Using C. elegans to discover therapeutic compounds for ageing-associated neurodegenerative diseases.
Age-associated neurodegenerative disorders such as Alzheimer's disease are a major public health challenge, due to the demographic increase in the proportion of older individuals in society. However, the relatively few currently approved drugs for these conditions provide only symptomatic relief. A major goal of neurodegeneration research is therefore to identify potential new therapeutic compounds that can slow or even reverse disease progression, either by impacting directly on the neurodegenerative process or by activating endogenous physiological neuroprotective mechanisms that decline with ageing. This requires model systems that can recapitulate key features of human neurodegenerative diseases that are also amenable to compound screening approaches. Mammalian models are very powerful, but are prohibitively expensive for high-throughput drug screens. Given the highly conserved neurological pathways between mammals and invertebrates, Caenorhabditis elegans has emerged as a powerful tool for neuroprotective compound screening. Here we describe how C. elegans has been used to model various human ageing-associated neurodegenerative diseases and provide an extensive list of compounds that have therapeutic activity in these worm models and so may have translational potential.


Using a 3D virtual muscle model to link gene expression changes during myogenesis to protein spatial location in muscle.
Myogenesis is an ordered process whereby mononucleated muscle precursor cells (myoblasts) fuse into multinucleated myotubes that eventually differentiate into myofibres, involving substantial changes in gene expression and the organisation of structural components of the cells. To gain further insight into the orchestration of these structural changes we have overlaid the spatial organisation of the protein components of a muscle cell with their gene expression changes during differentiation using a new 3D visualisation tool: the Virtual Muscle 3D (VMus3D). Sets of generic striated muscle costamere, Z-disk and filament proteins were constructed from the literature and protein-interaction databases. Expression profiles of the genes encoding these proteins were obtained from mouse C2C12 cells undergoing myogenesis in vitro, as well as a mouse tissue survey dataset. Visualisation of the expression data in VMus3D yielded novel observations with significant relationships between the spatial location and the temporal expression profiles of the structural protein products of these genes. A muscle specificity index was calculated based on muscle expression relative to the median expression in all tissues and, as expected, genes with the highest muscle specificity were also expressed most dynamically during differentiation. Interestingly, most genes encoding costamere as well as some Z-disk proteins appeared to be broadly expressed across most tissues and showed little change in expression during muscle differentiation, in line with the broader cellular role described for some of these proteins. By studying gene expression patterns from a structural perspective we have demonstrated that not all genes encoding proteins that are part of muscle specific structures are simply up-regulated during muscle cell differentiation. Indeed, a group of genes whose expression program appears to be minimally affected by the differentiation process, code for proteins participating in vital skeletal muscle structures. Expression alone is a poor metric of gene behaviour. Instead, the "connectivity model of muscle development" is proposed as a mechanism for muscle development: whereby the closer to the myofibril core of muscle cells, the greater the gene expression changes during muscle differentiation and the greater the muscle specificity.


Testicular toxicity of ethylene glycol monomethyl and monoethyl ethers in the rat.
Ethylene glycol monomethyl (EGM) and monoethyl (EGE) ethers were administered po to rats at dosages varying from 50 to 500 mg/kg body weight/day for EGM and 250 to 1000 mg/kg body weight/day EGE for 11 days. First evidence of testicular damage following EGM treatment was observed 24 hr after a single dose of 100 mg/kg body weight when the lesion appeared localized in the primary spermatocyte. At 16 hr after a single dose of 500 mg/kg, mitochondrial damage was one of the first subcellular changes to be demonstrated. Treatment of animals with EGE resulted in a similar lesion; however, to obtain damage of equivalent severity, a larger dosage for a longer period was required. In limited studies with 2-methoxy- and 2-ethoxyacetic acids (putative metabolites of EGM and EGE, respectively), using equimolar doses to their parent compounds (500 mg EGM or EGE/kg for 4 or 11 days, respectively) gave damage of equivalent severity to the corresponding glycol ether. After dosing animals with 500 mg EGM/kg body weight for 4 days, the testes recovered weight, and the majority of tubules recovered their spermatogenic potential within one full maturation cycle. The recovery study also indicated a possible effect on the spermatogonia in a small number of tubules although no morphological abnormalities to this cell type could be observed. No effect levels over the 11-day treatment period were 50 and 250 mg/kg body weight/day for EGM and EGE, respectively.


Racial/ethnic differences in clinical and biochemical type 2 diabetes mellitus risk factors in children.
To examine whether periadolescent children demonstrate the significant racial/ethnic differences in body fatness relative to BMI and in the prevalence and relationship of body composition to risk factors for type 2 diabetes (T2DM) as in adults. Family history of obesity and T2DM, anthropometry, insulin sensitivity and secretory capacity, lipids, and cytokines (IL-6, CRP, TNF-α, and adiponectin) were examined in a cohort of 994 middle school students (47% male, 53%, female; 12% African American, 14% East Asian, 13% South Asian, 9% Caucasian, 44% Hispanic, and 8% other). Fractional body fat content was significantly greater at any BMI among South Asians. There were racial/ethnic specific differences in lipid profiles, insulin secretory capacity, insulin sensitivity, and inflammatory markers corrected for body fatness that are similar to those seen in adults. Family history of T2DM was associated with lower insulin secretory capacity while family history of obesity was more associated with insulin resistance. Children show some of the same racial/ethnic differences in risk factors for adiposity-related comorbidities as adults. BMI and waist circumference cutoffs to identify children at-risk for adiposity-related comorbidities should be adjusted by racial/ethnic group as well as other variables such as birthweight and family history.


Riboflavin uptake by rat small intestinal brush border membrane vesicles: a dual mechanism involving specific membrane binding.
The first step of riboflavin absorption was studied by determining the uptake of the vitamin by rat small intestinal brush border membrane vesicles. Vesicles were incubated at 25 degrees C in the presence of [3H]-riboflavin at concentrations within the physiological intraluminal range for rat. The time course of [3H]-riboflavin uptake was unaffected by Na+ or K+ gradients. The 5 sec uptake rate plotted as a function of the initial concentration of [3H]-riboflavin in the medium (0.125 to 7.5 microM) revealed the presence of a dual mechanism, with a saturable component (apparent kinetic constants: 0.12 microM for Km and 0.36 pmol.mg-1 protein x 5 sec-1 for Jmax) prevailing at low concentrations (< 2 microM), and a nonsaturable component prevailing at higher concentrations. The presence of a carrier-mediated system for riboflavin was validated by countertransport experiments. At equilibrium, uptake was almost completely accounted for by membrane binding, whereas at earlier times the transport component accounted for about 30% of total uptake. The plot of [3H]-riboflavin binding at equilibrium as a function of its concentration in the medium was quite similar to that of the 5 sec uptake rate in both intact and osmotically shocked vesicles and demonstrated the occurrence of a saturable component: binding constants were 0.07 (Kd in microM), 0.54 (Bmax in pmol.mg-1 protein), and 0.11 (Kd), 1.13 (Bmax), respectively, indicating the existence of specific riboflavin binding sites. The specificity of riboflavin binding to the membrane was confirmed by preliminary studies with structural analogues. Specific binding could represent the first step of a specific riboflavin entry mechanism in enterocytes.


TBC: a clustering algorithm based on prokaryotic taxonomy.
High-throughput DNA sequencing technologies have revolutionized the study of microbial ecology. Massive sequencing of PCR amplicons of the 16S rRNA gene has been widely used to understand the microbial community structure of a variety of environmental samples. The resulting sequencing reads are clustered into operational taxonomic units that are then used to calculate various statistical indices that represent the degree of species diversity in a given sample. Several algorithms have been developed to perform this task, but they tend to produce different outcomes. Herein, we propose a novel sequence clustering algorithm, namely Taxonomy-Based Clustering (TBC). This algorithm incorporates the basic concept of prokaryotic taxonomy in which only comparisons to the type strain are made and used to form species while omitting full-scale multiple sequence alignment. The clustering quality of the proposed method was compared with those of MOTHUR, BLASTClust, ESPRIT-Tree, CD-HIT, and UCLUST. A comprehensive comparison using three different experimental datasets produced by pyrosequencing demonstrated that the clustering obtained using TBC is comparable to those obtained using MOTHUR and ESPRIT-Tree and is computationally efficient. The program was written in JAVA and is available from http://sw.ezbiocloud.net/tbc.


Diagnosis of sleep apnea by the analysis of heart rate variation: a mini review.
Cyclic variation of heart rate (CVHR) associated with sleep apnea/hypopnea episodes has been suggested as a marker of sleep disordered breathing (SDB). This study examined the utility of ECG-based CVHR detection for diagnosing SDB using simultaneous polysomnography as the reference standard. We used a previously developed automated CVHR detection algorithm (autocorrelated wave detection with adaptive threshold, ACAT) that provides the number of CVHR per hour (CVHR index). The ACAT was refined using a polysomnographic database of 194 subjects with various severities of SDB and then, applied to a single channel ECG obtained during standard overnight polysomnography in 862 consecutive subjects referred for SDB diagnosis. Using multiple thresholds of CVHR index ≥ 38 and <27, positive and negative predictive values of 95.6% and 95.1%, respectively, were achieved for detecting and excluding subjects with apnea-hypopnea index (AHI) ≥ 30, leaving 58 (6.7%) unclassified subjects. Positive and negative likelihood ratios (LRs) were 97.3 and 0.23, respectively. Also, thresholds of CVHR index ≥ 29 and <7 provided 96.1% and 95.1% of positive and negative predictive values, respectively, for subjects with AHI ≥ 15 (LRs, 50.6 and 0.11), leaving 426 (49.4%) unclassified subjects. The CVHR correlated with the AHI (r = 0.86) and showed the limits of agreement with the AHI of 19.6 and -18.6. Automated detection of CVHR by the ACAT algorithm provides useful screening tool for both increasing and decreasing probability of moderate and sever SDB with adequate thresholds.


Axillary hibernoma: review of the literature with report of a case examined angiographically.
A case of hibernoma of the axilla and a review of the literature are presented. This benign tumor showed angiographic findings of hypervascularity without neovascularity or A-V shunting which differentiate it from lesions such as lipoma, fibroma, or neurofibroma.


