Innovations to enhance the quality of health professions education at the University of Zimbabwe College of Health Sciences--NECTAR program.
The University of Zimbabwe College of Health Sciences (UZCHS) is Zimbabwe's premier health professions training institution. However, several concerns were raised during the past decade over the quality of health education at UZCHS. The number of faculty and students declined markedly until 2010, when there was a medical student intake of 147 while the faculty comprised only 122 (39%) of a possible 314 positions. The economic and political crises that the country experienced from 1999 to 2009 compounded the difficulties faced by the institution by limiting the availability of resources. The Medical Education Partnership Initiative funding opportunity has given UZCHS the stimulus to embark on reforms to improve the quality of health education it offers. UZCHS, in partnership with the University of Colorado School of Medicine, the University of Colorado Denver Evaluation Center, and Stanford University, designed the Novel Education Clinical Trainees and Researchers (NECTAR) program to implement a series of health education innovations to meet this challenge. Between 2010 and 2013, innovations that have positively affected the quality of health professions education at UZCHS include the launch of comprehensive faculty development programs and mentored clinical and research programs for postgraduate students. A competency-based curriculum reform process has been initiated, a health professions department has been established, and the Research Support Center has been strengthened, providing critical resources to institutionalize health education and research implementation at the college. A core group of faculty trained in medical education has been assembled, helping to ensure the sustainability of these NECTAR activities.


Time and temperature dependence of granulocyte damage by leucotoxic supernatants from Pasteurella haemolytica A1.
Bacterial exotoxins may contribute to the pathogenic potential of micro-organisms through interactions with cells of the host defence system as well as by directly damaging host tissue. The present studies were designed to explore mechanisms of interaction between bovine granulocytes and the leucotoxin produced by Pasteurella haemolytica, a major cause of bovine respiratory disease. Leucotoxin-containing supernatant from P. haemolytica A1 caused rapid cell death in isolated bovine granulocytes that was close to half-maximal by 5 min and nearly 90% complete after 30 min at 37 degrees C. Maintaining granulocytes at ice-water temperature markedly attenuated or prevented the toxic effect; furthermore, if exposed to supernatants at ice-water temperature and then washed, most cells remained viable even after rewarming to room temperature. However, even a very brief exposure (about 5 s) at 37 degrees C led to extensive cell death even after immediate cold dilution and washing. Granule enzymes such as arylsulphatase were released far more slowly than cytosol contents. Leucotoxin purified by column chromatography showed temperature dependence and divergence between cytosol and granule marker release similar to those observed with the crude supernatant preparation. These findings indicate that irreversible interaction between P. haemolytica leucotoxin and bovine granulocytes is initiated very rapidly at 37 degrees C but markedly impeded at low temperature, while granule enzyme release follows cytosol marker release over a much longer period. The results suggest either a requirement for target cell metabolic activity to initiate toxin effects or a temperature-dependent receptor conformation, with granule enzyme release following as a secondary consequence of granulocyte death.


Role of HBsAg levels in guiding hepatitis B virus prophylaxis in pregnancy: Insights from a multi-ethnic cohort.
Pregnant mothers with chronic hepatitis B infection (CHB) need peri-partum antiviral prophylaxis (PAP) to reduce the risk of mother-to-child-transmission. Currently, PAP is recommended in those with high viral load (VL) that is, HBV DNA >200,000 IU/mL. Quantitative hepatitis B surface antigen (qHBsAg) >10,000 IU/mL, a cut-off derived primarily from hepatitis B e-antigen (HBeAg) positive antenatal cohorts in Chinese populations, is advocated as a surrogate marker of VL for guiding PAP. We investigated the utility of qHBsAg to predict high-VL in a multi-ethnic urban cohort with CHB. A consecutive cohort of women with CHB was identified from Barts Health NHS Trust databases in the United Kingdom. We included women with paired HBV DNA and qHBsAg during pregnancy. Women already on antiviral at conception were excluded. A total of 769 pregnancies in 678 CHB pregnant mothers (median age 31 years-old, 8.6% HBeAg+) were included. At median gestational age of 15.3 weeks, HBV DNA was 336 (IQR 44-2998) IU/mL, with 65 (8.5%) being high-VL. Serum qHBsAg was most useful in Black/Black-British/Caribbean/African (AUROC 0.946) with 100% sensitivity and 80.6% specificity to predict high-VL; but it performed less well for other ethnicities: Asian (AUROC 0.877), White (AUROC 0.797) and mixed ethnicities (AUROC 0.742). In conclusion, for settings where healthcare resources are not limited, HBV DNA remains the optimal marker to identify highly viraemic pregnancies for guiding PAP. For resource-limited settings where the prevailing cost is treatment, serum qHBsAg can be used in Black/Black British/Caribbean/African sub-cohorts, but not for other ethnicities.


Immunoassay of P2 protein in cerebrospinal fluid in neurological disorders.
Cerebrospinal fluid samples were obtained at lumbar puncture from 53 patients with a wide variety of neurological disorders. Cerebrospinal fluid samples were tested for the presence of P2 protein, a constituent of myelin, with an enzyme linked immunosorbent assay technique using a specific polyclonal antibody. High concentrations of P2 in the cerebrospinal fluid paralleled a raised IgG index (clearance ratio), the presence of oligoclonal bands, as well as raised white cell counts or depressed albumin:IgG ratios. Twenty one patients had been diagnosed as having definite or probable multiple sclerosis and the remaining 32 had other conditions. Of the 13 patients with high positive P2, 12 (92%) were in the multiple sclerosis category; of the 40 patients with low (12) or undetectable (28) P2 concentrations, only nine (23%) were diagnosed as having multiple sclerosis. In this patient population the presence of high immunoreactive P2 concentrations in cerebrospinal fluid was closely associated with evidence of intrathecal immunoglobulin synthesis and with the clinical diagnosis of multiple sclerosis. On this basis it is suggested that immunoassay of P2 concentration in the cerebrospinal fluid may be of potential value in the investigation of patients with demyelinating disorders.


Self-Reported Sleep Duration and Pattern in Old Order Amish and Non-Amish Adults.
We hypothesized that sleep duration in the Amish would be longer than in non-Amish. Sleep duration was obtained by questionnaire administered to Amish individuals (n = 3,418) and from the 2015-2016 National Health and Nutrition Examination Survey (NHANES; n = 1,912). Self-reported sleep duration was calculated as the difference in usual times that the participants went to bed at night and woke up in the morning. In Amish (43.7 ± 16.7 years) and NHANES (50.0 ± 20.6 years), women had a longer sleep duration than men (P < .0001 in both groups) and sleep was significantly longer in those aged 18-29 years and ≥ 70 years, compared to those aged 30-69 years. Seasonal-adjusted sleep duration was shorter in Amish than that in NHANES (7.8 minutes shorter, age- and sex-adjusted P < .0001). However, Amish were less likely to report sleeping fewer than 7 hours per night (15.4% in Amish versus 20.5% in NHANES, P < .0001). Amish went to bed 80.4 minutes earlier than NHANES and arose 87.6 minutes earlier (age-, sex-, and season-adjusted P < .0001 for both). In the Amish, sleep duration was longer in clerks than in farmers (P < .0001) and was significantly correlated among household members (.15 < r < .62, P < .001), although there was no evidence that this trait was heritable (h² approximately 0) after adjustment for household. The lower frequency of short sleepers in the Amish may contribute to the relatively lower risks of cardiometabolic diseases observed in this population. Zhang M, Ryan KA, Wickwire E, Postolache TT, Xu H, Daue M, Snitker S, Pollin TI, Shuldiner AR, Mitchell BD. Self-reported sleep duration and pattern in old order amish and non-amish adults. J Clin Sleep Med. 2019;15(9):1321-1328.


When disclosing a serious diagnosis to a minor conflicts with family values.
An 11-year old Asian-Indian boy was recently discovered to have acute myelogenous leukemia. The pediatric hematologist-oncologist arranged a meeting to inform the parents about the diagnosis, prognosis and treatment. The physician planned to include the child in this process. However, the child's father, a computer programmer, made a request that his son should not be informed about the diagnosis of leukemia. The father asked that his son should be told that he has a severe infection and will require intensive treatment. The oncologist then informed the father that, as a physician, she has the responsibility to truthfully disclose the diagnosis to a patient, and she insisted on informing the child about the leukemia in an open and truthful manner.


Association Between Chronic Use of Immunosuppresive Drugs and Clinical Outcomes From Coronavirus Disease 2019 (COVID-19) Hospitalization: A Retrospective Cohort Study in a Large US Health System.
It is unclear whether chronic use of immunosuppressive drugs worsens or improves the severity of coronavirus disease 2019 (COVID-19), with plausible mechanisms for both. Retrospective cohort study in 2121 consecutive adults with acute inpatient hospital admission between 4 March and 29 August 2020 with confirmed or suspected COVID-19 in a large academic health system, with adjustment for confounding with propensity score-derived stabilized inverse probability of treatment weights. Chronic immunosuppression was defined as prescriptions for immunosuppressive drugs current at the time of admission. Outcomes included mechanical ventilation, in-hospital mortality, and length of stay. There were 2121 patients admitted with laboratory-confirmed (1967, 93%) or suspected (154, 7%) COVID-19 during the study period, with a median age of 55 years (interquartile range, 40-67). Of these, 108 (5%) were classified as immunosuppressed before COVID-19, primarily with prednisone (>7.5 mg/day), tacrolimus, or mycophenolate mofetil. Among the entire cohort, 311 (15%) received mechanical ventilation; the median (interquartile range) length of stay was 5.2 (2.5-10.6) days, and 1927 (91%) survived to discharge. After adjustment, there were no significant differences in the risk of mechanical ventilation (hazard ratio [HR], .79; 95% confidence interval [CI], .46-1.35), in-hospital mortality (HR, .66; 95% CI, .28-1.55), or length of stay (HR, 1.16; 95% CI, .92-1.47) among individuals with immunosuppression and counterparts. Chronic use of immunosuppressive drugs was neither associated with worse nor better clinical outcomes among adults hospitalized with COVID-19 in one US health system.


