 0.040). The use of ketorolac was also decreased (49.0 vs 18.3 mg; p < 0.001). In subgroup analysis, the decrease in opioid use was observed between laparoscopic and robotic procedures but not with laparotomies. No significant differences were noted in the use of oral opioids, acetaminophen, or ibuprofen. Postoperative length of stay and total cost were decreased in the liposomal bupivacaine group but did not achieve statistical significance. The study was limited by its retrospective, single-center design and heterogeneity of block administration. Attenuated pain scores observed with liposomal bupivacaine use were associated with significantly lower intravenous opioid and ketorolac use, suggesting that liposomal bupivacaine-containing transversus abdominis plane blocks are well aligned with the opioid-reducing goals of many enhanced recovery protocols.


Drastic post-LGM expansion and lack of historical genetic structure of a subtropical fig-pollinating wasp (Ceratosolen sp. 1) of Ficus septica in Taiwan.
The climatic oscillations of the last glacial period have had profound influences on the demography and levels of genetic diversity of extant species. Molecular evidence of glacial effects on temperate species has been well documented, whereas little is known regarding that on subtropical species. Here we present analyses based on partial sequences of the mitochondrial cytochrome c oxidase subunit I (COI) gene (1052 bp) and genotypes at 15 microsatellite loci to investigate the historical demography, population structure and ongoing gene flow of an undescribed fig-pollinating wasp (Ceratosolen sp. 1) of Ficus septica in subtropical Taiwan. Reconstructed historical demography based on the coalescent tree of COI sequences suggests that C. sp. 1 has undergone a drastic population expansion which was tightly coupled with climatic changes since the last glacial maximum (LGM). The magnitude of the population size change was approximately 500-fold, indicating that the population of this wasp and its host was likely highly compressed during the last glacial period. The lack of significant population differentiation (F(ST) < 0.02, for all pairwise F(ST) values) may be due to rapid postglacial expansion facilitated by long-distance dispersal, although a low frequency of first-generation migrants was detected. Our results clearly demonstrate how recent climatic changes since the LGM and dispersal ability have jointly shaped the genetic composition of a subtropical fig-pollinating wasp.


Loss of FAM46C Promotes Cell Survival in Myeloma.
FAM46C is one of the most recurrently mutated genes in multiple myeloma; however its role in disease pathogenesis has not been determined. Here we demonstrate that wild-type (WT) FAM46C overexpression induces substantial cytotoxicity in multiple myeloma cells. In contrast, FAM46C mutations found in multiple myeloma patients abrogate this cytotoxicity, indicating a survival advantage conferred by the FAM46C mutant phenotype. WT FAM46C overexpression downregulated IRF4, CEBPB, and MYC and upregulated immunoglobulin (Ig) light chain and HSPA5/BIP Furthermore, pathway analysis suggests that enforced FAM46C expression activated the unfolded protein response pathway and induced mitochondrial dysfunction. CRISPR-mediated depletion of endogenous FAM46C enhanced multiple myeloma cell growth, decreased Ig light chain and HSPA5/BIP expression, activated ERK and antiapoptotic signaling, and conferred relative resistance to dexamethasone and lenalidomide treatments. Genes altered in FAM46C-depleted cells were enriched for signaling pathways regulating estrogen, glucocorticoid, B-cell receptor signaling, and ATM signaling. Together these results implicate FAM46C in myeloma cell growth and survival and identify FAM46C mutation as a contributor to myeloma pathogenesis and disease progression via perturbation in plasma cell differentiation and endoplasmic reticulum homeostasis. Cancer Res; 77(16); 4317-27. ©2017 AACR.


Tibial nerve transection - a standardized model for denervation-induced skeletal muscle atrophy in mice.
The tibial nerve transection model is a well-tolerated, validated, and reproducible model of denervation-induced skeletal muscle atrophy in rodents. Although originally developed and used extensively in the rat due to its larger size, the tibial nerve in mice is big enough that it can be easily manipulated with either crush or transection, leaving the peroneal and sural nerve branches of the sciatic nerve intact and thereby preserving their target muscles. Thus, this model offers the advantages of inducing less morbidity and impediment of ambulation than the sciatic nerve transection model and also allows investigators to study the physiologic, cellular and molecular biologic mechanisms regulating the process of muscle atrophy in genetically engineered mice. The tibial nerve supplies the gastrocnemius, soleus and plantaris muscles, so its transection permits the study of denervated skeletal muscle composed of fast twitch type II fibers and/or slow twitch type I fibers. Here we demonstrate the tibial nerve transection model in the C57Black6 mouse. We assess the atrophy of the gastrocnemius muscle, as a representative muscle, at 1, 2, and 4 weeks post-denervation by measuring muscle weights and fiber type specific cross-sectional area on paraffin-embedded histologic sections immunostained for fast twitch myosin.


A novel mutation in the last exon of ATRX in a patient with alpha-thalassemia myelodysplastic syndrome.
We describe a patient with acquired alpha-thalassemia myelodysplastic syndrome (ATMDS). A previously healthy 66-year-old man presented with hemoglobin of 9.3 g/dL, mean corpuscular volume 59 fL, and a bone marrow aspirate with increased erythroid precursors and hypolobulated megakaryocytes. Hemoglobin H inclusions were seen in most red cells after 1% brilliant cresyl blue supravital stain of the peripheral blood. At the molecular level, we identified of a novel mutation in the most 3' exon of the ATRX gene (CGA-->TGA substitution in codon 2407) resulting in a premature termination codon (p.R2407X). This case provides further evidence for a link between ATRX mutations and ATMDS, and suggests a possible role for the conserved Q-box element in ATRX function.


Carbohydrate ingestion immediately before exercise does not improve 20 km time trial performance in well trained cyclists.
This study examined the effects of carbohydrate ingestion on 20 km cycle time-trial (TT) performance in 14 well-trained cyclists (11 males, 3 females; peak oxygen uptake [VO2peak] 4.52 +/- 0.60 l/min; values are mean +/- SD). All subjects performed two experimental trials on their own bicycles mounted on an air-braked ergometry system (Kingcycle). Subjects were instructed to maintain the same training and dietary regimens before trials, which were conducted in a random order, 3-7 days apart, and at the same time of day for each subject. On the day of a trial, subjects reported to the laboratory and ingested an 8 ml/kg body mass bolus of either a 6.8 g/100 ml commercial carbohydrate-electrolyte (CHO) beverage (39 +/- 4 g of CHO), or a coloured, flavoured placebo. Ten min after finishing the drink, subjects commenced a 5 min warm-up at 150 W, before commencing the 20 km TT. The average power output (312 +/- 40 vs 311 +/- 38 W) and heart-rate (171 +/- 6 vs 171 +/- 5 beats/min for CHO and placebo, respectively) during the two rides did not differ between treatments. Accordingly, the performance times for the two TT's were the same (27:41 +/- 1:39 min:sec, for both CHO and placebo). We conclude that the ingestion of approximately 40 g of carbohydrate does not improve maximal cycling performance lasting approximately 30 min, and that carbohydrate availability, in the form of circulating blood glucose, does not limit high-intensity exercise of this duration.