Gender differences in compensatory behaviors, weight and shape salience, and drive for thinness.
Gender differences in compensatory behaviors, weight and shape salience, and drive for thinness have rarely been examined in nonclinical samples. The present study examines gender differences in a sample of 1111 male and 1510 female twins responding to a questionnaire on eating attitudes and behaviors. Logistic regression using generalized estimating equations (GEE) tested the extent to which gender could be predicted from compensatory behaviors, weight and shape salience, and drive for thinness. The results indicated that use of compensatory behaviors predicted female gender for all except exercise and "other," where no gender differences were found. Greater importance of weight and shape also predicted female gender, as did drive for thinness. Findings with respect to exercise use and "other" compensatory behaviors have nosological implications for the eating disorders, especially as regards eating disorders in males. These findings suggest that both the nature and function of compensatory behaviors may differ by gender.


[Evaluation of the analgesic action of clofelin in cardiogenic pain (clinico-experimental research)].
In chronic experiments on conscious rats analgesic and autonomic-corrective effects of clopheline in cardiogenic pain were demonstrated. The drug was also shown to decrease emotional and motor manifestations and to stabilize central hemodynamics in patients with acute myocardial infarction.


Underweight and obesity increase the risk of mortality after lung transplantation: a systematic review and meta-analysis.
Many studies have found an association between abnormal body mass index (BMI) and poor outcomes among lung transplant recipients. We performed a systematic review and meta-analysis to identify outcomes associated with an abnormal pretransplant BMI after lung transplantation (LTx). The MEDLINE and EMBASE databases were searched from inception to May 2015 with focus on original observational studies with post-transplant survival data in candidates with abnormal BMI (underweight, overweight, or obese). We performed meta-analyses examining survival and primary graft dysfunction after LTx. We identified 866 citations; 13 observational cohort studies involving 40 742 participants met our inclusion criteria for systematic review. Seven of the 13 were included in the meta-analysis. There was a significant risk of mortality after LTx in candidates with underweight and obesity (underweight versus normal, relative risk [RR] 1.36, 95% confidence interval [CI] 1.11-1.66, I(2) = 0%; obesity vs. normal, RR 1.90, 95% CI 1.45-2.56, I(2) = 0%; overweight vs. normal, RR 1.36, 95% CI 1.11-1.66, I(2) = 0). There was also a significant risk of primary graft dysfunction in obese (RR 1.92, 95% CI 1.39-2.65, I(2) = 0%) and overweight (RR 1.72, 95% CI, 1.32-2.24, I(2) = 0%) candidates. Lung transplant candidates who are underweight or obese have a higher risk of post-transplant mortality than recipients with a normal BMI.


Multi-oligomeric states of alamethicin ion channel: Assemblies and conductance.
Transmembrane assemblies of the peptaibol alamethicin (ALM) are among the most extensively studied ion channels not only because of their antimicrobial activity but also as models for channel structure and aggregation. In this study, several oligomeric states of ALM are investigated with molecular dynamics simulations to establish properties of the channel and obtain free energy profiles for ion transport and the corresponding values of conductance. The hexamer, heptamer, and octamer of ALM in phospholipid membrane are found to be stable but highly dynamic in barrel-stave structures, with calculated conductance equal to 18, 195, and 1270 pS, respectively, in 1 M KCl ion solution. The corresponding free energy profiles, reported for the first time, are reconstructed from simulations at applied voltage of 200 mV with the aid of the electrodiffusion model both with and without the knowledge of diffusivity. The calculated free energy barriers are equal to 2.5, 1.5, and 0.5 kcal/mol for K+ and 4.0, 2.2, and 1.5 kcal/mol for Cl-, for hexamer, heptamer, and octamer, respectively. The calculated conductance and the ratio between conductance in consecutive states are in good agreement with those measured experimentally. This suggests that the hexamer is the lowest conducting state, with measured conductance equal to 19 pS. The selectivity of K+ over Cl- is calculated as 1.5 and 2.3 for the octameric and heptameric channels, close to the selectivity measured for high-conductance states. Selectivity increases to 13 in the hexameric channel in which the narrowest Gln7 site has a pore radius of only ∼1.6 Å, again in accord with experiment. A good agreement found between calculated and measured conductance through a hexamer templated on cyclodextrin lands additional support for the results of our simulations, and the comparison with ALM reveals the dependence of conductance on the nature of phospholipid membrane.


Midkine is highly expressed in neuroblastoma tissues.
Neuroblastoma (NBL) is a tumor from neural crest cells, and is the most frequent solid tumor in children. Midkine (MK) is a pleiotropin analogon, which is frequently expressed in neuronal and epithelial tumors and is a marker for a poor clinical outcome. The aims of this study were to assess MK expression in NBL and investigate the correlation with clinical outcome. Fifty-six specimens of NBL were stained for MK on a tissue microarray by immunohistochemistry (IHC). Fresh frozen tumor tissues were used for RNA isolation, and RT-PCR analysis for MK-mRNA expression was performed. Survival data, risk factors and disease stages were correlated with MK status assessed by IHC and RT-PCR analysis. MK-mRNA expression was found in the majority of the tumor tissues (75%), whereas MK protein could be detected only in 46% of the NBL by IHC. No correlation of MK status with survival, risk factors or disease stage was observed. A majority of NBL express MK-mRNA, whereas not all MK mRNA positive tumors showed also a positive MK IHC staining. The high expression of MK-mRNA expression might present a promising target for new adenovirus-based gene therapeutic approaches for the treatment of NBL.


Anaphylaxis after dental treatment with a formaldehyde-containing tooth-filling material.
A 67-year-old patient developed systemic reactions after application of a formaldehyde-containing tooth filling. She had a clearly positive RAST result for formaldehyde, whereas skin prick testing and patch tests were negative. Sensitization to formaldehyde appears to have occurred 1 year previously. Induction of formaldehyde allergy may represent a major complication during dental treatment, and assessment of specific IgE should be considered in patients at risk.


What we can learn about running from barefoot running: an evolutionary medical perspective.
Barefoot running, which was how people ran for millions of years, provides an opportunity to study how natural selection adapted the human body to run. Because humans evolved to run barefoot, a barefoot running style that minimizes impact peaks and provides increased proprioception and foot strength, is hypothesized to help avoid injury, regardless of whether one is wearing shoes.


Disparity in checkpoint inhibitor utilization among commercially insured adult patients with metastatic lung cancer.
There is a lack of evidence from nationwide samples on the disparity of initiating immune checkpoint inhibitors (ICIs) after metastatic lung cancer diagnosis. We identified metastatic lung cancer patients diagnosed between 2015 and 2020 from a large, nationwide commercial claims database. We analyzed the time from metastatic lung cancer diagnosis to ICI therapy using Cox proportional hazard models. Independent variables included county-level measures (quintiles of percentage of racialized population, quintiles of percentage of population below poverty, urbanity, and density of medical oncologists) and patient characteristics (age, sex, Charlson comorbidity index, Medicare Advantage, and year of diagnosis). All tests were 2-sided. A total of 17 022 patients were included. Counties with a larger proportion of racialized population appeared to be more urban, have a greater percentage of its residents in poverty, and have a higher density of medical oncologists. In Cox analysis, the adjusted hazard ratio of the second, third, fourth, and highest quintile of percentage of racialized population were 0.89 (95% confidence interval [CI] = 0.82 to 0.98), 0.85 (95% CI = 0.78 to 0.93), 0.78 (95% CI = 0.71 to 0.86), and 0.71 (95% CI = 0.62 to 0.81), respectively, compared with counties in the lowest quintile. The slower ICI therapy initiation was driven by counties with the highest percentage of Hispanic population and other non-Black racialized groups. Commercially insured patients with metastatic lung cancer who lived in counties with greater percentage of racialized population had slower initiation of ICI therapy after lung cancer diagnosis, despite greater density of oncologists in their neighborhood.


Heterogeneity in tumours: Validating the use of radiomic features on 18F-FDG PET/CT scans of lung cancer patients as a prognostic tool.
The aim was to validate promising radiomic features (RFs)1 on 18F-flourodeoxyglucose positron emission tomography/computed tomography-scans (18F-FDG PET/CT) of non-small cell lung cancer (NSCLC) patients undergoing definitive chemo-radiotherapy. 18F-FDG PET/CT scans performed for radiotherapy (RT) planning were retrieved. Auto-segmentation with visual adaption was used to define the primary tumour on PET images. Six pre-selected prognostic and reproducible PET texture -and shape-features were calculated using texture respectively shape analysis. The correlation between these RFs and metabolic active tumour volume (MTV)3, gross tumour volume (GTV)4 and maximum and mean of standardized uptake value (SUV)5 was tested with a Spearman's Rank test. The prognostic value of RFs was tested in a univariate cox regression analysis and a multivariate cox regression analysis with GTV, clinical stage and histology. P-value ≤ 0.05 were considered significant. Image analysis was performed for 233 patients: 145 males and 88 females, mean age of 65.7 and clinical stage II-IV. Mean GTV was 129.87 cm3 (SD 130.30 cm3). Texture and shape-features correlated more strongly to MTV and GTV compared to SUV-measurements. Four RFs predicted PFS in the univariate analysis. No RFs predicted PFS in the multivariate analysis, whereas GTV and clinical stage predicted PFS (p = 0.001 and p = 0.008 respectively). The pre-selected RFs were insignificant in predicting PFS in combination with GTV, clinical stage and histology. These results might be due to variations in technical parameters. However, it is relevant to question whether RFs are stable enough to provide clinically useful information.


Laboratory studies of seed size and seed species selection by heteromyid rodents.
There have been conflicting reports in the last decade on the extent to which coexisting heteromyid rodent species select different sizes or species of seeds. Here I report results of laboratory choice experiments that show heteromyids of different size and genus to have similar preferences for wheat particles of various sizes, and for commercially available seed species that differ considerably in nutritional and morphological characteristics. I also discuss the significance of this finding for mechanisms of coexistence in natural communities.


Massive Retro-Pneumoperitoneum and Lower Limb Subcutaneous Emphysema After Pediatric Heart Transplantation: A Case Report.
An emphysema in a lower limb is usually a clinical sign of a severe and life-threatening infection. We report a rare case of subcutaneous emphysema of the left lower limb associated with a massive retro-pneumoperitoneum and pneumatosis intestinalis after cardiac transplantation in a 4-year-old girl. The child was nearly asymptomatic beside an abdominal distension. A benign pneumoperitoneum associated with an extensive pneumatosis intestinalis is a rare complication after organ transplantation and should be treated conservatively. The association with an emphysema in a lower limb in a child has not been previously reported to our knowledge in the literature.