Bacterial vaginosis. Transmission, role in genital tract infection and pregnancy outcome: an enigma.
Whether bacterial vaginosis (BV) is acquired from an endogenous or an exogenous source is subject to controversy. Despite findings of an association between sexual behaviour and BV, some data indicate that BV is not a sexually transmitted infection in the traditional sense, while other data indicate that BV is an exogenous infection. A third aspect of BV is its tendency to go unnoticed by affected women. All of this will have a strong impact on how physicians view the risks of asymptomatic BV. This review focuses on whether or not BV should be regarded as a sexually transmitted infection (STI), its role in postoperative infections and pelvic inflammatory disease (PID), and on whether or not treatment of BV during pregnancy to reduce preterm delivery should be recommended. The reviewed studies do not lend unequivocal support to an endogenous or exogenous transmission of the bacteria present in BV. For women undergoing gynaecological surgery such as therapeutic abortion, the relative risk of postoperative infection is clearly elevated (approx. 2.3-2.8). A weaker association exists between BV and pelvic inflammatory disease. Data on treatment of BV as a way of reducing preterm delivery are inconclusive and do not support recommendations for general treatment of BV during pregnancy. The discrepant associations between BV and preterm birth found in recent studies may be explained by variations in immunological response to BV. Genetic polymorphism in the cytokine response--both regarding the TNF alleles and in interleukin production--could make women more or less susceptible to BV, causing different risks of preterm birth. Thus, studies on the vaginal inflammatory response to microbial colonization should be given priority.


Proteomic analysis for phenanthrene-elicited wheat chloroplast deformation.
The exposure of polycyclic aromatic hydrocarbons (PAHs) can cause wheat leaf chlorosis. Thus, we hypothesize that chloroplast inner structure damage is the reason for leaf chlorosis. This study was conducted with the wheat seedlings exposed to Hoagland nutrient solution containing 1.0 mg L-1 phenanthrene for 9 days. Subcellular observation showed that chloroplast turns round and loses its structural integrity. Herein, iTRAQ (isobaric tag for relative and absolute quantification) was applied to analyze the changes of protein profile in chloroplast exposed to phenanthrene. A total of 517 proteins are identified, 261 of which are up-regulated. Eight proteins related with thylakoid (the structural component of chloroplast) are down-regulated and the expression of related genes further confirms the proteomic results through real-time PCR under phenanthrene treatment, suggesting that the thylakoid destruction is the reason for chloroplast deformation. Four proteins related with envelope and stroma are up-regulated, and this is the reason why chloroplast remains round. This study is useful in discussing the carcinogenic and teratogenic effects of PAHs in plant cells in the environment, and provides necessary knowledge for improving crop resistance to PAH pollution.


Anterior cervical discectomy, fusion and stabilization by plate and screw--early experience.
Anterior cervical plating is commonly performed to stabilize anterior cervical fusion. The aim of the study was to evaluate the clinical and functional outcome, radiological fusion and operative complications in cases of cervical spondylotic myelopathy and radiculopathy who underwent Anterior Cervical Discectomy and Fusion (ACDF) by autograft and stabilized with plate and screw. We evaluated 16 consecutive patients (M: F = 10:6) from January 2008 to December 2010 in Bangabandhu Sheikh Mujib Medical University (BSMMU) and different private hospitals in Dhaka, in cases where adequate conservative treatment failed. Single level ACDF by autograft and stabilization by plate and screw was done in 10 patients and 06 patients had two levels fusion. The mean follow up period was 18 months. The patients improved significantly (p < 0.05) and the recovery rate was 87.50%. All patients showed radiological fusion (p < 0.001). There was no hardware failure, graft extrusion or plate breakage. ACDF with plate and screw is fairly safe and effective therapy for cervical disc degeneration leading to myelo-radiculopathy where major post operative complications are uncommon.


Prescribing pattern of glucose lowering drugs in the United Kingdom in the last decade: a focus on the effects of safety warnings about rosiglitazone.
In the last decade, new glucose lowering drugs (GLDs) have been launched, and also several warnings regarding their safety. The cardiovascular safety of thiazolidinediones (TZD) has been questioned. We analyzed the prescription pattern of GLDs from 2000 to November 2009 in the United Kingdom (UK) using the THIN database with special focus on the effects of the safety warnings about rosiglitazone issued in May 2007 and January 2008. Annual prevalence and incidence of GLD prescriptions were measured. For TZD, the monthly prevalence and incidence of prescription were calculated from May 2006 to January 2009. The switching pattern around the FDA alert and the characteristics of subjects starting treatment with TZD before and after the alerts were observed. The prevalence of prescriptions of GLDs increased during the 10 year period, metformin increasing more than three times. Rosiglitazone prevalence showed an increased trend until May 2007, (2.3/1000 person-years) and decreased thereafter (January 2009: 1.1/1000 person-years). The use of pioglitazone increased surpassing rosiglitazone from April 2008 onwards. The incidence of rosiglitazone use decreased sharply after May 2007 (0.8/1000 person-years). The prevalence of use of other therapies remained rather stable from 2000 to 2007 but increased afterwards. After May 2007, rosiglitazone users were increasingly switched to pioglitazone. There was an increased proportion of new users of pioglitazone with cardiovascular risk after the alerts. The prescription of GLDs in the UK has increased in the last decade. For TZDs, it changed after May 2007 as well as the characteristics of the subjects treated with them.


Perioperative covert stroke in patients undergoing non-cardiac surgery (NeuroVISION): a prospective cohort study.
In non-surgical settings, covert stroke is more common than overt stroke and is associated with cognitive decline. Although overt stroke occurs in less than 1% of adults after non-cardiac surgery and is associated with substantial morbidity, we know little about perioperative covert stroke. Therefore, our primary aim was to investigate the relationship between perioperative covert stroke (ie, an acute brain infarct detected on an MRI after non-cardiac surgery in a patient with no clinical stroke symptoms) and cognitive decline 1 year after surgery. NeuroVISION was a prospective cohort study done in 12 academic centres in nine countries, in which we assessed patients aged 65 years or older who underwent inpatient, elective, non-cardiac surgery and had brain MRI after surgery. Two independent neuroradiology experts, masked to clinical data, assessed each MRI for acute brain infarction. Using multivariable regression, we explored the association between covert stroke and the primary outcome of cognitive decline, defined as a decrease of 2 points or more on the Montreal Cognitive Assessment from preoperative baseline to 1-year follow-up. Patients, health-care providers, and outcome adjudicators were masked to MRI results. Between March 24, 2014, and July 21, 2017, of 1114 participants recruited to the study, 78 (7%; 95% CI 6-9) had a perioperative covert stroke. Among the patients who completed the 1-year follow-up, cognitive decline 1 year after surgery occurred in 29 (42%) of 69 participants who had a perioperative covert stroke and in 274 (29%) of 932 participants who did not have a perioperative covert stroke (adjusted odds ratio 1·98, 95% CI 1·22-3·20, absolute risk increase 13%; p=0·0055). Covert stroke was also associated with an increased risk of perioperative delirium (hazard ratio [HR] 2·24, 95% CI 1·06-4·73, absolute risk increase 6%; p=0·030) and overt stroke or transient ischaemic attack at 1-year follow-up (HR 4·13, 1·14-14·99, absolute risk increase 3%; p=0·019). Perioperative covert stroke is associated with an increased risk of cognitive decline 1 year after non-cardiac surgery, and perioperative covert stroke occurred in one in 14 patients aged 65 years and older undergoing non-cardiac surgery. Research is needed to establish prevention and management strategies for perioperative covert stroke. Canadian Institutes of Health Research; The Ontario Strategy for Patient Oriented Research support unit; The Ontario Ministry of Health and Long-Term Care; Health and Medical Research Fund, Government of the Hong Kong Special Administrative Region, China; and The Neurological Foundation of New Zealand.


Relation between emotional distress and heart rate variability in patients with an implantable cardioverter-defibrillator.
We investigated the relationship between Type D personality, depression, and anxiety, and heart rate variability (HRV) in 64 patients with an implantable cardioverter-defibrillator (ICD). HRV was obtained via 24-h Holter monitoring, and 24-h, 30-min daytime rest and 30-min nighttime sleep HRV were analyzed. In adjusted analyses, significant associations (standard deviation of normal-to-normal [NN] intervals [SDNN]: p = .043; standard deviation of NN intervals over 5-min periods [SDANN]: p = .010) and a trend (HRV triangular index: p = .09) were found for Type D personality, and trends were found for depression (lower RMSSD: p = .10; lower pNN50: p = .09). During daytime rest, similar results were found for anxiety and depression. During sleep, only noteworthy adjusted associations were found for depression (lower root mean square of successive differences in NN intervals [RMSSD]: p = .06; lower pNN50: p = .043). A Benjamini-Hochberg correction for multiple testing led to reduction of the number of significant relationships, but there was still support for lower autonomic control patients with Type D personality and depression. Future research with larger sample sizes is warranted.


An ancestral 10-bp repeat expansion in VWA1 causes recessive hereditary motor neuropathy.
The extracellular matrix comprises a network of macromolecules such as collagens, proteoglycans and glycoproteins. VWA1 (von Willebrand factor A domain containing 1) encodes a component of the extracellular matrix that interacts with perlecan/collagen VI, appears to be involved in stabilizing extracellular matrix structures, and demonstrates high expression levels in tibial nerve. Vwa1-deficient mice manifest with abnormal peripheral nerve structure/function; however, VWA1 variants have not previously been associated with human disease. By interrogating the genome sequences of 74 180 individuals from the 100K Genomes Project in combination with international gene-matching efforts and targeted sequencing, we identified 17 individuals from 15 families with an autosomal-recessive, non-length dependent, hereditary motor neuropathy and rare biallelic variants in VWA1. A single disease-associated allele p.(G25Rfs*74), a 10-bp repeat expansion, was observed in 14/15 families and was homozygous in 10/15. Given an allele frequency in European populations approaching 1/1000, the seven unrelated homozygote individuals ascertained from the 100K Genomes Project represents a substantial enrichment above expected. Haplotype analysis identified a shared 220 kb region suggesting that this founder mutation arose >7000 years ago. A wide age-range of patients (6-83 years) helped delineate the clinical phenotype over time. The commonest disease presentation in the cohort was an early-onset (mean 2.0 ± 1.4 years) non-length-dependent axonal hereditary motor neuropathy, confirmed on electrophysiology, which will have to be differentiated from other predominantly or pure motor neuropathies and neuronopathies. Because of slow disease progression, ambulation was largely preserved. Neurophysiology, muscle histopathology, and muscle MRI findings typically revealed clear neurogenic changes with single isolated cases displaying additional myopathic process. We speculate that a few findings of myopathic changes might be secondary to chronic denervation rather than indicating an additional myopathic disease process. Duplex reverse transcription polymerase chain reaction and immunoblotting using patient fibroblasts revealed that the founder allele results in partial nonsense mediated decay and an absence of detectable protein. CRISPR and morpholino vwa1 modelling in zebrafish demonstrated reductions in motor neuron axonal growth, synaptic formation in the skeletal muscles and locomotive behaviour. In summary, we estimate that biallelic variants in VWA1 may be responsible for up to 1% of unexplained hereditary motor neuropathy cases in Europeans. The detailed clinical characterization provided here will facilitate targeted testing on suitable patient cohorts. This novel disease gene may have previously evaded detection because of high GC content, consequential low coverage and computational difficulties associated with robustly detecting repeat-expansions. Reviewing previously unsolved exomes using lower QC filters may generate further diagnoses.


