Diabetes-Related Emotional Distress Over Time.
Many adolescents with type 1 diabetes experience diabetes-related distress (DRD; the negative emotional reactions specific to managing diabetes), but most research on DRD among adolescents relies on cross-sectional data. We assess adolescents' longitudinal DRD patterns and predictors of chronic DRD. This secondary analysis of data from a depression prevention clinical trial included 264 adolescents with type 1 diabetes randomly assigned to a resilience or education intervention (mean age: 15.7 ± 1.1 years; 59.8% female). Youth reported their DRD at 5 assessments over 16 months. Using latent class growth analysis, we classified adolescents into trajectory groups according to baseline starting point (intercept) and rate of change (slope) of DRD. We examined bivariate associations between trajectory group membership and demographic and clinical factors. Baseline predictors of chronic DRD were assessed via multiple logistic regression. Participants were classified into 4 groups: stable high DRD (7.2%; high intercept, flat slope), stable moderate DRD (28.0%; above-average intercept, flat slope), improving DRD (33.7%; average intercept, downward slope), and low DRD (31.1%; below-average intercept, downward slope). Lower hemoglobin A1c, greater adherence, fewer socioemotional difficulties, and more adaptive coping distinguished the improving and low DRD trajectories. Chronic DRD patterns were associated with female sex and higher depressive symptoms and hemoglobin A1c. In this study of adolescents' DRD trajectories during and after a psychoeducational intervention, one-third of youth were classified as having chronic, elevated DRD. Links with multiple clinical factors support efforts for routine DRD screening and comprehensive interventions for distressed youth.


Genome Editing Using the CRISPR-Cas9 System to Generate a Solid-Red Germline of Nile Tilapia (Oreochromis niloticus).
In recent years, there has been increasing demand for red tilapia, which are commercial strains of hybrids of different tilapiine species or red variants of highly inbred Nile tilapia. However, red tilapia phenotypes are genetically unstable and affected by environmental factors, resulting in nonuniform coloration with black or dark-red color blotches that reduce their market value. Solute carrier family 45 member 2 (SLC45A2) is a membrane transporter that mediates melanin biosynthesis and is evolutionarily conserved from fish to humans. In the present study, we describe the generation of a stable and heritable red tilapia phenotype by inducing loss-of-function mutations in the slc45a2 gene. For this purpose, we identified the slc45a2 gene in Nile tilapia and designed highly specific guide RNAs (gRNA) for its genomic sequence. Multiplex microinjection of slc45a2-specific ribonucleoproteins to Nile tilapia zygotes induced up to 97-99% albinism, including loss of melanin in the eye. Next-generation sequencing of the injected zygotes demonstrated that all injected fish carried mutant alleles with variable mutagenesis efficiencies. Sanger sequencing of the genomic target region in the slc45a2 gene from fin clips, sperm, and F1 offspring of a highly mutant male identified various genomic indels and germline transmission of the sperm-identified indels. Overall, this work demonstrates the generation of somatic and germline slc45a2 mutant alleles, which leads to complete albinism in Nile tilapia.


Timeliness of postnatal surgery in newborns with open neural tube defects: a single center experience.
This study aims to evaluate the experience of a tertiary health center on the timeliness of postnatal management in newborns with open neural tube defects (NTDs). This is a retrospective review of 38 neonates with NTDs who were treated surgically at a tertiary health care center between January 2009 and January 2019. Five neonates with genetic syndromes were excluded. Twenty-six neonates with NTD underwent surgery on the first postnatal day while 12 neonates with NTD had surgery after the first postnatal day. The reasons for the latency in operative treatment were the delay in the referral of the affected newborn from other health care centers (n=8) and the transient abnormalities in coagulation tests (n=4). Rural residence was significantly more frequent, gestational age at delivery was significantly lower, preterm delivery was significantly more frequent and prenatal diagnosis was significantly less frequent in neonates that underwent surgery for NTD repair after the first postnatal day (p=0.001, p=0.048, p=0.024 and p=0.003 respectively). Postoperative motor dysfunction was significantly more severe (p=0.002), postoperative complications were significantly more frequent (p=0.008), the reoperation and postoperative mortality rates were significantly higher (p=0.009 and p=0.048 respectively) and the duration of hospital stay was significantly longer (p=0.033) for the neonates who underwent surgery after the first postnatal day. Our study appears to favor the early repair of NTD`s within the first 24 hours of life. Such an approach may reduce the risk of infectious and neurological complications significantly.