Engagement with the HCV care cascade among high-risk groups: A population-based study.
HCV elimination requires a thorough understanding of the care cascade. A direct-acting antiviral (DAA)-era description of the care cascade has not been undertaken in Ontario, Canada's most populous jurisdiction. Our primary objective was to describe the current population-level care cascade in the general Ontario population and among key risk groups ─ baby boomers, immigrants, and individuals experiencing residential instability. The secondary objective was to identify predictors of engagement. We conducted a population-based cohort study of Ontario residents undergoing HCV testing between January 1, 1999, and December 31, 2018, and mapped the care cascade [antibody-diagnosed, RNA tested, RNA positive, genotyped, treated, achieved sustained virologic response, reinfected/relapsed] as of December 31, 2018. The cascade was stratified by risk groups. Cause-specific hazard modeling was used to identify demographic, and socioeconomic predictors of engagement with key steps of the cascade. Among 108,428 Ontario residents living with an HCV antibody diagnosis, 88% received confirmatory RNA testing; of these, 62% tested positive and 94% of positive tests were genotyped. Of those with confirmed viremia, 53% initiated treatment and 76% of treated individuals achieved sustained virologic response, while ~1% experienced reinfection or relapse. Males, older birth cohorts, long-term residents, those with a history of substance use disorder and social marginalization (eg, material deprivation, residential instability), and those initially diagnosed in the pre-DAA era exhibited lower rates of engagement with almost every step of HCV care. Despite DAA era improvements, treatment initiation remains a major gap. HCV screening and linkage-to-treatment, particularly for those with a history of substance use disorder and social marginalization, will be needed to equitably close gaps in HCV care in the province.


IGF-1 receptor-mediated ERK/MAPK signaling couples status epilepticus to progenitor cell proliferation in the subgranular layer of the dentate gyrus.
Adult progenitor cell proliferation in the subgranular zone (SGZ) of the dentate gyrus is a dynamic process that is modulated by an array of physiological process, including locomotor activity and novel environmental stimuli. In addition, pathophysiological events, such as ischemia and status epilepticus (SE), have been shown to stimulate neurogenesis. Currently, limited information is available regarding the extracellular stimuli, receptors, and downstream intracellular effectors that couple excitotoxic stimulation to progenitor cell proliferation. Here we show that pilocarpine-induced SE triggers a set of signaling events that impinge upon the p42/44 mitogen-activated protein kinase (MAPK) pathway to drive progenitor cell proliferation in the SGZ at 2-days post-SE. Increased proliferation was dependent on insulin-like growth factor-1 (IGF-1), which was localized to activated microglia near the SGZ. Using a combination of techniques, we show that IGF-1 is a CREB-regulated gene and that SE triggered CRE-dependent transcription in microglia at 2-days post-SE. Together, these data identify a potential signaling program that couples SE to progenitor cell proliferation. SE triggers CREB-dependent transcription in reactive microglia. As a CREB-target gene, IGF-1 expression is upregulated, and by 2-days post-SE, IGF-1 triggers MAPK pathway activation in progenitor cells and, in turn, an increase in progenitor cell proliferation.


Effect of sputum quality on Mycobacterium avium-intracellulare complex lung disease diagnosis and treatment initiation according to disease type.
We evaluated sputum quality to establish a diagnostic and treatment strategy for Mycobacterium avium-intracellulare complex lung disease (MAC-LD). Of all 905 MAC-LD patients, 564 (62.3%) had nonpurulent sputum. Furthermore, 88 treated patients were associated with purulent sputum. Therefore, sputum quality may be useful for diagnosing MAC-LD and deciding treatment initiation.


A randomized, double-blind, placebo-controlled study of the effect of sustained-release bupropion on blood pressure in individuals with mild untreated hypertension.
The effects of bupropion on blood pressure and heart rate were evaluated in a double-blind, placebo-controlled study of community volunteers with untreated mild (stage 1) hypertension (systolic blood pressure [SBP], 140-159 mm Hg, and/or diastolic blood pressure, 90-99 mm Hg). Three hundred subjects were randomly assigned (1:1:1:1) to 4 weeks of placebo or bupropion sustained release (SR) 150, 300, or 400 mg/d. Mean clinical blood pressures decreased from baseline to the end of protocol in all groups (n = 296): -6.53, -6.46, -4.20, -4.87 mm Hg for SBP; and -2.36, -2.27, -1.95, -1.55 mm Hg for diastolic blood pressure, for each group, respectively. Although decreases in mean clinical blood pressure were observed in all groups, the reduction in SBP was less on bupropion SR 300 mg/d than on placebo (-4.20 vs -6.53 mm Hg, respectively; Delta = 2.33, P = 0.020). Neither mean 24-hour ambulatory blood pressure measurements nor the proportion of subjects with clinically significant increases in blood pressure differed between any bupropion SR dose and placebo. Mean heart rate increases were small but statistically significant at 400 mg/d versus placebo (2.28 vs -0.64 beats/min; Delta = 2.92, P = 0.004). Although only minor effects on blood pressure were observed in this trial, an infrequent association of bupropion therapy and treatment-emergent hypertension cannot be ruled out.


Effect of particle size on the pharmacokinetics and biodistribution of parenteral nanoemulsions.
This study aims to investigate the effect of particle size on the pharmacokinetics and biodistributions of parenteral blank nanoemulsions (NEs). To monitor intact NEs in vivo, a near-infrared fluorescent dye is utilized to label NEs by exploiting its aggregation-caused quenching (ACQ) properties. After a single intravenous dose of NEs with mean sizes of 70, 200, 500 and 900 nm is administered to rats, the pharmacokinetic profiles are plotted based on semiquantification of the NE particles in blood by monitoring particle-bound fluorescence. All NE groups are cleared from the blood rapidly in a size-dependent manner. Reductions in particle size lead to prolonged residence times in blood which indicates size-dependent effect on the circulation time. Live imaging reveals pervasive distribution of NEs throughout the body in rats with an apparent size-dependency. Ex vivo bioimaging demonstrates the dynamic biodistribution of NEs in different organs and tissues with different patterns. The smallest NEs (70 nm) are prone to be taken up gradually by the liver, whereas the larger NEs are distributed in greater amounts in the spleen and lungs. The distribution in other tissues and organs is quite low. It is concluded that reductions in particle size lead to enhanced circulatory residence and hepatic exposure of NEs.


An evaluation of night vision mobility aids.
Two night vision aids are commercially available to help individuals who have diseases that cause night blindness. The ITT Night Vision Aid (NVA) is a light amplification device; the Wide Angle Mobility Light (WAML) is a wide beam flashlight. The effectiveness of both instruments in helping night-blind, field-restricted subjects to walk a course of residential streets at night was tested. WAML users were also surveyed to determine the usage, applications, and reliability of the device. We found that the WAML significantly reduced error rates and was preferred by most subjects; it was reported to be used regularly by individuals who owned it. The NVA did not significantly improve error scores, and was not effective as an ambulatory night mobility aid for most patients.


Protective effects of exogenous gangliosides on ROS-induced changes in human spermatozoa.
This article summarizes the available evidence on the efficacy of gangliosides to reduce the degree of reactive oxygen species (ROS)-mediated damage. The antioxidative efficacy of exogenous gangliosides in protecting different cells encouraged us to examine their ability to protect human spermatozoa. Gangliosides are sialic acid-containing glycosphingolipids with strong amphiphilic character due to the bulky headgroup made of several sugar rings with sialic acid residues and the double-tailed hydrophobic lipid moiety. The amphiphilicity of gangliosides allows them to exist as micelles in aqueous media when they are present at a concentration above their critical micellar concentration. The protective effect of ganglioside micelles on spermatozoa is believed to stem from their ability to scavenge free radicals and prevent their damaging effects. In our study, we particularly focused our attention on the protective effect of ganglioside micelles on DNA in human spermatozoa exposed to cryopreservation. The results indicate that ganglioside micelles can modulate the hydrophobic properties of the sperm membrane to increase tolerance to DNA fragmentation, thus protecting the DNA from cryopreservation-induced damage. Further actions of ganglioside micelles, which were documented by biochemical and biophysical studies, included (i) the modulation of superoxide anion generation by increasing the diffusion barrier for membrane events responsible for signal translocation to the interior of the cell; (ii) the inhibition of iron-catalysed hydroxyl radical formation due to the iron chelation potential of gangliosides; and (iii) inhibition of hydrogen peroxide diffusion across the sperm membrane.


Learning from the first wave of the COVID-19 pandemic: Comparing policy responses in Uruguay with 10 other Latin American and Caribbean countries.
A range of public health and social measures have been employed in response to the disproportionate impact of COVID-19 in Latin America and the Caribbean (LAC). Yet, pandemic responses have varied across the region, particularly during the first 6 months of the pandemic, with Uruguay effectively limiting transmission during this crucial phase. This review describes features of pandemic responses which may have contributed to Uruguay's early success relative to 10 other LAC countries - Argentina, Chile, Ecuador, El Salvador, Guatemala, Haiti, Honduras, Panama, Paraguay, and Trinidad and Tobago. Uruguay differentiated its early response efforts from reviewed countries by foregoing strict border closures and restrictions on movement, and rapidly implementing a suite of economic and social measures. Our findings describe the importance of supporting adherence to public health interventions by ensuring that effective social and economic safety net measures are in place to permit compliance with public health measures.


Evaluating the Impact of the Healthy Beverage Executive Order for City Agencies in Boston, Massachusetts, 2011-2013.
Intake of sugar-sweetened beverages (SSBs) is associated with negative health effects. Access to healthy beverages may be promoted by policies such as the Healthy Beverage Executive Order (HBEO) established by former Boston mayor Thomas M. Menino, which directed city departments to eliminate the sale of SSBs on city property. Implementation consisted of "traffic-light signage" and educational materials at point of purchase. This study evaluates the impact of the HBEO on changes in beverage availability. Researchers collected data on price, brand, and size of beverages for sale in spring 2011 (899 beverage slots) and for sale in spring 2013, two years after HBEO implementation (836 beverage slots) at access points (n = 31) at city agency locations in Boston. Nutrient data, including calories and sugar content, from manufacturer websites were used to determine HBEO beverage traffic-light classification category. We used paired t tests to examine change in average calories and sugar content of beverages and the proportion of beverages by traffic-light classification at access points before and after HBEO implementation. Average beverage sugar grams and calories at access points decreased (sugar, -13.1 g; calories, -48.6 kcal; p<.001) following the implementation of the HBEO. The average proportion of high-sugar ("red") beverages available per access point declined (-27.8%, p<.001). Beverage prices did not change over time. City agencies were significantly more likely to sell only low-sugar beverages after the HBEO was implemented (OR = 4.88; 95% CI, 1.49-16.0). Policies such as the HBEO can promote community-wide changes that make healthier beverage options more accessible on city-owned properties.