Blood-brain barrier transporters: An overview of function, dysfunction in Alzheimer's disease and strategies for treatment.
The blood-brain-barrier (BBB) has a major function in maintaining brain homeostasis by regulating the entry of molecules from the blood to the brain. Key players in BBB function are BBB transporters which are highly expressed in brain endothelial cells (BECs) and critical in mediating the exchange of nutrients and waste products. BBB transporters can also influence drug delivery into the brain by inhibiting or facilitating the entry of brain targeting therapeutics for the treatment of brain disorders, such as Alzheimer's disease (AD). Recent studies have shown that AD is associated with a disrupted BBB and transporter dysfunction, although their roles in the development in AD are not fully understand. Modulation of BBB transporter activity may pose a novel approach to enhance the delivery of drugs to the brain for enhanced treatment of AD. In this review, we will give an overview of key functions of BBB transporters and known changes in AD. In addition, we will discuss current strategies for transporter modulation for enhanced drug delivery into the brain.


Binding of βL-Crystallin with Models of Animal and Human Eye Lens-Lipid Membrane.
Several discoveries show that with age and cataract formation, β-crystallin binds with the lens membrane or associates with other lens proteins, which bind with the fiber cell plasma membrane, accompanied by light scattering and cataract formation. However, how lipids (phospholipids and sphingolipids) and cholesterol (Chol) influence β-crystallin binding to the membrane is unclear. This research aims to elucidate the role of lipids and Chol in the binding of β-crystallin to the membrane and the membrane's physical properties (mobility, order, and hydrophobicity) with β-crystallin binding. We used electron paramagnetic resonance (EPR) spin-labeling methods to investigate the binding of βL-crystallin with a model of porcine lens-lipid (MPLL), model of mouse lens-lipid (MMLL), and model of human lens-lipid (MHLL) membrane with and without Chol. Our results show that βL-crystallin binds with all of the investigated membranes in a saturation manner, and the maximum parentage of the membrane surface occupied (MMSO) by βL-crystallin and the binding affinity (Ka) of βL-crystallin to the membranes followed trends: MMSO (MPLL) > MMSO (MMLL) > MMSO (MHLL) and Ka (MHLL) > Ka (MMLL) ≈ Ka (MPLL), respectively, in which the presence of Chol reduces the MMSO and Ka for all membranes. The mobility near the headgroup regions of the membranes decreases with an increase in the binding of βL-crystallin; however, the decrease is more pronounced in the MPLL and MMLL membranes than the MHLL membrane. In the MPLL and MMLL membranes, the membranes become slightly ordered near the headgroup with an increase in βL-crystallin binding compared to the MHLL membrane. The hydrophobicity near the headgroup region of the membrane increases with βL-crystallin binding; however, the increase is more pronounced in the MPLL and MMLL membranes than the MHLL membrane, indicating that βL-crystallin binding creates a hydrophobic barrier for the passage of polar molecules, which supports the barrier hypothesis in cataract formation. However, in the presence of Chol, there is no significant increase in hydrophobicity with βL-crystallin binding, suggesting that Chol prevents the formation of a hydrophobic barrier, possibly protecting against cataract formation.


Gender differences in cardiac repolarization following intravenous sotalol administration.
Females are more susceptible to drug-induced torsade de pointes (TdP), which is associated with excessive prolongation of the heart rate-corrected QT interval (QTc). Sotalol prolongs the cardiac action potential that can be observed as QT prolongation and can induce TdP. The aim of this study was to assess gender differences in sotalol-induced QTc prolongation. A total of 15 healthy volunteers, 9 female and 6 male (age: 32 ± 8 years) received 75 mg intravenous sotalol over 2.5 hours at a constant infusion rate. A 12-lead electrocardiograph (ECG) was recorded at baseline, 0.5, 1, 2, 3, 4, and 5 hours following the start of the infusion, and blood samples were collected simultaneously. QTc was calculated by the Fridericia and Framingham formulas. The 2 formulas resulted in virtually identical QTc intervals. The data analysis included repeated measures of analysis of variance (ANOVA), univariate analysis, and linear regression analysis. The longest average QTc intervals were observed at 2 hours of sotalol infusion in both genders. Compared to baseline, the increase was very significant in females (411 ± 13 vs 438 ± 13 ms, P < .001), while it was less significant in males (395 ± 23 vs 413 ± 27 ms, P < .05). The magnitude of individual changes from baseline were greater in females than in males (34 ± 8 vs 21 ± 12 ms, P < .05). In each gender, QTc and serum sotalol concentration strongly correlated (r = .93, P < .001). An upward shift of the regression line in females indicates a longer QTc at any concentration level. Males had greater body weight and body surface area than females (P < .05) but neither correlated with QTc or predicted QTc prolongation. The univariate analysis indicated that the single predictor for the greater QTc prolongation was female gender. Females had greater QTc prolongation than males following sotalol administration. This enhanced response to drug action may explain the higher incidence of drug-induced TdP seen in females.


The neuronal apoptosis inhibitory protein suppresses neuronal differentiation and apoptosis in PC12 cells.
The human neuronal apoptosis inhibitory protein (NAIP) gene has been discovered as a candidate gene for spinal muscular atrophy, a genetic disorder characterized by motor neuron loss in the spinal cord. The telomeric NAIP gene on human chromosome 5 is deleted together with survival motor neurons (SMN) in many cases of the most severe forms of the disorder. NAIP, c-IAP1 (inhibitor of apoptosis-1), c-IAP2, X-IAP, survivin and Apollon comprise the mammalian inhibitors of the apoptosis family and contain an N-terminal domain with 1-3 imperfect repeats of an approximately 65 amino acids domain named the baculovirus IAP repeat (BIR) motif. We identified six NAIP genes in the mouse genome which were found to be expressed in a broad range of tissues. Furthermore, we have investigated the effects of NAIP in the rat pheochromocytoma PC12 cell line. These cells differentiate in the presence of nerve growth factor (NGF) into cells that resemble sympathetic neurons. We observed that NAIP overexpression impaired NGF-induced neurite outgrowth. The BIR motifs of NAIP (residues 1-345) were not required for this effect. However, the BIR domains of NAIP were essential to prevent apoptosis in PC12 cells after NGF deprivation or TNF-alpha receptor stimulation. Expression of full-length but not BIR-deleted-NAIP protects against cell death. This correlates with reduced activity of the cell death effector protease, caspase-3, in lysates of NAIP-PC12 cells, as measured by cleavage of the fluorogenic tetrapeptide substrate Asp-Glu-Val-Asp. Thus, unregulation of cellular differentiation and/or caspase suppression may contribute to motoneuron dysfunction and cell death in spinal muscular atrophy where NAIP is mutated.


Improved Dried Blood Spot-Based Metabolomics: A Targeted, Broad-Spectrum, Single-Injection Method.
Dried blood spots (DBS) have proven to be a powerful sampling and storage method for newborn screening and many other applications. However, DBS methods have not yet been optimized for broad-spectrum targeted metabolomic analysis. In this study, we developed a robust, DBS-based, broad-spectrum, targeted metabolomic method that was able to measure over 400 metabolites from a 6.3 mm punch from standard Whatman 903TM filter paper cards. The effects of blood spot volumes, hematocrit, vacutainer chemistry, extraction methods, carryover, and comparability with plasma and fingerstick capillary blood samples were analyzed. The stability of over 400 metabolites stored under varying conditions over one year was also tested. No significant impacts of blood volume and hematocrit variations were observed when the spotted blood volume was over 60 µL and the hematocrit was between 31% and 50%. The median area under the curve (AUC) of metabolites in the DBS metabolome declined by 40% in the first 3 months and then did not decline further for at least 1 year. All originally detectable metabolites remained within detectable limits. The optimal storage conditions for metabolomic analysis were -80 °C with desiccants and without an O2 scavenger. The method was clinically validated for its potential utility in the diagnosis of the mitochondrial disease mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS). Our method provides a convenient alternative to freezing, storing, and shipping liquid blood samples for comparative metabolomic studies.


Genetic diversity at six short tandem repeat loci within the state of Victoria, Australia.
A new multiplex PCR system, developed by the Forensic Science Service (FSS) in the United Kingdom, permits the coamplification and typing of six short tandem repeat (STR) loci: HUMFGA, D8S1179, HUMTHO1, HUMvWA, D18S51, D21S11 and the sex determining marker Amelogenin. Data are presented on these six STRs for two populations in the state of Victoria, Australia: Caucasian and Asian. Whilst several worldwide databases are already available for the STR loci HUMTHO1 and HUMvWA, only relatively few databases exist for D8S1179, D18S51, D21S11 and HUMFGA. Allele frequencies at each locus displayed some fluctuations between the two populations. This is particularly so for HUMTHO1. Generally, however, the most common allele at each locus was the same in all populations, at all loci. A novel D8S1179 allele was found in Asians, provisionally identified as allele 19. Results for the six loci were compared with similar data from three UK resident populations: Caucasian, Afro-Caribbean and Asian (Indian/Pakistani) populations. These indicated that ethnically similar populations display similar allele frequencies, while the Australian Asian and UK Afro-Caribbean were found to be distinct.


Lens implantation: lessons learned from the first million. The Third Rayner Lecture, 1982.
Experience gained from over one million intraocular lens implants has emphasized the importance of quality control, correct design and knowledgeable use of materials. Biodegradation of nylon is well known; polypropylene also degrades, but much more slowly; polymethylmethacrylate does not show evidence of biodegradation even, in one specimen for which I have a control, after 23 years.


Prophylactic central neck lymphadenectomy in high risk patients with T1 or T2 papillary thyroid carcinoma: is it useful?
The aim of this study was to evaluate the role of prophylactic central neck lymph node dissection in high risk patients with T1 or T2 papillary thyroid cancer. Seventy-three patients who had undergone total thyroidectomy for papillary thyroid cancer smaller than 4cm, without cervical lymphadenopathy and prophylactic central neck lymph node dissection were included. Patients were divided in two groups: low risk patients (group A) and high risk patients (group B). High risk patients were considered those with at least one of the followings: male sex, age ≥ 45 years, and extracapsular or extrathyroid disease. Statistical significant differences in persistent disease, recurrence and complications rates between the two groups were studied. Persistence of the disease was observed in one case in group A (5.9%) and in three cases in group B (5.4%), while thyroid cancer recurrence was registered in zero and two (3.6%) cases respectively. One single case (5.9%) of transitory recurrent laryngeal nerve damage was reported in group A and none in group B, while transitory hypoparathyroidism was observed in 2 (3.6%) patients in group A, and 1 (1.8%) patient in group B. Permanent recurrent laryngeal nerve damage was observed in one patient in group A, while permanent hypoparathyroidism was registered in one case in group B. Logistic regression evidenced that multifocality was the only risk factor significantly related to persistence of disease and recurrence. Our results suggests that prophylactic central neck lymph node dissection can be safely avoided in patients with T1 or T2 papillary thyroid cancer, except in those with multifocal disease. Cancer, Central neck, Cervical, Lymphadenectomy, Lymph nodes, Papillary carcinoma, Thyroid.