Ecosensitivity and genetic polymorphism of somatic traits in the perinatal development of twins.
In view of criticism regarding the usefulness of heritability coefficients, the aim of this study was to analyze separately the information on genetic and environmental variability. Such an approach, based on the normalization of trait's variability for its value, is determined by the coefficients of genetic polymorphism (Pg) and ecosensitivity (De). The studied material included 1263 twin pairs of both sexes (among them 424 pairs of monozygotic twins and 839 pairs of dizygotic twins) born between the 22nd and 41st week of gestation. Variability of six somatic traits was analyzed. The zygosity of same-sex twins was determined based on the polymorphism of DNA from lymphocytes of the umbilical cord blood, obtained at birth. The coefficients of genetic polymorphism and ecosensitivity for analyzed traits of male and female twins born at various months of gestation were calculated. Our study revealed that a contribution of the genetic component predominated over that of the environmental component in determining the phenotypic variability of somatic traits of newborns from twin pregnancies. The genetically determined phenotypic variability in male twins was greater than in the females. The genetic polymorphism and ecosensitivity of somatic traits were relatively stable during the period of fetal ontogeny analyzed in this study. Only in the case of body weight, a slight increase in the genetic contribution of polygenes to the phenotypic variance could be observed with gestational age, along with a slight decrease in the influence of environmental factors.


[Characteristics of lung cancer in a region in northern Spain].
To gather information on the disease characteristics and survival rate of patients diagnosed with bronchogenic carcinoma in the respiratory medicine departments of hospitals in Asturias, Spain. This was a retrospective observational study carried out using a standardized data collection protocol. All cases of lung cancer diagnosed during 2001 were included provided there was cytologic or histologic confirmation or they fulfilled a series of clinical, radiological, and/or endoscopic criteria consistent with such a diagnosis. Standard incidence rates adjusted to the world population were 22.4, 42.6, and 4.6 per 100,000 population for the whole population, men, and women respectively. The mean (SD) age was 67 (10.9) years, and 92% of the patients were men. Overall, 98% of the men and 44% of the women were smokers. Diagnosis was confirmed by cytologic or histologic findings in 92% of patients, and the majority were non-small cell tumors (81.4%). At the time of diagnosis, 65% of the patients had advanced disease, with distant metastasis in 26.6% of the non-small cell cancers and 52.8% of the small cell cancers. Patients received surgical treatment in 21.3% of cases, chemotherapy alone or combined with radiation therapy in 43.1%, and radiation therapy alone in 9.3%. In 26.2% of patients only palliative care was given. Overall, median survival in weeks was 36.4 (95% confidence interval [CI], 29.4-43.4). Median survival by treatment type was as follows: 69.3 (95% CI, 49-9.5) for surgery; 39.6 (95% CI, 31.2-48) for chemotherapy alone or with radiation therapy; 30 (95% CI, 15.4-44.6) for radiation therapy alone; and 13.3 (95% CI, 5.9-20.6) for patients who received palliative care alone (P< .05). The findings with respect to age, sex, incidence, histology, extent of tumor, and smoking status of patients with bronchogenic carcinoma in our region does not differ significantly from those reported for other areas of Spain. Current smoking is the primary cause of the high prevalence of this disease. Twenty-six percent of patients received only palliative care. The percentage of patients treated with surgery was low.


Organochlorine exposure and risk of breast cancer.
Some organochlorine compounds may have weak oestrogenic effects and are, therefore, suspected of increasing the risk of breast cancer. We assessed prospectively the risk of breast cancer in relation to serum concentrations of several organochlorine compounds. In 1976, serum samples from 7712 women were obtained from participants in the Copenhagen City Heart Study as part of physical examinations and interviews about lifestyle factors. During 17 years of follow-up, 268 women developed invasive breast cancer. Each woman with breast cancer was matched with two breast-cancer-free women from the remaining cohort. We analysed in 1996-97 the serum samples from 240 women with breast cancer and 477 controls. Dieldrin was associated with a significantly increased dose-related risk of breast cancer (adjusted odds ratio 2.05 [95% CI 1.17-3.57], p for trend 0.01). Beta-hexachlorocyclohexane increased risk slightly but not significantly (p for trend 0.24). There was no overall association between risk of breast cancer and p,p'-dichlorodiphenyltrichloroethane or metabolites or for polychlorinated biphenyls. Exclusion of women with breast cancer diagnosed within 5 years of blood sampling strengthened the result for dieldrin, but did not affect the other results. These findings support the hypothesis that exposure to xeno-oestrogens may increase the risk of breast cancer.


Outcomes of catheter ablation for ventricular tachycardia in patients with sarcoidosis: Insights from the National Inpatient Sample database (2002-2018).
Data on utilization, major complications, and in-hospital mortality of catheter ablation (CA) for sarcoidosis-related ventricular tachycardia (VT) are limited. We sought to determine the outcomes of sarcoidosis-related VT, and incidence and predictors of complications associated with the CA procedure. We queried the 2002-2018 National Inpatient Sample database to identify patients aged ≥18 years with sarcoidosis admitted with VT. A 1:3 propensity score-matched (PSM) analysis was used to compare patient outcomes between CA and medically managed groups. Multivariable regression was performed to determine independent predictors of in-hospital mortality and procedural complications associated with the CA procedure. Of 3220 sarcoidosis patients with VT, 132 (4.1%) underwent CA. Patients who underwent CA were younger, male predominant, more likely Caucasian, had differences in baseline comorbidities including more likely to have heart failure, less likely to have prior myocardial infarction, COPD, or severe renal disease, had a higher mean household income, and more likely admitted to a larger/urban teaching hospital. After PSM, we examined 106 CA cases and 318 medically managed cases. There was a trend toward a lower in-hospital mortality rate in the CA group when compared to the medically managed group (1.9% vs. 6.6%, p = 0.08). The most common complications were pericardial drainage (5.3%), postoperative hemorrhage (3.8%), accidental puncture periprocedure (3.0%), and cardiac tamponade (2.3%). Independent predictors of in-hospital mortality and procedural complications among the CA group included congestive heart failure (odds ratio [OR], 13.2; 95% confidence interval [CI], 1.7-104.2) and mild to moderate renal disease (OR, 3.9; 95% CI, 1.1-13.3). Compared to patients with sarcoidosis-related VT who received medical therapy alone, those who underwent CA have a trend for a lower mortality rate despite procedure-related complications occurring as high as 9.1%. Additional studies are recommended to better evaluate the benefits and risks of VT ablation in this group.


Activation of phospholipase D by the fucose-sulfate glycoconjugate that induces an acrosome reaction in spermatozoa.
We report for the first time that phospholipase D activity in sea urchin spermatozoa can be regulated by a component of egg jelly known to induce an acrosome reaction. The fucose-sulfate glycoconjugate (FSG) of egg jelly that induces an acrosome reaction in spermatozoa caused Ca2+-dependent increases in 1,2-diacylglycerol and phosphatidic acid. Diacylglycerol concentrations were increased 2-fold, and phosphatidic acid concentrations were elevated up to 10-fold 2 min after the addition of FSG to spermatozoa. FSG also caused increases in choline, but not in choline phosphate concentrations. Neither phosphorylation of diacylglycerol nor de novo synthesis from glycerol were significant routes of synthesis of phosphatidic acid during the acrosome reaction. When spermatozoa were incubated with FSG in the presence of ethanol, phosphatidylethanol was produced. As ethanol concentrations in the extracellular medium were increased from 0.1 to 2.5%, the amount of phosphatidylethanol increased, whereas phosphatidic acid concentrations decreased, suggesting a competitive transphosphatidylation reaction catalyzed by phospholipase D. Furthermore, when a phosphatidylcholine pool in spermatozoa was radiolabeled using [3H]1-O-alkyl-2-lyso-glycerol-3-phosphorylcholine, the subsequent addition of FSG caused a 4-fold accumulation of [3H]phosphatidic acid. FSG-induced elevations in [3H]phosphatidic acid were positively correlated with the percent of cells that had undergone an acrosome reaction.


Standing Balance Strategies and Dual-Task Interference Are Differentially Modulated Across Various Sensory Contexts and Cognitive Tests in Individuals With Chronic Stroke.
Mental tracking and verbal fluency tests have been linked to poor mobility and falls; however, no studies have examined the influence of imposing these tests on standing balance post-stroke. The purpose of this study was to investigate standing balance and cognitive performance across sensory conditions and cognitive tests post-stroke. Ninety-two participants with chronic stroke stood on dual-force platforms while performing various sensory conditions (eyes open/fixed surface, eyes closed/fixed surface, eyes open/sway-referenced surface, and eyes closed/sway-referenced surface) and cognitive tests (no cognitive test, serial subtractions, and verbal fluency). Equilibrium scores were computed based on the anterior-posterior sway angle. The number of correct verbal responses was recorded. Performing serial subtractions during eyes closed/sway-referenced surface revealed the highest equilibrium score (64.0 ± 13.5), followed by the same sensory condition with added verbal fluency test (59.6 ± 15.1), followed by the single-task condition with no cognitive test (52.6 ± 20.9). The number of correct serial subtractions between seated (7.7 ± 3.7) and standing (7.2 ± 3.5) conditions was similar. A trend for more correct verbal fluency responses emerged when seated (8.1 ± 2.9) than the eyes open/sway-referenced surface condition (7.5 ± 2.8). Greater correct verbal fluency responses emerged when seated (8.6 ± 3.1) than the eyes closed/sway-referenced surface condition (7.8 ± 2.7). Standing balance enhancement (higher equilibrium score/better balance) depends on the neuropsychological process targeted and the sensory input available post-stroke. Cognitive dual-task interference emerged for the verbal fluency test during the most attention demanding sensory condition. Cognitive tests that enhance standing balance should be considered in assessments and interventions to evaluate and improve dual-tasking post-stroke.Video Abstract available for more insights from the authors (see the Video, Supplemental Digital Content 1, available at: http://links.lww.com/JNPT/A321).


Conversion of dried Aspergillus candidus mycelia grown on waste whey to biodiesel by in situ acid transesterification.
This study reports optimization of the transesterification reaction step on dried biomass of an oleaginous fungus Aspergillus candidus grown on agro-dairy waste, whey. Acid catalyzed transesterification was performed and variables affecting esterification, viz., catalyst methanol and chloroform concentrations, temperature, time, and biomass were investigated. Statistical optimization of the transesterification reaction using Plackett-Burman Design showed biomass to be the predominant factor with a 12.5-fold increase in total FAME from 25.6 to 320mg. Studies indicate that the transesterification efficiency in terms of conversion is favored by employing lower biomass loadings. A. candidus exhibited FAME profiles containing desirable saturated (30.2%), monounsaturated (31.5%) and polyunsaturated methyl esters (38.3%). The predicted and experimentally determined biodiesel properties (density, kinematic viscosity, iodine value, cetane number, TAN, water content, total and free glycerol) were in accordance with international (ASTM D6751, EN 14214) and national (IS 15607) standards.


[Participation of thyroid hormones in the regulation of the genetic activity of normal and transformed human cells].
It is shown that 125J-thyroid hormones are localized on the structures of the interphasic nucleus and metaphasic chromosomes of cultured fibroblasts of 8--10-day human embryos. At the same time, the labelled thyroid hormones, though localizing in the interphasic nuclei of HeLa cells, are not accepted, unlike normal cells, by their metaphasic chromosomes. It is suggested that during transformation the acceptor ares of the HeLa cells genome lost their property to bind their own receptor complexes with thyroid hormones.


RNA interference targeting cytosolic NADP(+)-dependent isocitrate dehydrogenase exerts anti-obesity effect in vitro and in vivo.
A metabolic abnormality in lipid biosynthesis is frequently associated with obesity and hyperlipidemia. Nicotinamide adenine dinucleotide phosphate-oxidase (NADPH) is an essential reducing equivalent for numerous enzymes required in fat and cholesterol biosynthesis. Cytosolic NADP(+)-dependent isocitrate dehydrogenase (IDPc) has been proposed as a key enzyme for supplying cytosolic NADPH. We report here that knockdown of IDPc expression by Ribonucleic acid (RNA) interference (RNAi) inhibited adipocyte differentiation and lipogenesis in 3T3-L1 preadipocytes and mice. Attenuated IDPc expression by IDPc small interfering RNA (siRNA) resulted in a reduction of differentiation and triglyceride level and adipogenic protein expression as well as suppression of glucose uptake in cultured adipocytes. In addition, the attenuation of Nox activity and Reactive oxygen species (ROS) generation accompanied with knockdown of IDPc was associated with inhibition of adipogenesis and lipogenesis. The loss of body weight and the reduction of triglyceride level were also observed in diet-induced obese mice transduced with IDPc short-hairpin (shRNA). Taken together, the inhibiting effect of RNAi targeting IDPc on adipogenesis and lipid biosynthesis is considered to be of therapeutic value in the treatment and prevention of obesity and obesity-associated metabolic syndrome.


Controllable Preparation of Ultrathin Sandwich-Like Membrane with Porous Organic Framework and Graphene Oxide for Molecular Filtration.
Porous organic frameworks (POFs) based membranes have potential applications in molecular filtration, despite the lack of a corresponding study. This study reports an interesting strategy to get processable POFs dispersion and a novel ultrathin sandwich-like membrane design. It was accidentally found that the hydrophobic N-rich Schiff based POFs agglomerates could react with lithium-ethylamine and formed stable dispersion in water. By successively filtrating the obtained POFs dispersion and graphene oxide (GO), we successfully prepared ultrathin sandwich-like hybrid membranes with layered structure, which showed significantly improved separation efficiency in molecular filtration of organic dyes. This study may provide a universal way to the preparation of processable POFs and their hybrid membranes with GO.


Contribution of membrane localization to the apoptotic activity of PUMA.
The BH3-only protein PUMA plays an important role in the activation of apoptosis in response to p53. In different studies, PUMA has been described to function by either directly activating the pro-apoptotic proteins Bax and Bak, or by neutralizing anti-apoptotic members of the Bcl2 family. We have examined the contribution of regions of PUMA other than the BH3 domain to its localization and function. Although the hydrophobic domain in the C-terminus of PUMA is necessary for efficient mitochondrial localization of PUMA itself, PUMA proteins lacking this region can still induce apoptosis and localize to the mitochondria through binding to Bcl2. Even a nuclear localization signal (NLS)-tagged PUMA protein retains apoptotic activity and can be efficiently relocalized from the nucleus after interaction with ectopically expressed Bcl2, underscoring the efficiency of this interaction. Interestingly, unlike the Bcl2 interaction, the binding of PUMA to Bax is severely compromised by the loss of the C-terminal domain of PUMA. However, since the loss of the C-terminus does not compromise the ability of PUMA to induce cell death, our results indicate that the key apoptotic function of PUMA is through interaction with anti-apoptotic proteins such as Bcl2.


Implementation of guidelines in primary health care. A challenge for the municipal health centres in Finland.
To assess the implementation of guidelines in Finnish primary health care units. A semi-quantitative analysis of a cross-sectional interview survey. All municipal health centres in a selected region in Finland. Head physicians and head nurses of the 31 participating units. Number of guidelines adopted; methods used in the implementation; and the unit's estimated purposefulness in the implementation of guidelines. All health centres had adopted at least one guideline in the defined task areas, but only one-third of the units had implemented several guidelines. The implementation methods utilised were usually directive and passive rather than co-operative and problem-solving. Half of the units used training and methods involving active participation of the personnel, and in one-third a multiprofessional approach was applied. Clients' representatives were hardly ever involved in the adaptation of guidelines. A quarter of the health centres were assessed as purposeful in their policy to implement guidelines, the large units being more goal-oriented than the smaller ones. A minority of health centres are goal-oriented in the adoption of guidelines and use versatile methods to support the implementation; this presents an important managerial challenge for national health care development in Finland.


Esophageal hypertensive peristaltic disorders.
Esophageal motility abnormalities include a series of manometric findings that differ to a significant degree from findings in normal, asymptomatic volunteers. Current review summarizes conventional and high-resolution esophageal manometry criteria used to define and characterize esophageal hypertensive motility abnormalities. In the conventional esophageal manometry classification scheme hypertensive esophageal motility abnormalities include nutcracker esophagus (average distal contraction amplitude >180 mmHg), hypertensive lower esophageal sphincter (average resting LES pressure >45 mmHg) and poorly relaxing lower esophageal sphincter (average LES residual pressure >8 mmHg). The new, high resolution esophageal manometry scheme includes in the group of hypertensive peristaltic disorders hypertensive peristalsis ("nutcracker esophagus": mean DCI >5000 mmHg*sec*cm) and hypercontractile esophagus ("jackhammer esophagus": at least one contraction with DCI > 8,000 mmHg*sec*cm) and defines a separate group for disorders with impaired esophageal-gastric junction relaxation (mean integrated residual (LES) pressure >15 mmHg). Hypertensive motility disorders represent a heterogeneous condition subdivided into hypercontractile esophagus and hypertensive peristalsis. Further studies are required to determine the clinical relevance of this new classification.


[Salter-II fracture of the proximal tibia with avulsion of the tuberositas tibiae in the dog].
The combination of a fracture of the proximal tibia (Salter-Harris type II) with an avulsion of the tibial tuberosity is a rare injury in the growing dog. Internal fixation of the tibial plateau with K-wires, in some cases combined with a tension band wire for the avulsed tuberosity, resulted in complete healing. There is the possibility of developing growing deformities, therefore control radiographs should routinely be taken in 10 days intervals.


[Autoimmune neuropathies--current aspects of immunopathologic diagnostics and therapy].
The group of autoimmune neuropathies includes the Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuritis, multifocal motor neuropathy, neuropathies associated with monoclonal gammopathies, and vasculitic neuropathies. This educational review first addresses diagnostic pathways that facilitate more rational diagnostic decisions. Many therapies are effective for treating immune neuropathies. Unfortunately, none of the available therapies are specific. In the acute phase, glucocorticosteroids, plasmapheresis, and intravenous immunoglobulins play key roles. The list of long-term therapies includes azathioprine, cyclosporine, cyclophosphamide, and immunoglobulins. The therapeutic mechanisms involved are not clear for most of these compounds. Modern immunotherapy has to consider medical aspects, available therapeutic evidence, and long-term economic burden.


Four psychological processes navigated by patients during their journey of healing and recovering from depression: a grounded theory study.
This study explored the psychological processes that patients navigated when healing and recovering from depression. A grounded theory approach was used. Twenty patients who had recovered from depression participated. Four categories emerged depicting the psychological processes navigated by the participants during the recovery process: (1) acceptance: acceptance of depression and agreement to treatment; (2) transformation: change of mindsets and behaviours; (3) adaptation: stress regulation and change of focus; (4) integration: progress of depressive symptoms and moving on with 'regular' life. Each phase is related to the other phases, mental health professionals could assist patients with depression achieve the integration phase.


Vacuum-venipuncture skills: time required and importance of tube order.
The purpose of this study was to assess specific vacuum-venipuncture skills and the influence of the time involved in skin puncture and blood collection. Thirty subjects undergoing venipuncture in which video analysis was possible were included. These procedures were carried out by four nurses and recorded with a digital camera. Venipuncture skills classified by our observations were delineated on the basis of frame-by-frame video images, and a graph of x and y coordinates was created. With the first blood-collection tube, strong blood flow required the practitioner to push the tube back in to compensate for the strong repulsive force in approximately 46% of cases. By the third blood-collection tube, the blood flow had weakened; therefore, the tube was moved up and down. In cases that required a second venipuncture, the tube was already pierced, so the time required to fill it to 5 mL was significantly longer. Hand movement of the practitioner is adjusted according to blood flow. Reflex movement in response to strong blood flow may increase the risk of pushing the needle through the vein with excessive force. The time required to fill the tube varies among nurses, tube order, and level of venipuncture skills.