LncRNA AFAP1-AS1 promotes growth and metastasis of cholangiocarcinoma cells.
We investigated the role of actin filament associated protein 1 antisense RNA1 (AFAP1-AS1) lncRNA in promoting cholangiocarcinoma (CCA). qRT-PCR analysis of patient samples showed that AFAP1-AS1 expression was higher in CCA tumors than matched adjacent non-tumor tissue. AFAP1-AS1 levels were also higher in CCA cell lines (HuCCT1 and TFK-1) than a normal biliary epithelium cell line (HIBEpic). AFAP1-AS1 knockdown in CCA cell lines using shAFAP1-AS1 reduced cell proliferation and colony formation in CCK-8 and colony formation assays, respectively. Cell cycle analysis demonstrated that AFAP1-AS1 knockdown resulted in G0/G1 cell cycle arrest and inhibition of S-G2/M transition compared to the controls. CCA cells transfected with shAFAP1-AS1 also exhibited reduced metastasis and invasiveness in Transwell and wound healing assays. This was further confirmed in xenograft experiments with nude mice using CCA cells transfected with shAFAP1-AS1 or control shRNA. AFAP1-AS1 knockdown cells produced smaller tumors, demonstrating that AFAP1-AS1 promotes tumor growth in vivo. AFAP1-AS1 knockdown also increased expression of actin filament associated protein 1 (AFAP1) and reduced cell stress filament integrity, as determined from western blot and immunofluorescence assays, respectively. These findings indicate that AFAP1-AS1 exerts oncogenic effects in CCA. We postulate that AFAP1-AS1 is a potentially useful diagnostic and prognostic biomarker and therapeutic target for CCA.


Evaluation of clonality and carbapenem resistance mechanisms among Acinetobacter baumannii-Acinetobacter calcoaceticus complex and Enterobacteriaceae isolates collected in European and Mediterranean countries and detection of two novel β-lactamases, GES-22 and VIM-35.
We evaluated doripenem-resistant Acinetobacter baumannii-Acinetobacter calcoaceticus complex (ACB; n = 411) and Enterobacteriaceae (n = 92) isolates collected from patients from 14 European and Mediterranean countries during 2009 to 2011 for the presence of carbapenemase-encoding genes and clonality. Following susceptibility testing, carbapenem-resistant (doripenem MIC, >2 μg/ml) isolates were screened for carbapenemases. New β-lactamase genes were expressed in a common background and susceptibility was tested. Class 1 integrons were sequenced. Clonality was evaluated by pulsed-field gel electrophoresis and multilocus sequence typing (Pasteur scheme). Relative expression of β-lactam intrinsic resistance mechanisms was determined for carbapenemase-negative Enterobacteriaceae. ACB and Enterobacteriaceae displayed 58.9 and 0.9% doripenem resistance, respectively. bla(OXA-23), bla(OXA-58), and bla(OXA-24/OXA-40) were detected among 277, 77, and 29 ACB, respectively (in 8, 6, and 5 countries). Ten Turkish isolates carried bla(GES-11) or bla(GES-22). GES-22 (G243A and M169L mutations in GES-1) had an extended-spectrum β-lactamase profile. A total of 33 clusters of ≥ 2 ACB isolates were observed, and 227 isolates belonged to sequence type 2/international clone II. Other international clones were limited to Turkey and Israel. Doripenem-resistant Enterobacteriaceae increased significantly (0.7 to 1.6%), and 15 blaKPC-2- and 22 blaKPC-3-carrying isolates, mostly belonging to clonal complexes 11 and 258, were observed. Enterobacteriaceae isolates producing OXA-48 (n = 16; in Turkey and Italy), VIM-1 (n = 10; in Greece, Poland, and Spain), VIM-26 (n = 1; in Greece), and IMP-19, VIM-4, and the novel VIM-35 (n = 1 each from Poland) were detected. VIM-35 had one substitution compared to VIM-1 (A235T) and a similar susceptibility profile. One or more resistance mechanisms were identified in 4/6 carbapenemase-negative Enterobacteriaceae. This broad evaluation confirms results from country-specific surveys and shows a highly diverse population of carbapenemase-producing ACB and Enterobacteriaceae in Europe and Mediterranean countries.


Screen time and passive school travel as independent predictors of cardiorespiratory fitness in youth.
The most prevalent sedentary behaviours in children and adolescents are engagement with small screen media (screen-time) and passive travel (by motorised vehicle). The objective of this research was to assess the independence of these behaviours from one another and from physical activity as predictors of cardiorespiratory fitness in youth. We measured cardiorespiratory fitness in n=6819 10-16 year olds (53% male) who self-reported their physical activity (7-day recall) school travel and screen time habits. Travel was classified as active (walking, cycling) or passive; screen time as <2 h, 2-4 h or >4 h. The multivariate odds of being fit were higher in active travel (Boys: OR 1.32, 95% CI: 1.09-1.59; Girls: OR 1.46, 1.15-1.84) than in passive travel groups. Boys reporting low screen time were more likely to be fit than those reporting >4 h (OR 2.11, 95% CI: 1.68-2.63) as were girls (OR 1.66, 95% CI: 1.24-2.20). These odds remained significant after additionally controlling for physical activity. Passive travel and high screen time are independently associated with poor cardiorespiratory fitness in youth, and this relationship is independent of physical activity levels. A lifestyle involving high screen time and habitual passive school travel appears incompatible with healthful levels of cardiorespiratory fitness in youth.


Clinical factors associated with contact lens dropout.
Contact lens (CL) dropout is estimated to be approximately equal to the number of new wearers per year, resulting in virtually no growth in the global CL market. The purpose of this study was to determine ocular and CL factors associated with CL dropout. This five-site study recruited subjects 18-45 years of age who had ceased CL wear within the past 6-12 months due to discomfort. Dropout subjects were compared to age- and sex-matched currently successful CL wearers. Each subject was administered a symptoms survey and a study-specific survey that queried general CL history and compliance. Clinical testing included non-invasive tear break-up time, tear meniscus height, blepharitis assessment, meibum quality and expression, and meibography. A total of 56 matched-pairs were recruited. Dry eye was found to significantly increase a subject's odds of dropping out of CLs. The odds of dropping out of CLs was also significantly increased with each worsening grade of upper or lower eyelid meibomian gland (MG) plugging, upper eyelid meibum quality, and upper eyelid MG tortuosity. No other factors analyzed increased a subject's odds of dropping out of CLs. CL dropout may be precipitated by underlying dry eye symptoms, though most dry eye signs, with the exception of MG structure and function, had minimal predictive value for CL dropout. Nevertheless, evidence suggests that practitioners should screen for and educate CL patients about the importance of maintaining healthy MGs, which may potentially allow them to maintain comfortable CL use and increase their CL longevity.


Combined delivery of TLR2 and TLR7 agonists by Nanostructured lipid carriers induces potent vaccine adjuvant activity in mice.
Toll-like receptor (TLR) agonists are promising adjuvants and the combination of TLR agonists enhance immune responses by providing synergistic immune activity via triggering different signalling pathways. However, systematic cytotoxicity due to the immediate release of such immune potentiators from the site of injection hampers its clinical performance. Nanostructured lipid carriers (NLCs) offer a possibility to incorporate multiple TLR agonists with high encapsulation efficiency and slow drug release. Herein, we synthesized NLCs from didodecyldimethylammonium bromide (D12DAB) and oleic acid and used these to co-encapsulate a Pam2CS derivative (T-2, TLR2 agonist) with an imidazoquinoline derivative (T-7, TLR7 agonist) as a combination vaccine adjuvant. Hydrodynamic diameter and zeta potential of the prepared NLCs were found to be in the range of 200-500 nm and 23-27 mV, respectively. Spherical shape and size of prepared NLCs were also assessed through Field Emission Scanning Electron Microscopy (FE-SEM) and Transmission Electron Microscopy (TEM) analysis. In-vitro release studies of T-7 demonstrated sustained release and the addition of lipopeptide T-2 augmented encapsulation efficiency (from 84 to 92.9%) with a slight trigger in the release percentage. All NLC formulations were screened in TLR2/1, TLR2/6, TLR7 and TLR8 reporter cell lines and loaded NLC formulation showed high TLR2 and TLR7 agonistic activity. Adjuvant potency was evaluated through intramuscular immunization of female C57BL/6 mice with recombinant hepatitis B surface antigen and influenza hemagglutinin protein. T-2 and T-7 loaded NLCs induced good protective efficacy in mice challenged with a lethal dose of influenza virus.


Modeling the efficiency of a magnetic needle for collecting magnetic cells.
As new magnetic nanoparticle-based technologies are developed and new target cells are identified, there is a critical need to understand the features important for magnetic isolation of specific cells in fluids, an increasingly important tool in disease research and diagnosis. To investigate magnetic cell collection, cell-sized spherical microparticles, coated with superparamagnetic nanoparticles, were suspended in (1) glycerine-water solutions, chosen to approximate the range of viscosities of bone marrow, and (2) water in which 3, 5, 10 and 100% of the total suspended microspheres are coated with magnetic nanoparticles, to model collection of rare magnetic nanoparticle-coated cells from a mixture of cells in a fluid. The magnetic microspheres were collected on a magnetic needle, and we demonstrate that the collection efficiency versus time can be modeled using a simple, heuristically-derived function, with three physically-significant parameters. The function enables experimentally-obtained collection efficiencies to be scaled to extract the effective drag of the suspending medium. The results of this analysis demonstrate that the effective drag scales linearly with fluid viscosity, as expected. Surprisingly, increasing the number of non-magnetic microspheres in the suspending fluid results increases the collection of magnetic microspheres, corresponding to a decrease in the effective drag of the medium.