Administration of peripheral parenteral nutrition: a prospective study comparing rotation of venous access sites with ultrafine cannulas.
Peripheral veins have been used successfully for patients requiring short- to medium-term total parenteral nutrition. This study prospectively compares two methods of peripheral parenteral nutrition (PPN). Forty-six patients requiring parenteral nutrition (PN) were identified prospectively. Fifty courses of PPN were prescribed using a standardized PPN formula of 9.3 g nitrogen, 1400 kCal, 2500 ml (KABI II, Pharmacia). Patients were randomized to receive PPN via 23G, 15 cm flexane catheters (Nutriline) inserted into an antecubital vein which remained in-situ with a continuous infusion over 24 h, or to receive 12-h cyclical infusions through peripherally sited 18G catheters (Venflon) which were removed postinfusion and reinserted into the contralateral forearm on alternate days. Data collected included duration, complications and cost of materials for each prescribed course. A scoring system to determine patient anxiety and depression and a questionnaire regarding patients' perspectives were evaluated. Fifty courses were prescribed, 26 by rotation of veins (RV) and 24 by Nutriline (N). Mean duration of feeding was 7.9 and 8.6 days, respectively; cost of materials were comparable 6.48/day (RV) vs 5.17/day (N); 2 RV patients failed to complete their course (no access [P< 0.05], whilst 9 N patients failed to complete their course (4 severe phlebitis, 2 no venous access, 2 septicaemia, 1 dislodged). Five patients required CPN (RV, N 3) while 4 remaining patients were fed by an alternative PPN method. The overall incidence of anxiety was 20% and of depression 16%, with no significant difference between groups. The majority of patients (87%) found mobility restricted. Twelve-hourly infusions via alternate forearm veins were significantly more successful than continuous infusions via Nutriline, both in terms of completion of the prescribed course and less venous morbidity. This study confirms that rotation of forearm veins allows affordable and successful PN administration to the majority of patients, with low PN-related morbidity.


Bilingual language experience and the neural underpinnings of working memory.
A longstanding question in cognitive neuroscience and in the bilingualism literature is how early language experience influences brain development and cognitive outcomes, and whether these effects are global or specific to language-related processes. The current investigation examined the effect of the timing of language learning on the performance and neural correlates of phonological and non-verbal working memory, subcomponents of executive function. Three groups of bilinguals, who varied in terms of the timing of second language learning (i.e., simultaneous bilinguals learned their two languages from birth; early and late bilinguals who learned their second language before or after 5 years of age, respectively), performed phonological and non-verbal working memory tasks in the magnetic resonance imaging scanner. Results showed that there were no group differences in performance on either of the tasks, or in the neural correlates of performance of the non-verbal task. However, critically, we showed that despite similar behavioural performance, the groups differed in the patterns of neural recruitment during performance of the phonological working memory task. The pattern of group differences was non-linear, demonstrating similar neural recruitment for simultaneous and late bilinguals that differed from early bilinguals. Findings from the current study suggest a dynamic mapping between the brain and cognition, contributing to our current understanding of the effect of the timing of language learning on cognitive processes and demonstrating a specific effect on language-related executive function.


COVID-19 Suspected myopericarditis without pulmonary involvement.
Myopericarditis is a rare consequence of COVID-19 infection. Although extremely rare, COVID-19 can present without pulmonary involvement, and there have been reports of isolated cardiac involvement in one prior case We report a case of a young African American man presenting with myopericarditis following a recently recovered COVID-19 infection. Complicated by ICU admission requiring vasopressors; with eventual resolution following initiation of aspirin and colchicine for myopericarditis. Life threatening myopericarditis can occur following resolution of COVID-19 disease. The degree of cardiac involvement correlates poorly to the severity of pulmonary involvement.


Correspondence on "Cyanine Dyes Containing Quinoline Moieties: History, Synthesis, Optical Properties and Applications".
In the review on "Cyanine Dyes Containing Quinoline Moieties: History, Synthesis, Optical Properties and Applications" (K. Ilina, M. Henary, Chem Eur. J. 2021, 27, 2430; https://doi.org/10.1002/chem.202003697), some essential aspects were incorrectly described and discussed. To avoid further confusion, this correspondence tries to clarify both the structures and the history of some cyanine and apocyanine dyes that were not presented sufficiently.


Steady-state fluorescence anisotropy and multifrequency phase fluorometry on oxidized phosphatidylcholine vesicles.
Multilamellar liposomes, from mixtures of unoxidized (control) and singlet oxygen oxidized phosphatidylcholine, were studied by steady-state fluorescence anisotropy and multifrequency phase fluorometry using 1,6-diphenyl-1,3,5-hexatriene (DPH) as fluorescent probe. Lifetime fluorescence decay of the DPH-labeled liposomes was analyzed either by a model of discrete exponential components and a model that assumes a continuous distribution of lifetime values. Increasing the oxidized phosphatidylcholine content in the liposomes, an increase of the membrane interior polarity and a decrease of membrane fluidity occurs which can be related to the hydroperoxide-lipids and double bonds conjugation, respectively.


Clinical efficacy of mefloquine in children suffering from chloroquine-resistant Plasmodium falciparum malaria in Nigeria.
One hundred and thirteen children with symptomatic uncomplicated falciparum malaria were treated with either chloroquine 25 mg/kg body weight over 3 d (51 subjects) or mefloquine 25 mg/kg body weight single dose (62 subjects). The cure rate in the chloroquine group was 65% and in the mefloquine group 100%. 14 patients with chloroquine-resistant falciparum malaria (7 RI, 6 RII and one RIII) were successfully treated with mefloquine. The clearance times of parasitaemia and fever were 60 +/- 21.5 h and 24.7 +/- 10.1 h respectively in the chloroquine-sensitive group and 52.3 +/- 18.2 h and 24.5 +/- 23.7 h respectively in the mefloquine group. In the chloroquine-resistant group treated successfully with mefloquine, these clearance times were 44.0 +/- 8.9 and 24.0 h respectively. The only remarkable adverse reaction in the chloroquine group was pruritus which occurred in 7 subjects. Abdominal pain and diarrhoea (8 subjects) and dizziness (3 subjects) were the only important adverse reactions in the mefloquine group. It is concluded that, despite previous reports of primary reduced susceptibility to mefloquine in vitro of some West African isolates of Plasmodium falciparum, this drug may be useful in the treatment of both chloroquine-sensitive and chloroquine-resistant falciparum malaria in West Africa.


Association between improved compliance with enhanced recovery after cardiac surgery guidelines and postoperative outcomes: A retrospective study.
Enhanced recovery after cardiac surgery is a multidisciplinary clinical care pathway that relies on a bundle of interventions, aiming to reduce the stress response to surgery and promote early recovery of organ function. In 2011, our institution introduced an institutional enhanced recovery after cardiac surgery program focusing on 9 central interventions, which have been expanded during the past decade by additional interventions now considered standard of care. After the recent publication of the enhanced recovery after cardiac surgery guidelines, we evaluated the relation between the compliance with these enhanced recovery after cardiac surgery guidelines and postoperative outcomes. All patients enrolled in our enhanced recovery after cardiac surgery program in 2019 were included in this retrospective single-center audit. The primary outcome was compliance with 23 enhanced recovery after cardiac surgery guidelines. Secondary outcomes included occurrence of at least 1 postoperative complication and hospital length of stay. A total of 356 patients were included in this study. Compliance with the enhanced recovery after cardiac surgery guidelines was 64%. Postoperatively, 51% of the patients experienced at least 1 complication and had a median hospital length of stay of 6 days. Multivariable analysis showed that an increased compliance (per 10%) with the enhanced recovery after cardiac surgery guidelines was associated with a lower risk for any complication (odds ratio, 0.60; 95% confidence interval, 0.46-0.79; P = .0003) and a higher probability of earlier hospital discharge (hazard ratio, 1.25; 95% confidence interval, 1.10-1.43; P = .0008). This audit revealed a correlation between increased compliance with enhanced recovery after cardiac surgery guidelines and a reduction of postoperative complications and hospital length of stay. Future trials are needed to establish evidence-based recommendations for each separate intervention of the enhanced recovery after cardiac surgery guidelines and to create a minimum core-set of enhanced recovery after cardiac surgery interventions.


Multicenter open trial of cefotetan and cefoxitin in elective biliary surgery.
The present study was performed in two phases. In phase I, 112 patients were randomized to either 2 g cefotetan as a single prophylactic dose or 2 g cefoxitin every 6 hours for a maximum of 4 doses; phase II included 148 patients who were randomized to either 1 g cefotetan as a single dose or cefoxitin dosed as in phase I. The randomization was 2:1 cefotetan to cefoxitin in both phases. Nonevaluability rates were 10 percent for the cefotetan patients and 22 percent for the cefoxitin patients, the majority being due to dosing errors. Demographic characteristics demonstrated 88 percent to be female, 81 percent to be less than 65 years of age, and the average weight to be 165 lb. There were no differences in these characteristics among the groups. Common duct exploration was performed in 6 percent of the 2 g cefotetan patients, 9 percent in the 1 g cefotetan patients, and 13 percent in the 2 g cefoxitin patients. There were five clinical failures of prophylaxis: one wound infection in the 2 g cefotetan patients, one wound infection and one drain tract infection in the 1 g cefotetan patients, and one wound infection and one case of cholangitis in the 2 g cefoxitin patients. The clinical success rates were 98 percent in the 2 g cefotetan patients, 98 percent in the 1 g cefotetan patients, and 97 percent in the 2 g cefoxitin patients.


Development of an enzyme-coupled activity assay for Janus kinase 2 inhibitor screening.
JAK2 transmits signals of several important cytokines, such as growth hormone and erythropoietin. The interest toward the therapeutic targeting of JAK2 was boosted in 2005, when the somatic JAK2 V617F mutation, responsible for the majority of myeloproliferative neoplasms (MPNs) was discovered. JAK2 inhibitors have been approved for MPN therapy and they are effective in alleviating symptoms and improving the quality of life of the patients, but they do not lead to molecular remission. This calls for the discovery of new compounds for JAK2-targeted therapeutic approaches. Here we describe the development of a fluorescence-based activity assay for the screening of versatile inhibitor types against JAK2. The assay was utilized to screen a diverse set of small molecule weight natural products and the assay performance was compared to that of differential scanning fluorimetry. We identified 37 hits and further analysis of the most potent hits revealed that most of them displayed non-ATP competitive binding modes. The hits were profiled against other JAK family members and showed distinctive selectivity profiles. The developed assay is consistent, simple and inexpensive to use, and can be utilized for inhibitor screening of diverse compound classes against all JAK family members.


Acceptance of clinical decision support system to prevent venous thromboembolism among nurses: an extension of the UTAUT model.
Venous thromboembolism has been a major public health problem and caused a heavy disease burden. Venous thromboembolism clinical decision support system was proved to have a positive influence on the prevention and management of venous thromboembolism. As the direct users, nurses' acceptance of this system is of great importance to support the successful implementation of it. However, there are few relevant studies to investigate nurses' acceptance and the associated factors are still unclear. To investigate the determinant factors of nurses' acceptance of venous thromboembolism clinical decision support system with the modified Unified Theory of Acceptance and Use of Technology. We designed a questionnaire based on the modified Unified Theory of Acceptance and Use of Technology and then a cross-sectional survey was conducted among nurses in a tertiary hospital in Nanjing, China. Statistically, a Structural Equation Modeling -Partial Least Squares path modeling approach was applied to examine the research model. A total of 1100 valid questionnaires were recycled. The modified model explained 74.7%, 83.0% and 86% of the variance in user satisfaction, behavioral intention and user behavior, respectively. The results showed that performance expectancy (β = 0.254, p = 0.000), social influence (β = 0.136, p = 0.047), facilitating conditions (β = 0.245, p = 0.000), self-efficacy (β = 0.121, p = 0.048) and user satisfaction (β = 0.193, p = 0.001) all had significant effects on nurses' intention. Although effort expectancy (β = 0.010, p = 0.785) did not have a direct effect on nurses' intention, it could indirectly influence nurses' intention with user satisfaction as the mediator (β = 0.296, p = 0.000). User behavior was significantly predicted by facilitating conditions (β = 0.298, p = 0.000) and user intention (β = 0.654, p = 0.001). The research enhances our understanding of the determinants of nurses' acceptance of venous thromboembolism clinical decision support system. Among these factors, performance expectancy was considered as the top priority. It highlights the importance of optimizing system performance to fit the users' needs. Generally, the findings in our research provide clinical technology designers and administrators with valuable information to better meet users' requirements and promote the implementation of venous thromboembolism clinical decision support system.


Tregs biomimetic nanoparticle to reprogram inflammatory and redox microenvironment in infarct tissue to treat myocardial ischemia reperfusion injury in mice.
At present, patients with myocardial infarction remain an increased risk for myocardial ischemia/reperfusion injury (MI/RI). There lacks effectively method to treat MI/RI in clinic. For the treatment of MI/RI, it is still a bottleneck to effectively deliver drug to ischemic myocardium. In this paper, a regulatory T cells (Tregs) biomimetic nanoparticle (CsA@PPTK) was prepared by camouflaging nanoparticle with platelet membrane. CsA@PPTK actively accumulated in ischemic myocardium of MI/RI mice. CsA@PPTK significantly scavenged reactive oxygen species (ROS) and increased the generation of Tregs and the ratio of M2 type macrophage to M1 type macrophage in ischemic myocardium. Moreover, CsA@PPTK significantly attenuated apoptosis of cardiomyocytes and reduced the infarct size and fibrosis area in ischemic myocardium. CsA@PPTK markedly decreased the protein expression of MMP-9 and increased the protein expression of CX43 in ischemic myocardium tissue. Subsequently, the remodeling of the left ventricle was significant alleviated, and heart function of MI/RI mice was markedly improved. CsA@PPTK showed significant therapeutic effect on MI/RI, and it has great potential application in the treatment of MI/RI.


Modeling of serum C-telopeptide levels with daily and monthly oral ibandronate in humans.
A previously validated kinetic-pharmacodynamic model was applied to changes in a marker of bone resorption (serum C-telopeptide cross-links of type I collagen [sCTX]) using data from a large-scale clinical trial of ibandronate (Monthly Oral iBandronate In LadiEs [MOBILE]). The model showed rapid and significant suppression of sCTX compared to baseline with daily and monthly ibandronate, and gradual recovery of sCTX levels between monthly doses. This modeled, post-dose oscillatory pattern of sCTX paralleled significant increases in BMD and was associated with an acceptable safety profile for patients in MOBILE, suggesting that the between-dose recovery of sCTX does not negatively affect the efficacy of once-monthly ibandronate.


Lower Limbs are the Most Difficult-to-Treat Body Region of Patients with Psoriasis: Pooled Analysis of CLEAR and CLARITY Studies of Secukinumab Versus Ustekinumab by Body Region.
The impact of psoriasis, response to treatment, and patients' perceptions of treatment satisfaction vary by body area. We aimed to evaluate the level of response in lower limbs versus other body regions in patient with moderate to severe psoriasis treated with secukinumab and ustekinumab. Data were pooled from CLEAR and CLARITY trials, which included patients with moderate to severe plaque psoriasis (Psoriasis Area and Severity Index [PASI] score of ≥ 12) aged ≥ 18 years and a diagnosis of ≥ 6 months before randomisation. Patients received either secukinumab 300 mg or ustekinumab 45/90 mg. The PASI 100 responders and mean PASI scores at weeks 4, 12, 16, 28, 40 and 52 in the head and neck, trunk, upper limbs and lower limbs were measured. At baseline, analysis of PASI scores for each body region revealed that the lower limbs were the most severely affected body region in both treatment arms (mean PASI scores: secukinumab 24.0; ustekinumab 24.4). For both drugs, the highest clearance rates at week 52 were achieved in the trunk (secukinumab 85.2% vs ustekinumab 68.7%) and head and neck (80.7% vs 68.9%), followed by the upper limbs (72.6% vs 61.9%) and lower limbs (68.1% vs 57.2%). At week 52, the mean PASI score was higher in the lower limbs in both treatment arms versus other body regions. Lower limbs were the most severely affected and most difficult-to-treat regions in patients with psoriasis. Consistent with the individual results of both studies, secukinumab demonstrated numerically faster and higher skin clearance than ustekinumab in all body regions. CLEAR: NCT02074982; CLARITY: NCT02826603.


Taste responsivity of amygdaloid units in behaving rabbit: a methodological report.
A technique is described for studying unit electrophysiology of taste in the behaving animal. Preliminary observations on response patterns by amygdaloid units to four putative basic types of taste qualities (represented by sucrose, saline, acid, and quinine), which also vary in motivational properties, revealed evidence of units with exclusive or highly differential response to either sucrose or saline in food-deprived animals. Small quantities (0.3 ml) of these palatable tastants injected intra-orally evoked neural responses lasting 5-8 sec that did not relate directly to the characteristics of the oro-lingual reaction as detected electromyographically; such sensorimotor relations were found in units sampled in the globus pallidus. Some amygdaloid units displayed differential excitatory and inhibitory modes of response to different tastants. Other cells exhibited more phasic patterns of response lasting 1-2 sec to 2 or more tastants, including unpalatable acid and quinine. The results underscore the sensitivity of the technique to stimulus parameters of taste-processing, which is basic to the study of all neurobehavioral functions of taste stimuli.


Biopsy pathology predicts patients with ulcerative colitis subsequently requiring surgery.
The clinical course of patients with ulcerative colitis (UC) is unpredictable, and 17%-38% ultimately require surgery. We hypothesized that mucosal histology may differ between patients requiring surgery and those receiving medication alone. The aim of this study was to elucidate comprehensive criteria consisting of specific histologic features enabling the prediction of failure to medical treatment. We studied colorectal biopsy specimens from 67 patients ultimately requiring surgery (UC-S) and 90 receiving medication alone for more than 3 years (UC-M), and conducted multiple logistic regression analysis on 70 histologic features together with endoscopic disease extent and patient age. The analysis constructed an equation finding probability of UC-S (P(UC-S)). Based on a receiver-operating characteristic curve, we selected four cut-off values of P(UC-S), and determined criteria of five categories: highest-risk, higher-risk, unpredictable, lower-risk and lowest-risk of surgery. Sensitivity and specificity of criteria were evaluated in a 2 x 5 table. Statistically significant features predicting UC-S were deep ulceration (X1), frequent crypt abscesses (X2), focal and segmental mononuclear cell infiltration (X3 and X4), paucity of eosinophils (X5: eosinophil infiltration) and wide extent of the disease (X6). The regression equation was as follows: logitP(UC-S) = -16.26 + 3.20X1 + 4.83X2 + 11.65X3 + 5. 10X4 - 5.59X5 + 5.53X6. Higher-risk and lower-risk showed sensitivity exceeding 91.0% and specificity exceeding 98.5% in predicting the outcome. Our criteria incorporating specific histologic features and endoscopic disease extent reliably predict eventual clinical outcome, and are expected to prove useful in determining the necessity of surgery.


[Alterations of heparin coating on intraocular lenses caused by implantation instruments].
In the last years heparin surface-modified intraocular lenses (HSM IOLs) were used for special indications like uveitis, synechia, congenital cataract or pseudoexfoliation syndrome. A monolayer of heparin molecules on the surface of PMMA-IOLs causes a reduced postoperative inflammatory reaction and produces a higher long-term biocompatibility than PMMA-IOLs without surface-modification. The study was designed to evaluate the possible damage of this heparin-monolayer on the PMMA-IOL by different metallic implantation forceps and different grasp-pressure. Different implantation instruments were used to grasp HSM and conventional PMMA-IOLS. We designed a new device to generate and measure the pressure by the implantation forceps on the IOL in online-mode. After staining the heparin-monolayer with toluidin blue the surface alterations on the intraocular lenses were examined for surface alterations, especially of the heparin-monolayer, by light and scanning electron microscopy subsequently. Implant forceps produced defects of the heparin layer and the PMMA-material. Each implantation forceps induced a specific pattern of destructed heparin surface in the grasp area. These defects showed high correlation with the pressure and the morphology of the forceps as shown by light and scanning electron microscopy. Mechanical irritation during the implantation procedure destroyed the heparin layer on PMMA-IOLs in the grasp-area. Clinical consequences are not yet known, but possible. An instrument with rounded, soft and smooth grasp-surface is required for implantation of HSM IOLs to avoid surface alterations, so that the patients get maximum profit by the heparin-modification.


Predicting Medication Nonadherence in Older Adults With Difficult-to-Treat Depression in the IRL-GRey Randomized Controlled Trial.
Nonadherence to antidepressants interferes with optimal treatment of late-life depression. This analysis examines clinical and treatment factors predicting medication nonadherence in difficult-to-treat late-life depression. Secondary analysis of data from a clinical trial of antidepressant pharmacotherapy for Major Depressive Disorder in 468 adults aged 60+ years. All participants received venlafaxine XR for 12 weeks. Nonremitters were randomized to augmentation with either aripiprazole or placebo for 12 additional weeks. Medication adherence was assessed 14 times over 24 weeks. The analyses examined sociodemographic, clinical, and treatment factors that may predict antidepressant nonadherence during early (weeks 1-6), late (weeks 7-12), and augmentation (weeks 13--24) treatment. Poor cognitive function and early response were predictive of early nonadherence. Poor cognitive function and prior nonadherence were predictive of late nonadherence. Living alone was associated with nonadherence both late and during augmentation treatment. Future studies should consider the role of early response and cognitive function to improve antidepressant adherence, particularly among older adults who live alone.