An Effective Terrain Aided Navigation for Low-Cost Autonomous Underwater Vehicles.
Terrain-aided navigation is a potentially powerful solution for obtaining submerged position fixes for autonomous underwater vehicles. The application of terrain-aided navigation with high-accuracy inertial navigation systems has demonstrated meter-level navigation accuracy in sea trials. However, available sensors may be limited depending on the type of the mission. Such limitations, especially for low-grade navigation sensors, not only degrade the accuracy of traditional navigation systems, but further impact the ability to successfully employ terrain-aided navigation. To address this problem, a tightly-coupled navigation is presented to successfully estimate the critical sensor errors by incorporating raw sensor data directly into an augmented navigation system. Furthermore, three-dimensional distance errors are calculated, providing measurement updates through the particle filter for absolute and bounded position error. The development of the terrain aided navigation system is elaborated for a vehicle equipped with a non-inertial-grade strapdown inertial navigation system, a 4-beam Doppler Velocity Log range sensor and a sonar altimeter. Using experimental data for navigation performance evaluation in areas with different terrain characteristics, the experiment results further show that the proposed method can be successfully applied to the low-cost AUVs and significantly improves navigation performance.


Molecular genetics of attention.
The sequencing of the human genome and the identification of a vast array of DNA polymorphisms has afforded cognitive scientists with the opportunity to interrogate the genetic basis of cognition with renewed vigor. The extant literature on the molecular genetics of sustained and spatial attention is reviewed herein. Advances in our understanding of the neural substrates of sustained and spatial attention arising from the cognitive neurosciences can help guide putative linkages in cognitive genetics. In line with catecholamine models of sustained attention, associations have been reported between sustained attention and allelic variation in the dopamine beta hydroxylase gene (DBH), the dopamine D2 and D4 receptor genes (DRD2; DRD4) and the dopamine transporter gene (DAT1). Much evidence implicates the cholinergic system in spatial attention. Accordingly, individual differences in spatial attention have been associated with variation in an alpha-4 cholinergic receptor gene (CHRNA4). APOE-epsilon4 allele dosage has been shown to influence the speed of attentional reorienting in independent samples of nonaffected individuals. Preliminary evidence in both healthy children and children with attention deficit hyperactivity disorder (ADHD) suggests and association with variants of the DAT1 gene and the control of spatial attention across the hemifields. With the recent development of high-throughput genotyping techniques, such as microarrays, the time seems ripe for a genomewide association study that can identify quantitative trait loci (QTLs) for sustained and spatial attention. The identification of QTLs for attention will provide a range of novel candidate genes for disorders of attention, such as ADHD and schizophrenia, and will drive cognitive neuroscientists to understand how DNA variation influences the neural substrates of attention.


Basic clinical parameters predict gefitinib efficacy in non-small cell lung cancer.
In epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC), the tyrosine-kinase inhibitor gefitinib is in broad use. We retrospectively analysed data for 82 patients with advanced NSCLC treated with gefitinib and correlated benefits with clinical baseline and therapy-related parameters. Of all patients 48/82 were male; the median age at start of gefitinib was 67.2 years; 14/58 informative patients were never-smokers; 57/82 patients suffered from adenocarcinoma, including 7 with bronchoalveolar-carcinomas. As to be expected, partial remission was observed in 10% of patients, stable disease in 29%, progression-free survival was 3.1 months and overall survival 9.2 months. Gefitinib was more efficacious in women, never-smokers and patients with bronchoalveolar-carcinoma. Furthermore, anemia and elevated C-reactive protein levels were unfavourable for therapeutic efficacy. Patients developing skin reactions under gefitinib achieved response far more frequently, with longer progression-free survival and overall survival. Basic clinical parameters are good predictors for response to EGFR tyrosine-kinase inhibitor therapy, which may be of value if EGFR mutation status is not available.


Neuroimmune activation in chronic heart failure.
Cardiac hypertrophy/remodeling manifests as a critical condition which may likely predispose to the risk of fatal heart failure and multiple organ dysfunction if not efficiently addressed, as a result of irreversible neuroendocrine, autonomic and immune system imbalances. Undeniably, the over-excitation of sympathetic and/or the breakdown of central parasympathetic tone play a significant role to be the basis of the persistent immune activation in chronic heart failure (CHF) which, to a certain extent, is primed by inflammatory reactions in the Central Nervous System. Moreover, till today, the clinical management of CHF seeks the identification of molecularly targeted drugs in comparison to those considered so far. This review focuses on the possible neuroimmune-mediated pathways involved in CHF and throws light on the current therapeutic strategies.


A prolegomenon for a viable evolutionary psychology--the myth and the reality: comment on Lickliter and Honeycutt (2003).
R. Lickliter and H. Honeycutt (2003) attempted to create a dynamic developmental systems theory of evolutionary psychology. In this commentary, the author argues that the quality of their reasoning, their conflation of evolution and evolution by natural selection, their failure to explain the relative importance of multilevel, epigenetic interactions, their lack of population thinking, and their failure to define adaptation undermines their endeavor.


AUSDRISK: an Australian Type 2 Diabetes Risk Assessment Tool based on demographic, lifestyle and simple anthropometric measures.
To develop and validate a diabetes risk assessment tool for Australia based on demographic, lifestyle and simple anthropometric measures. 5-year follow-up (2004-2005) of the Australian Diabetes, Obesity and Lifestyle study (AusDiab, 1999-2000). 6060 AusDiab participants aged 25 years or older who did not have diagnosed diabetes at baseline. Incident diabetes at follow-up was defined by treatment with insulin or oral hypoglycaemic agents or by fasting plasma glucose level > or = 7.0 mmol/L or 2-hour plasma glucose level in an oral glucose tolerance test > or = 11.1 mmol/L. The risk prediction model was developed using logistic regression and converted to a simple score, which was then validated in two independent Australian cohorts (the Blue Mountains Eye Study and the North West Adelaide Health Study) using the area under the receiver operating characteristic curve (AROC) and the Hosmer-Lemeshow (HL) chi(2) statistic. 362 people developed diabetes. Age, sex, ethnicity, parental history of diabetes, history of high blood glucose level, use of antihypertensive medications, smoking, physical inactivity and waist circumference were included in the final prediction model. The AROC of the diabetes risk tool was 0.78 (95% CI, 0.76-0.81) and HL chi(2) statistic was 4.1 (P = 0.85). Using a score > or = 12 (maximum, 35), the sensitivity, specificity and positive predictive value for identifying incident diabetes were 74.0%, 67.7% and 12.7%, respectively. The AROC and HL chi(2) statistic in the two independent validation cohorts were 0.66 (95% CI, 0.60-0.71) and 9.2 (P = 0.32), and 0.79 (95% CI, 0.72-0.86) and 29.4 (P < 0.001), respectively. This diabetes risk assessment tool provides a simple, non-invasive method to identify Australian adults at high risk of type 2 diabetes who might benefit from interventions to prevent or delay its onset.


Timing of physical therapy consultation on 1-year healthcare utilization and costs in patients seeking care for neck pain: a retrospective cohort.
Patients seek care from physical therapists for neck pain but it is unclear what the association of the timing of physical therapy (PT) consultation is on 1-year healthcare utilization and costs. The purpose of this study was to compare the 1-year healthcare utilization and costs between three PT timing groups: patients who consulted a physical therapist (PT) for neck pain within 14 days (early PT consultation), between 15 and 90 days (delayed PT consultation) or between 91 and 364 days (late PT consultation). A retrospective cohort of 308 patients (69.2% female, ages 48.7[±14.5] years) were categorized into PT timing groups. Descriptive statistics were calculated for each group. In adjusted regression models, 1-year healthcare utilization of injections, imaging, opioids and costs were compared between groups. Compared to early PT consultation, the odds of receiving an opioid prescription (aOR = 2.79, 95%CI: 1.35-5.79), spinal injection (aOR = 4.36, 95%CI:2.26-8.45), undergoing an MRI (aOR = 4.68, 95%CI:2.25-9.74), X-ray (aOR = 2.97, 95%CI:1.61-5.47) or CT scan (aOR = 3.36, 95%CI: 1.14-9.97) were increased in patients in the late PT consultation group. Similar increases in risk were found in the delayed group (except CT and Opioids). Compared to the early PT consultation group, mean costs were $2172 ($557, $3786) higher in the late PT contact group and $1063 (95%CI: $ 138 - $1988) higher in the delayed PT consultation group. There was an association with the timing of physical therapy consultation on healthcare utilization and costs, where later consultation was associated with increases costs and healthcare utilization. This study examined the association of timing of physical therapy consultation on costs and healthcare utilization, but not the association of increased access to physical therapy consultation. Therefore, the findings warrant further investigation to explore the effects of increased access to physical therapy consultation on healthcare utilization and costs in a prospective study.


Planar and van der Waals heterostructures for vertical tunnelling single electron transistors.
Despite a rich choice of two-dimensional materials, which exists these days, heterostructures, both vertical (van der Waals) and in-plane, offer an unprecedented control over the properties and functionalities of the resulted structures. Thus, planar heterostructures allow p-n junctions between different two-dimensional semiconductors and graphene nanoribbons with well-defined edges; and vertical heterostructures resulted in the observation of superconductivity in purely carbon-based systems and realisation of vertical tunnelling transistors. Here we demonstrate simultaneous use of in-plane and van der Waals heterostructures to build vertical single electron tunnelling transistors. We grow graphene quantum dots inside the matrix of hexagonal boron nitride, which allows a dramatic reduction of the number of localised states along the perimeter of the quantum dots. The use of hexagonal boron nitride tunnel barriers as contacts to the graphene quantum dots make our transistors reproducible and not dependent on the localised states, opening even larger flexibility when designing future devices.


Response to treatment in a prospective cohort of patients with large ulcerated lesions suspected to be Buruli Ulcer (Mycobacterium ulcerans disease).
The World Health Organization (WHO) advises treatment of Mycobacterium ulcerans disease, also called "Buruli ulcer" (BU), with a combination of the antibiotics rifampicin and streptomycin (R+S), whether followed by surgery or not. In endemic areas, a clinical case definition is recommended. We evaluated the effectiveness of this strategy in a series of patients with large ulcers of > or =10 cm in longest diameter in a rural health zone of the Democratic Republic of Congo (DRC). A cohort of 92 patients with large ulcerated lesions suspected to be BU was enrolled between October 2006 and September 2007 and treated according to WHO recommendations. The following microbiologic data were obtained: Ziehl-Neelsen (ZN) stained smear, culture and PCR. Histopathology was performed on a sub-sample. Directly observed treatment with R+S was administered daily for 12 weeks and surgery was performed after 4 weeks. Patients were followed up for two years after treatment. Out of 92 treated patients, 61 tested positive for M. ulcerans by PCR. PCR negative patients had better clinical improvement than PCR positive patients after 4 weeks of antibiotics (54.8% versus 14.8%). For PCR positive patients, the outcome after 4 weeks of antibiotic treatment was related to the ZN positivity at the start. Deterioration of the ulcers was observed in 87.8% (36/41) of the ZN positive and in 12.2% (5/41) of the ZN negative patients. Deterioration due to paradoxical reaction seemed unlikely. After surgery and an additional 8 weeks of antibiotics, 98.4% of PCR positive patients and 83.3% of PCR negative patients were considered cured. The overall recurrence rate was very low (1.1%). Positive predictive value of the WHO clinical case definition was low. Low relapse rate confirms the efficacy of antibiotics. However, the need for and the best time for surgery for large Buruli ulcers requires clarification. We recommend confirmation by ZN stain at the rural health centers, since surgical intervention without delay may be necessary on the ZN positive cases to avoid progression of the disease. PCR negative patients were most likely not BU cases. Correct diagnosis and specific management of these non-BU ulcers cases are urgently needed.