IL-33 induces orofacial neuropathic pain through Fyn-dependent phosphorylation of GluN2B in the trigeminal spinal subnucleus caudalis.
Orofacial neuropathic pain can cause considerable disruptions in patients' daily lives, especially because of a lack of effective medications as its underlying causative mechanisms are not fully understood. Here, we found neuron-specific expression of the interleukin (IL)-33 receptor in the trigeminal spinal subnucleus caudalis (Vc), distinct from the spinal dorsal horn. Reduction in head withdrawal threshold in response to von Frey filament stimulation of the whisker pad skin was inversely correlated with the upregulation of IL-33 in the Vc after infraorbital nerve injury (IONI). Neutralization of IL-33 in the Vc alleviated mechanical allodynia in the whisker pad skin after IONI; conversely, intracisternal administration of IL-33 elicited mechanical allodynia in the whisker pad skin, which was relieved by GluN2B antagonism. Moreover, IL-33 triggered the potentiation of GluN2B-containing N-methyl-D-aspartate receptor-mediated synaptic currents and phosphorylation of synaptosomal GluN2B in the Vc, whereas IONI-induced GluN2B phosphorylation was inhibited by neutralization of IL-33 in the Vc. IL-33-induced GluN2B phosphorylation was mediated by phosphorylation of Fyn kinase, and inhibition of the Fyn kinase pathway prevented the development of IL-33-induced mechanical allodynia. Our findings provide insights into a new mechanism by which IL-33 directly regulates synaptic transmission and suggest that IL-33 signaling could be a candidate target for therapeutic interventions for orofacial neuropathic pain.


3D-printed tracheoesophageal puncture and prosthesis placement simulator.
A tracheoesophageal prosthesis (TEP) allows for speech after total laryngectomy. However, TEP placement is technically challenging, requiring a coordinated series of steps. Surgical simulators improve technical skills and reduce operative time. We hypothesize that a reusable 3-dimensional (3D)-printed TEP simulator will facilitate comprehension and rehearsal prior to actual procedures. The simulator was designed using Fusion360 (Autodesk, San Rafael, CA). Components were 3D-printed in-house using an Ultimaker 2+ (Ultimaker, Netherlands). Squid simulated the common tracheoesophageal wall. A Blom-Singer TEP (InHealth Technologies, Carpinteria, CA) replicated placement. Subjects watched an instructional video and completed pre- and post-simulation surveys. The simulator comprised 3D-printed parts: the esophageal lumen and superficial stoma. Squid was placed between components. Ten trainees participated. Significant differences existed between junior and senior residents with surveys regarding anatomy knowledge(p<0.05), technical details(p<0.01), and equipment setup(p<0.01). Subjects agreed that simulation felt accurate, and rehearsal raised confidence in future procedures. A 3D-printed TEP simulator is feasible for surgical training. Simulation involving multiple steps may accelerate technical skills and improve education.


Locomotor adaptation is influenced by the interaction between perturbation and baseline asymmetry after stroke.
Stroke survivors without cerebellar involvement retain the ability to adapt to the split-belt treadmill; however it has been suggested that their rate of adaptation may be slowed compared to those who are neurologically intact. Depending on limb placement, the split-belt treadmill can be configured to either exaggerate baseline asymmetry, or reduce it, which may affect the behavior of adaptation or de-adaptation. The objectives of this study were to characterize the rate and magnitude of locomotor (de)adaptation in chronic stroke survivors compared to healthy matched subjects, and to evaluate whether exaggeration or reduction of baseline asymmetry impact the responses. Seventeen stroke survivors and healthy subjects completed 10min of split-belt treadmill walking, then 5min of tied-belt walking. Stroke survivors completed this once with each leg on the fast belt. Magnitude and rate of (de)adaptation were evaluated for step length and limb phase asymmetry. There were no differences between the groups with the exception of the reduced step length asymmetry configuration, in which case there was a significantly reduced magnitude (p≤0.000) and rate (p=0.011) of adaptation when compared to controls. There was a similar trend observed during post-adaptation for the exaggerated asymmetry group. The rate and magnitude of locomotor (de)adaptation is similar between chronic stroke survivors and neurologically intact controls, except when the adaptation or de-adaptation response would take the stroke survivors away from a symmetric step length pattern. This suggests that there may be some benefit to symmetry that is recognized by the system.


Efficacy of Ologen matrix implant in Ahmed Glaucoma Valve Implantation.
To determine the efficacy and safety of the Ologen collagen matrix adjunctive to Ahmed valve surgery. A randomized prospective multicentre clinical trial involving 58 patients that were followed for one year. Conventional surgery with Ahmed valve was performed in 31 eyes (Control group/CG) and in 27 Ologen (Ologen group/OG) was placed over the valve's plate. Baseline data: age, corneal thickness, intraocular pressure(IOP) and antiglaucoma medications.Postoperative data (days 1, 7 and months 1, 3, 6 and 12): IOP, antiglaucoma medications, visual acuity and complications were recorded. Frequency of hypertensive phase, complete and qualified success and survival rate were studied. No differences were found between CG and OG in the baseline data. The only difference between groups was a significantly lower IOP at day 1. No other differences were found in the follow-up between groups. Hypertensive phase (56%CG and 55%OG, p = 0,947), complete success 28,6%CG and 30,4%OG (p = 0,88) and qualified success 96,4% and 95,9%(p = 0,794). Survival rates at 1 year were 76,7%(CG) and 69,2%(OG)(p = 0,531). 38,7% of patients in the CG suffered some complication during follow-up and 61,5% in OG(p = 0,086). Ologen does not increase safety or efficacy in Ahmed valve surgery at one-year follow-up. This is the first study that shows no benefit of Ologen adjunctive to this surgery.


HDL mimetic CER-001 targets atherosclerotic plaques in patients.
Infusion of high-density lipoprotein (HDL) mimetics aimed at reducing atherosclerotic burden has led to equivocal results, which may relate in part to the inability of HDL mimetics to adequately reach atherosclerotic lesions in humans. This study evaluated delivery of recombinant human apolipoprotein A-I (apoA-I) containing HDL mimetic CER-001 in carotid plaques in patients. CER-001 was radiolabeled with the long-lived positron emitter zirconium-89 ((89)Zr) to enable positron emission tomography with computed tomography (PET/CT) imaging. Eight patients with atherosclerotic carotid artery disease (>50% stenosis) received a single infusion of unlabeled CER-001 (3 mg/kg), co-administered with 10 mg of (89)Zr-labeled CER-001 (18 MBq). Serial PET/CT imaging and contrast enhanced-magnetic resonance imaging (CE-MRI) were performed to evaluate targeted delivery of CER-001. One hour after infusion, mean plasma apoA-I levels increased by 9.9 mg/dL (p = 0.026), with a concomitant relative increase in the plasma cholesterol efflux capacity of 13.8% (p < 0.001). Using serial PET/CT imaging, we showed that arterial uptake of CER-001 expressed as target-to-background ratio (TBRmax) increased significantly 24 h after infusion, and remained increased up to 48 h (TBRmax t = 10 min: 0.98; t = 24 h: 1.14 (p = 0.001); t = 48 h: 1.12 (p = 0.007)). TBRmax was higher in plaque compared with non-plaque segments (1.18 vs. 1.05; p < 0.001). Plaque TBRmax correlated with local plaque contrast enhancement (r = 0.56; p = 0.019) as assessed by CE-MRI. Infusion of HDL mimetic CER-001 increases plasma apoA-I concentration and plasma cholesterol efflux capacity. Our data support the concept that CER-001 targets plaque regions in patients, which correlates with plaque contrast enhancement. These clinical findings may also guide future nanomedicine development using HDL particles for drug delivery in atherosclerosis. Netherlands Trial Registry - NTR5178. http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=5178.


Investigating Multiple-Reported Bacterial Sexually Transmitted Infection Hot Spot Counties in the United States: Ordered Spatial Logistic Regression.
To identify and examine the correlates of multiple bacterial sexually transmitted infection (STI) hot spot counties in the United States. We assembled and analyzed 5 years (2008-2012) of cross-sectional STI morbidity data to identify multiple bacterial STI (chlamydia, gonorrhea, and syphilis) hot spot counties using hot spot analysis. Then, we examined the association between the multi-STI hot spots and select multiyear (2008-2012) sociodemographic factors (data obtained from the American Community Survey) using ordered spatial logistic regression analyses. Of the 2935 counties, the results indicated that 85 counties were hot spots for all 3 STIs (3-STI hot spot counties), 177 were hot spots for 2 STIs (2-STI hot spot counties), and 145 were hot spots for only 1 STI (1-STI hot spot counties). Approximately 93% (79 of 85) of the counties determined to be 3-STI hot spots were found in 4 southern states--Mississippi (n = 25), Arkansas (n = 22), Louisiana (n = 19), and Alabama (n = 13). Counties determined to be 2 STI hot spots were found in 7 southern states--Arkansas, Louisiana, Mississippi, Alabama, Georgia, and North and South Carolina had at least ten 2-STI hot spot counties each. The multi-STI hot spot classes were significantly (P < 0.05) associated with percent black (non-Hispanic), percent Hispanics, percent American Indians, population density, male-female sex ratio, percent aged 25 to 44 years, and violent crime rate. This study provides information on multiple STI hot spot counties in the United States and the associated sociodemographic factors. Such information can be used to assist planning, designing, and implementing effective integrated bacterial STI prevention and control programs/interventions.


Editorial: The Long-term Impact of Attention-Deficit/Hyperactivity Disorder: Lessons From the Past and Directions for the Future.
In this issue of the Journal, Cherkasova et al.1 provide a unique synthesis of 7 prospective longitudinal cohorts of children with attention-deficit/hyperactivity disorder (ADHD), all followed into adult life. The authors focus on a diverse range of outcome domains: educational performance, occupational/economic functioning, mental health, physical health, substance use, antisocial behavior, and driving. These not only are important for the quality of life and well-being of people with ADHD, but also have implications for health service use and the wider economic impact on society. Each cohort on its own has already provided significant insights into the course of ADHD and played a key role in our current understanding of the condition. All cohorts have a long follow-up period-in the New York cohort, 33 years after initial evaluation and well into mid-adulthood. The retention rates are impressive, ranging from 60% to 94%. All cohorts employ a comparison group, which is essential in interpreting the reported outcomes. In bringing together the 7 cohorts, the authors present a clear consensus that people with ADHD are at high risk of adverse outcomes in all functional domains. ADHD is considered by some experts to be one of the mental health conditions most responsive to intervention, and, as such, these findings challenge our management of the condition and mandate future research to improve outcomes.