Dystonia-Ataxia with early handwriting deterioration in COQ8A mutation carriers: A case series and literature review.
Cerebellar ataxia is a hallmark of coenzyme Q10 (CoQ10) deficiency associated with COQ8A mutations. We present four patients, one with novel COQ8A pathogenic variants all with early, prominent handwriting impairment, dystonia and only mild ataxia. To better define the phenotypic spectrum and course of COQ8A disease, we review the clinical presentation and evolution in 47 reported cases. Individuals with COQ8A mutation display great clinical variability and unpredictable responses to CoQ10 supplementation. Onset is typically during infancy or childhood with ataxic features associated with developmental delay or regression. When disease onset is later in life, first symptoms can include: incoordination, epilepsy, tremor, and deterioration of writing. The natural history is characterized by a progression to a multisystem brain disease dominated by ataxia, with disease severity inversely correlated with age at onset. Six previously reported cases share with ours, a clinical phenotype characterized by slowly progressive or static writing difficulties, focal dystonia, and speech disorder, with only minimal ataxia. The combination of writing difficulty, dystonia and ataxia is a distinctive constellation that is reminiscent of a previously described clinical entity called Dystonia Ataxia Syndrome (DYTCA) and is an important clinical indicator of COQ8A mutations, even when ataxia is mild or absent.


Feasibility of MR-temperature mapping of ultrasonic heating from a CMUT.
In the last decade, high intensity focused ultrasound (HIFU) has gained popularity as a minimally invasive and noninvasive therapeutic tool for treatment of cancers, arrhythmias, and other medical conditions. HIFU therapy is often guided by magnetic resonance imaging (MRI), which provides anatomical images for therapeutic device placement, temperature maps for treatment guidance, and postoperative evaluation of the region of interest. While piezoelectric transducers are dominantly used for MR-guided HIFU, capacitive micromachined ultrasonic transducers (CMUTs) show competitive advantages, such as ease of fabrication, integration with electronics, improved efficiency, and reduction of self-heating. In this paper, we will show our first results of an unfocused CMUT transducer monitored by MR-temperature maps. This 2.51 mm by 2.32 mm, unfocused CMUT heated a HIFU phantom by 14 degrees C in 2.5 min. This temperature rise was successfully monitored by MR thermometry in a 3.0 T General Electric scanner.


Risk factors for pancreatic neuroendocrine tumors: a clinic-based case-control study.
Pancreatic neuroendocrine tumors (PNETs) are uncommon, and little is known about their risk factors and association with other cancers. We evaluated whether the following risk factors known to be associated with pancreatic adenocarcinoma are also associated with PNETs: smoking, alcohol use, family history of PNET, and other cancers, and personal history of diabetes as potential risk factors. Patients with PNETs seen at Mayo Clinic Rochester between 2000 and 2011 were compared with controls seen for a general medical evaluation. Patients and controls completed the same questionnaires. After excluding insulinoma and high-grade PNETs, 355 cases were evaluated, and 309 were matched to 602 controls (2:1) on age, sex, and region of residence. Personal smoking history was not associated with PNETs. Alcohol use was less common among cases (54% vs 67%, P < 0.001). Cases were more likely to report a family member with sarcoma (P = 0.02), PNET (P = 0.02), gallbladder cancer (P = 0.02), ovarian cancer (P = 0.04), and gastric cancer (P = 0.01). There was no association with other cancers in family members. Diabetes was more commonly reported by cases than controls (19% vs 11%, P < 0.001). With the exception of diabetes, risk factors that are associated with pancreatic adenocarcinoma are not risk factors for PNETs.


A cognitive perspective on object relations, drive development and ego structure in the second and third years of life.
This paper extends a recent line of research by correlating Piaget's theory of cognitive development with several psychoanalytic perspectives on development during the second and third years of life. The concrete, imagistic, unintegrated nature of mental representations associated by Mahler and Kernberg with this period, along with the mental operation of splitting, are related to preconceptual representation, a cognitive mode described by Piaget. Psychoanalytic perspectives on the body ego and object world associated with the anal period are also seen to involve concrete, unintegrated representations which show correspondence with preconceptual cognition. Parallels are explored between cognitive stages and the psychoanalytic understanding of ego and superego development. While psychoanalysis is not a cognitive psychology, aspects of its theory are concerned with cognitive structure and are enriched by a consideration of cognitive development.


The P-POSSUM scoring systems for predicting the mortality of neurosurgical patients undergoing craniotomy: Further validation of usefulness and application across healthcare systems.
Continuous audit of clinical practice is an essential part of making improvements in medicine and enhancing patient care. Validated tools are needed to gather evidence for comparisons. Recently, Physiological and Operative Severity Score for the enumeration of Mortality and morbidity (POSSUM) and Portsmouth-POSSUM (P-POSSUM) scores were evaluated in Indian patients undergoing elective craniotomy and it was concluded that P-POSSUM was highly accurate in predicting overall mortality. We wished to study whether this system could be used in a different country and health care system [United Kingdom, UK]. We have evaluated these scores in patients undergoing elective and emergency craniotomies in a tertiary centre in the UK. Data was collected from all neurosurgical patients who underwent craniotomy overone year. Preoperative variables were collected prior to induction of anaesthesia, and operative variables were also collected. Chi-square test was used for expected and actual mortality differences. Survivor and non-survivor demographics were compared by one-way ANOVA for continuous and Chi-square for categorical variables. One hundred and forty-five patients were studied. Mean [SD] physiologic score of the patients was 18.83 [5.07], and mean [SD] operative score was 18.09 [3.75]. P-POSSUM was a better predictor for elective patients and for those undergoing immediate life-saving surgery. This study confirms and validates the findings of previous work that P-POSSUM is an accurate and reliable tool for estimating in-hospital mortality. It also confirms its usefulness in comparison of results across healthcare systems internationally. Larger scale evaluations may be needed to examine its usefulness in emergency procedures.


Comparison between human and artificial neural network detection of Laplacian-derived electroencephalographic activity related to unilateral voluntary movements.
A back-propagation artificial neural network (ANN) was tested to verify its capacity to select different classes of single trials (STs) based on the spatial information content of electroencephalographic activity related to voluntary unilateral finger movements. The rationale was that ipsilateral and contralateral primary sensorimotor cortex can be involved in a nonstationary way in the control of unilateral voluntary movements. The movement-related potentials were surface Laplacian-transformed (SL) to reduce head volume conductor effects and to model the response of the primary sensorimotor cortex. The ANN sampled the SL from four or two central channels overlying the primary motor area of both sides in the period of 80 ms preceding the electromyographic response onset in the active muscle. The performance of the ANN was evaluated statistically by calculating the percentage value of agreement between the STs classified by the ANN and those of two investigators (used as a reference). The results showed that both investigator and ANN were capable of selecting STs with the SL maximum in the central area contralateral to the movement (contralateral STs, about 25%), STs with considerable SL values also in the ipsilateral central area (bilateral STs, about 50%), and STs with neither the contralateral nor bilateral pattern ("spatially incoherent" single trials; about 25%). The maximum agreement (64-84%) between the ANN and the investigator was obtained when the ANN used four spatial inputs (P < 0.0000001). Importantly, the common means of all single trials showed a weak or absent ipsilateral response. These results may suggest that a back-propagation ANN could select EEG single trials showing stationary and nonstationary responses of the primary sensorimotor cortex, based on the same spatial criteria as the experimenter.


Increasing carbon discrimination rates and depth of water uptake favor the growth of Mediterranean evergreen trees in the ecotone with temperate deciduous forests.
Tree populations at the low-altitudinal or -latitudinal limits of species' distributional ranges are predicted to retreat toward higher altitudes and latitudes to track the ongoing changes in climate. Studies have focused on the climatic sensitivity of the retreating species, whereas little is known about the potential replacements. Competition between tree species in forest ecotones will likely be strongly influenced by the ecophysiological responses to heat and drought. We used tree-ring widths and δ13 C and δ18 O chronologies to compare the growth rates and long-term ecophysiological responses to climate in the temperate-Mediterranean ecotone formed by the deciduous Fagus sylvatica and the evergreen Quercus ilex at the low altitudinal and southern latitudinal limit of F. sylvatica (NE Iberian Peninsula). F. sylvatica growth rates were similar to those of other southern populations and were surprisingly not higher than those of Q. ilex, which were an order of magnitude higher than those in nearby drier sites. Higher Q. ilex growth rates were associated with high temperatures, which have increased carbon discrimination rates in the last 25 years. In contrast, stomatal regulation in F. sylvatica was proportional to the increase in atmospheric CO2 . Tree-ring δ18 O for both species were mostly correlated with δ18 O in the source water. In contrast to many previous studies, relative humidity was not negatively correlated with tree-ring δ18 O but had a positive effect on Q. ilex tree-ring δ18 O. Furthermore, tree-ring δ18 O decreased in Q. ilex over time. The sensitivity of Q. ilex to climate likely reflects the uptake of deep water that allowed it to benefit from the effect of CO2 fertilization, in contrast to the water-limited F. sylvatica. Consequently, Q. ilex is a strong competitor at sites currently dominated by F. sylvatica and could be favored by increasingly warmer conditions.


Effects of oral insulin in relatives of patients with type 1 diabetes: The Diabetes Prevention Trial--Type 1.
This randomized, double-masked, placebo-controlled clinical trial tested whether oral insulin administration could delay or prevent type 1 diabetes in nondiabetic relatives at risk for diabetes. We screened 103,391 first- and second-degree relatives of patients with type 1 diabetes and analyzed 97,273 samples for islet cell antibodies. A total of 3,483 were antibody positive; 2,523 underwent genetic, immunological, and metabolic staging to quantify risk of developing diabetes; 388 had a 5-year risk projection of 26-50%; and 372 (median age 10.25 years) were randomly assigned to oral insulin (7.5 mg/day) or placebo. Oral glucose tolerance tests were performed every 6 months. The median follow-up was 4.3 years, and the primary end point was diagnosis of diabetes. Diabetes was diagnosed in 44 oral insulin and 53 placebo subjects. Annualized rate of diabetes was similar in both groups: 6.4% with oral insulin and 8.2% with placebo (hazard ratio 0.764, P = 0.189). In a hypothesis-generating analysis of a subgroup with insulin autoantibody (IAA) levels confirmed (on two occasions) > or =80 nU/ml (n = 263), there was the suggestion of benefit: annualized diabetes rate 6.2% with oral insulin and 10.4% with placebo (0.566, P = 0.015). It is possible to identify individuals at high risk for type 1 diabetes and to enroll them in a large, multisite, randomized, controlled clinical trial. However, oral insulin did not delay or prevent type 1 diabetes. Further studies are needed to explore the potential role of oral insulin in delaying diabetes in relatives similar to those in the subgroup with higher IAA levels.


[Brachylepis gen. n.--a new genus of cestodes (Cyclophyllidea: Hymenolepididae) from shrews in Siberia and the Far East].
A new genus Brachylepis gen. n. hymenolepididean cestodes associated with common shrews (Sorex) in Siberia and Russian Far East is created. These genus includes three species removed from the genus Mathevolepis: Brachylepis morosovi (Karpenko, 1994) comb. n. (type species), B. sorextscherskii (Morosov, 1957) comb. n. and B. triovaria Karpenko, 1990) comb. n. The new genus is characterized by the gradual strobila with a little number of segments, unarmed scolex with apical glandular organ, by lack of internal seminal vesicle and differential seminal receptacle, by form of uterus as horse shoe in young worms and buble-like in mature worms. A tendency of inverse proportional dependence between the number of uterus segments in the strobila and the number of hexacanths in the uterus has been noticed. The table of differential characters for the species of the genus Brachylepis is proposed.


Superfast laser cooling.
Currently, laser cooling schemes are fundamentally based on the weak coupling regime. This requirement sets the trap frequency as an upper bound to the cooling rate. In this work we present a numerical study that shows the feasibility of cooling in the strong-coupling regime which then allows cooling rates that are faster than the trap frequency with experimentally feasible parameters. The scheme presented here can be applied to trapped atoms or ions as well as to mechanical oscillators. It can also cool medium sized ion chains close to the ground state.


Protein degradability and calcium salts of long-chain fatty acids in the diets of lactating dairy cows: productive responses.
Our objective was to evaluate the effect of excessive intake of ruminally degradable crude protein [11.1 and 15.7% of dietary dry matter (DM)] and supplemental fat (Ca salts of long-chain fatty acids at 0 or 2.2% of dietary DM) on the productive performance of lactating Holstein cows (n = 45) during the first 120 d postpartum. The main N sources were soybean meal and urea in the diets with high concentrations of degradable protein versus a combination of vegetable and animal by-product feedstuffs in the diets with less degradable protein. Cows fed the diets with excess degradable protein had slower rates of increase in DM intake (DMI) and milk production, had lower plasma insulin and greater plasma glucose and urea concentrations, and lost more than twice the body weight of cows fed the diets with less degradable protein. Supplemental fat in the highly degradable protein diet reduced the loss of body condition, stimulated DMI, and reduced concentrations of plasma nonesterified fatty acids early postpartum compared with the highly degradable protein diet without added fat. Without affecting DMI, supplemental fat stimulated milk production (2 kg/d) starting at 3 wk postpartum. During early lactation, DMI and milk production were sensitive to the degree of ruminal degradability of protein and energy supplementation in the form of fat.


[The hemodynamic characteristics of the central retinal artery and ophthalmic artery in atherosclerotic lesions of the carotid arteries based on the data from ultrasonic study methods].
Central retinal artery and orbital artery were examined by ultrasonograph in 348 patients with atherosclerosis of the carotid arteries. Doppler shift of frequency spectrum was detected in the central retinal artery, which is typical of the ischemic syndrome of the eye. Its characteristics include decreased diastolic component of velocity and increased resistance index. The possibility of using duplex scanning with color Doppler flow mapping for assessing the treatment efficacy is demonstrated. A direct relationship between the degree of stenosis in the internal carotid artery and blood flow in the orbital artery is revealed. The detected changes do not notably affect the Doppler spectrum characteristics in the central retinal artery.


Oral phages prophylaxis against mixed Escherichia coli O157:H7 and Salmonella Typhimurium infections in weaned piglets.
Escherichia coli and Salmonella Typhimurium are the main pathogens of diarrhea in weaned piglets. The prevention of bacterial diarrhea in weaned piglets by phage is rarely reported. We conducted this study to evaluate the preventive effect of phages on mixed Escherichia coli and Salmonella Typhimurium infections in weaned piglets. A novel phage named NJ12 was isolated by using Salmonella Typhimurium SM022 as host bacteria and characterized by electron microscopy, genomic analysis and in vitro bacteriostatic activity. Phage NJ12 and a previously reported phage EP01 were microencapsulated with sodium alginate to make phage cocktail. Microencapsulated phage cocktail and PBS (Phosphate buffer solution) were used to piglets the phage and phage-free group through oral administration before bacterial infection 2 h, respectively. Piglets of the phage and phage-free group were consumed with feed contaminated with 6 mL (108CFU/mL) Escherichia coli O157:H7 GN07 (GXEC-N07) and 6 mL (108CFU/mL) SM022 every day for seven consecutive days. The results showed that piglets in the phage-free group had more severe diarrhea, larger decreased average weight gain and higher levels of neutrophils compared with piglets in phage group. Meanwhile, piglets in the phage-free group had higher load of SM022 and GN07 in jejunal tissue and more severe intestinal damage compared with piglets in group phage in vivo. In addition, oral administration phage can significant decreased the relative abundance of Enterobacteriaceae but hardly repaired the changes of diversity and composition of gut microbiota caused by the mixed infection of SM022 and GN07. This implies that phage used as a feed additive have a marvelous preventive effect on bacterial diarrhea during weaning of piglets.


Squalene selectively protects mouse bone marrow progenitors against cisplatin and carboplatin-induced cytotoxicity in vivo without protecting tumor growth.
Squalene, an isoprenoid antioxidant is a potential cytoprotective agent against chemotherapy-induced toxicity. We have previously published that squalene protects light-density bone marrow cells against cis-diamminedichloroplatinum( II) (cisplatin)-induced toxicity without protecting tumor cells in vitro. Here, we developed an in vivo mouse model of cisplatin and cis-diammine (cyclobutane-1,1-dicarboxylato) platinum(II) (carboplatin)-induced toxicity to further investigate squalene-mediated LD-BM cytoprotection including the molecular mechanism behind selective cytoprotection. We found that squalene significantly reduced the body weight loss of cisplatin and carboplatin-treated mice. Light-density bone marrow cells from squalene-treated mice exhibited improved formation of hematopoietic colonies (colony-forming unit-granulocyte macrophage). Furthermore, squalene also protected mesenchymal stem cell colonies (colony-forming unit-fibroblast) from cisplatin and carboplatin-induced toxicity. Squalene-induced protection was associated with decreased reactive oxygen species and increased levels of glutathione and glutathione peroxidase/glutathione-S-transferase. Importantly, squalene did not protect neuroblastoma, small cell carcinoma, or medulloblastoma xenografts against cisplatin-induced toxicity. These results suggest that squalene is a potential candidate for future development as a cytoprotective agent against chemotherapeutic toxicity.


[Clinical variants and treatment of gastrointestinal fistulas].
The experience of 411 patients treatment, aged from 15 to 78 years with gastrointestinal tract fistulas are summarized. Depending on clinico-anatomical picture, fistulas are divided in 5 types. There were 110 (26.8%) patients with fistula type I, 36 (8.7%)--type II, 70 (17.03%)--type III, 29 (7.5%)--type IV, 66 (40.4%)--type V. Treatment policy was developed for each group. Necessity of urgent relaparotomy in patients with fistula type I, early relaparotomy in fistula type II, late relaparotomy and elective operations in fistula types III, IV and V were substantiated. At usage of this treatment 102 (24.8%) from 411 patients died.


A MYLK variant regulates asthmatic inflammation via alterations in mRNA secondary structure.
Myosin light-chain kinase (MYLK) is a gene known to be significantly associated with severe asthma in African Americans. Here we further examine the molecular function of a single-nucleotide polymorphism (SNP), located in the non-muscle myosin light-chain kinase isoform (nmMLCK), in asthma susceptibility and pathobiology. We identified nmMLCK variant (reference SNP: rs9840993, NM_053025: 721C>T, c.439C>T) with a distinct mRNA secondary structure from the other variants. The nmMLCK variant (721C) secondary structure exhibits increased stability with an elongated half-life in the human endothelial cell, and greater efficiency in protein translation initiation owing to an increased accessibility to translation start site. Finally, nmMLCK expression of 721C- and 721T-containing MYLK transgenes were compared in nmMLCK(-/-) mice and confirmed deleterious effects of nmMLCK expression on asthmatic indices and implicated the augmented influence of MYLK 721C>T (c.439C>T) SNP on asthma severity. The confirmation of the novel mechanism of the regulation of asthmatic inflammation by a MYLK advances knowledge of the genetic basis for asthma disparities, and further suggests the potential of nmMLCK as a therapeutic target. Our study suggests that in addition to altering protein structure and function, non-synonymous SNPs may also lead to phenotypic disparity by altering protein expression.


Same Day Discharge is a Successful Approach for the Majority of Patients Undergoing Holmium Laser Enucleation of the Prostate.
Limited research has focused on success with hospital discharge on the same day of surgery after holmium laser enucleation of the prostate (HoLEP). To determine the success of same-day discharge in our HoLEP cohort and factors associated with this approach. A retrospective review of our prospectively maintained HoLEP database demonstrated that 473 adult males underwent HoLEP from July 2018 to December 2019 at a tertiary referral center and high-volume HoLEP hospital. Patients were divided into groups according to planned inpatient admission (PIA), successful same-day discharge (SDD), or unplanned admission (UA). The PIA, SDD, and UA groups were assessed for differences in preoperative demographic data, perioperative surgical data, and postoperative follow-up data. SDD and UA were then compared to determine if any specific factors predicted UA, including univariate and multivariate logistic regression analyses. Age (p = 0.0049), use of anticoagulation (p = 0.037), American Society of Anesthesiologists score of 3-4 (p = 0.0017), and enucleation time (p=0.0178) were significantly higher in the PIA group. Morcellation time (p = 0.0059) and the rate of bedside catheter irrigation (p = 0.04) were higher in the UA group. The SDD group had the highest rate of successful voiding trial (p = 0.0001). Among the three groups, there was no difference in the rate of postoperative complications (p = 0.141). In a comparison of the SDD and UA groups, morcellation time (p = 0.041), the rate of bedside clot evacuation (p = 0.004), and successful voiding trial (p = 0.003) all favored SDD. There was no difference in 90-d complications (p = 0.536). A limitation is the retrospective nature of this study. HoLEP can be successfully performed as day surgery without an increase in postoperative complications. HoLEP as day surgery is possible for any patient who does not require admission for medical comorbidities. Same-day discharge (SDD) after holmium laser enucleation of the prostate (HoLEP) is possible and is successful in 87.4% of patients. Patients with longer morcellation times and with post-procedure hematuria with clots are more likely to have an unplanned admission. Use of a 120-W modulated-pulse laser resulted in a higher rate of SDD success. The culture change to day surgery is time-intensive owing to education of the postsurgical care units and clinic staff, and in our experience took approximately 9 mo to seamlessly integrate SDD as our HoLEP standard of care.


Hydrophobic AlOx Surfaces by Adsorption of a SAM on Large Areas for Application in Solar Cell Metallization Patterning.
A resist-free metallization of copper-plated contacts is attractive to replace screen-printed silver contacts and is demonstrated on large-area silicon heterojunction (SHJ) solar cells. In our approach, a self-passivated Al layer is used as a mask during the plating process. In this study, Al/AlOx or Al2O3 plating masks are further functionalized by a self-assembled monolayer (SAM) of octadecyl phosphonic acid (ODPA). The ODPA adsorption is characterized by X-ray photoelectron spectroscopy (XPS), Fourier transform infrared spectroscopy in attenuated total reflectance (FTIR-ATR) (in situ), and contact angle measurements to link the surface chemical composition to wetting properties. The SAM leads to homogeneous hydrophobic surfaces on large-area textured solar cells and planar flexible printed circuit boards (PCBs), which allows reproducible patterning of narrow lines by inkjet printing of an etchant. Selective copper plating is then performed to complete the metallization process and produce Cu contacts in the patterned areas. Silicon heterojunction (SHJ) solar cells metallized by the complete sequence reached up to 22.4% efficiency on a large area.


Laboratory identification of factor inhibitors: the perspective of a large tertiary hemophilia center.
Coagulation factor inhibitors are antibodies that bind and neutralize specific procoagulant plasma proteins. The identification of coagulation factor inhibitors by the hemostasis laboratory requires a careful and systematic approach that excludes other possible causes of prolonged screening tests such as the activated partial thromboplastin time and prothrombin time. Once the laboratory is confident that a specific coagulation factor inhibitor is present in a sample, its strength or titer must be measured. The clinician will use this information as a treatment guide. The most frequently occurring factor inhibitors encountered in the hemostasis laboratory are those directed against factor VIII (FVIII), which can arise in individuals with inherited hemophilia A as an immune response to factor replacement therapy or as an autoantibody leading to the condition of acquired hemophilia A. The Bethesda assay is the most widely used test for measuring the FVIII inhibitor titer. The Bethesda assay has several components that must be carefully controlled to achieve consistent results. This overview examines the behavior of various coagulation inhibitors and laboratory tests with an emphasis on the Bethesda assay for factor inhibitors.


Direct repeats of T-DNA integrated in tobacco chromosome: characterization of junction regions.
Plant transformation via Agrobacterium frequently results in formation of multiple copy T-DNA arrays at one target site of the chromosome. The T-DNA copies are arranged in repeats, direct or inverted around one of the T-DNA borders. A Ti plasmid-derived transformation vector has been constructed enabling direct selection of transformants carrying at least two linked copies of T-DNA in the same orientation. The selection is based on expression of a promoterless neomycin phosphotransferase gene on one T-DNA copy from a promoter located on the other T-DNA copy. After co-cultivation of tobacco protoplasts with Agrobacterium, as many as 30% of regenerated transformed plants carried directly repeated T-DNA copies. The junction regions between two T-DNAs were amplified and 13 amplified fragments were cloned and sequenced. The involvement of T-DNA left and right border sequences in direct repeat junctions was determined. In some junctions, additional filler DNA was detected. The length of filler DNA varied from a few up to almost 300 bp. The longer filler DNAs from two clones were found to be T-DNA fragments in direct or reverse orientation. We discuss the recently suggested models for T-DNA integration and propose that the formation of direct repeats in genomes does not necessarily result from ligation of intermediates (i.e. T-strands), but more likely from the co-integration of several intermediates into one target site.


CIH survey confirms communications networks as vital healthcare technologies.
The results of the Computers in Healthcare Networking Survey show a continued strong interest in networking technology, with accompanying real dollar investment now and in the future. Some skepticism remains, however, over what community networks and regional networks are all about and what will be needed to maintain them.


Hypolipidemic potential of sterol containing fractions of Jolyna laminarioides: a brown alga.
Solvent fractions (n-hexane, cholorofrom, methanol) and fractions containing sterols of Jolyna laminarioides was evaluated in triton-induced and high-fat-diet induced hyperlipidemic rats. Oral administration of J. laminarioides significantly reduced the elevated level of serum total cholesterol, triglycerides and LDL-c, both in triton induced and high fat diet induced hyperlipidemic rat models with increased serum HDL-c. Chloroform: methanol fraction (2:1) and n-hexane fraction containing sterol showed promising results in reducing LDL-c. The methanol fraction showed hypolipidemic effect by increasing HDL-c (90%). The extracts and fractions of the seaweed also decreased the increased level of cardiac and hepatic marker enzymes beside lowering lipid profile. J. laminarioides exhibited high anti-hyperlipidemic effects both in triton induced and high fat diet induced hyperlipidemic rats.


[Oral Health in the cohorts from the São Paulo Health, Well-Being, and Aging Study (SABE)].
The objective of this paper is to present the characteristics and methodological procedures used in the study SABE (Health, Well-Being, and Aging). This is a longitudinal study with multiple cohorts, carried out in the city of São Paulo, Brazil, since 2000. Follow-ups are conducted every five years when the new cohort is initiated. The SABE study employed a stratified, multistage sampling design to obtain a representative sample of community-dwelling individuals aged 60 years or more in the city of Sao Paulo. Data were collected by a structured questionnaire and clinical measurements taken by trained and calibrated examiners. The questionnaire included information on socioeconomic and demographic conditions, cognitive function, general health, medication, use and access to health services, oral health, nutrition, social support, functionality and well-being. The baseline study included self-reported oral health measurements, and clinical oral health measures were introduced in 2006.


Accuracy enhancement of laser induced breakdown spectra using permittivity and size optimized plasma confinement rings.
The inevitable problems in laser induced breakdown spectroscopy are matrix effect and statistical fluctuation of the spectral signal, which can be partly avoided by utilizing a proper confined unit. The dependences of spectral signal enhancement on relative permittivity were studied by varying materials to confine the plasma, which include polytetrafluoroethylene(PTFE), nylon/dacron, silicagel, and nitrile-butadiene rubber (NBR) with the relative permittivity 2.2, ~3.3, 3.6, 8~13, 15~22. We found that higher relative permittivity rings induce stronger enhancement ability, which restricts the energy dissipation of plasma better and due to the reflected electromagnetic wave from the wall of different materials, the electromagnetic field of plasma can be well confined and makes the distribution of plasma more orderly. The spectral intensities of the characteristic lines Si I 243.5 nm and Si I 263.1 nm increased approximately 2 times with relative permittivity values from 2.2 to ~20. The size dependent enhancement of PTFE was further checked and the maximum gain was realized by using a confinement ring with a diameter size of 5 mm and a height of 3 mm (D5mmH3mm), and the rings with D2mmH1mm and D3mmH2mm also show higher enhancement factor. In view of peak shift, peak lost and accidental peaks in the obtained spectra were properly treated in data progressing; the spectral fluctuation decreased drastically for various materials with different relative permittivities as confined units, which means the core of plasma is stabilized, attributing to the confinement effect. Furthermore, the quantitative analysis in coal shows wonderful results-the prediction fitting coefficient R2 reaches 0.98 for ash and 0.99 for both volatile and carbon.


Use of Maximum Likelihood-Mixed Models to select stable reference genes: a case of heat stress response in sheep.
Reference genes with stable expression are required to normalize expression differences of target genes in qPCR experiments. Several procedures and companion software have been proposed to find the most stable genes. Model based procedures are attractive because they provide a solid statistical framework. NormFinder, a widely used software, uses a model based method. The pairwise comparison procedure implemented in GeNorm is a simpler procedure but one of the most extensively used. In the present work a statistical approach based in Maximum Likelihood estimation under mixed models was tested and compared with NormFinder and geNorm softwares. Sixteen candidate genes were tested in whole blood samples from control and heat stressed sheep. A model including gene and treatment as fixed effects, sample (animal), gene by treatment, gene by sample and treatment by sample interactions as random effects with heteroskedastic residual variance in gene by treatment levels was selected using goodness of fit and predictive ability criteria among a variety of models. Mean Square Error obtained under the selected model was used as indicator of gene expression stability. Genes top and bottom ranked by the three approaches were similar; however, notable differences for the best pair of genes selected for each method and the remaining genes of the rankings were shown. Differences among the expression values of normalized targets for each statistical approach were also found. Optimal statistical properties of Maximum Likelihood estimation joined to mixed model flexibility allow for more accurate estimation of expression stability of genes under many different situations. Accurate selection of reference genes has a direct impact over the normalized expression values of a given target gene. This may be critical when the aim of the study is to compare expression rate differences among samples under different environmental conditions, tissues, cell types or genotypes. To select reference genes not only statistical but also functional and biological criteria should be considered. Under the method here proposed SDHA/MDH1 have arisen as the best set of reference genes to be used in qPCR assays to study heat shock in ovine blood samples.


Influence of cigarette smoking on ALS outcome: a population-based study.
To assess the prognostic influence of premorbid smoking habits and vascular risk profile on amyotrophic lateral sclerosis (ALS) phenotype and outcome in a population-based cohort of Italian patients. A total of 650 patients with ALS from the Piemonte/Valle d'Aosta Register for ALS, incident in the 2007-2011 period, were recruited. Information about premorbid cigarette smoking habits and chronic obstructive pulmonary disease (COPD) were collected at the time of diagnosis. Current smokers had a significantly shorter median survival (1.9 years, IQR 1.2-3.4) compared with former (2.3 years, IQR 1.5-4.2) and never smokers (2.7 years, IQR 1.8-4.6) (p=0.001). Also COPD adversely influenced patients' prognosis. Both smoking habits and CODP were retained in Cox multivariable model. This study has demonstrated in a large population-based cohort of patients with ALS that cigarette smoking is an independent negative prognostic factor for survival, with a dose-response gradient. Its effect is not related to the presence of COPD or to respiratory status at time of diagnosis. The understanding of the mechanisms, either genetic or epigenetic, through which exogenous factors influence disease phenotype is of major importance towards a more focused approach to cure ALS.