Just sustainability? Sustainability and social justice in professional codes of ethics for engineers.
Should environmental, social, and economic sustainability be of primary concern to engineers? Should social justice be among these concerns? Although the deterioration of our natural environment and the increase in social injustices are among today's most pressing and important issues, engineering codes of ethics and their paramountcy clause, which contains those values most important to engineering and to what it means to be an engineer, do not yet put either concept on a par with the safety, health, and welfare of the public. This paper addresses a recent proposal by Michelfelder and Jones (2011) to include sustainability in the paramountcy clause as a way of rectifying the current disregard for social justice issues in the engineering codes. That proposal builds on a certain notion of sustainability that includes social justice as one of its dimensions and claims that social justice is a necessary condition for sustainability, not vice versa. The relationship between these concepts is discussed, and the original proposal is rejected. Drawing on insights developed throughout the paper, some suggestions are made as to how one should address the different requirements that theory and practice demand of the value taxonomy of professional codes of ethics.


The soluble CTLA-4 splice variant protects from type 1 diabetes and potentiates regulatory T-cell function.
CTLA4 gene variation associates with multiple autoimmune disorders, including type 1 diabetes. The CTLA4 susceptibility allele was found to generate decreased levels of mRNA encoding soluble CTLA-4 (sCTLA-4) relative to the full-length isoform, the functional consequence of which is as yet unknown. In this study, we investigated the contribution of sCTLA-4 to immune regulation with the aim to elucidate the functional basis of the disease association of CTLA4. To model the disease-associated splicing variation of CTLA4, we generated NOD mice in which sCTLA-4 mRNA is silenced by RNA interference. We found that loss of sCTLA-4 impairs the function of regulatory T (Treg) cells. This functional defect could be attributed, at least in part, to the failure of sCTLA-4 knockdown (KD) Treg cells to downregulate dendritic cell costimulation. sCTLA-4 KD Treg cells, in contrast with wild-type Treg cells, failed to inhibit colitis induced by transfer of CD4(+)CD45RB(hi) cells into NOD.SCID animals. Furthermore, diminished sCTLA-4 expression accelerated the onset of autoimmune diabetes in transgenic mice. Our results demonstrate that sCTLA-4 participates in immune regulation by potentiating the function of Treg cells. The functional outcome of silencing this splice variant in the NOD model provides an explanation for the association of CTLA4 variation with autoimmunity. Lower sCTLA-4 expression from the susceptibility allele may directly affect the suppressive capacity of Treg cells and thereby modulate disease risk. Our unprecedented approach establishes the feasibility of modeling splicing variations relevant to autoimmunity.


Biologicals in childhood severe asthma: the European PERMEABLE survey on the status quo.
Severe asthma is a rare disease in children, for which three biologicals, anti-immunoglobulin E, anti-interleukin-5 and anti-IL4RA antibodies, are available in European countries. While global guidelines exist on who should receive biologicals, knowledge is lacking on how those guidelines are implemented in real life and which unmet needs exist in the field. In this survey, we aimed to investigate the status quo and identify open questions in biological therapy of childhood asthma across Europe. Structured interviews regarding experience with biologicals, regulations on access to the different treatment options, drug selection, therapy success and discontinuation of therapy were performed. Content analysis was used to analyse data. We interviewed 37 experts from 25 European countries and Turkey and found a considerable range in the number of children treated with biologicals per centre. All participating countries provide public access to at least one biological. Most countries allow different medical disciplines to prescribe biologicals to children with asthma, and only a few restrict therapy to specialised centres. We observed significant variation in the time point at which treatment success is assessed, in therapy duration and in the success rate of discontinuation. Most participating centres intend to apply a personalised medicine approach in the future to match patients a priori to available biologicals. Substantial differences exist in the management of childhood severe asthma across Europe, and the need for further studies on biomarkers supporting selection of biologicals, on criteria to assess therapy response and on how/when to end therapy in stable patients is evident.


Fetal tachycardias: management and outcome of 127 consecutive cases.
To review the management and outcome of fetal tachycardia, and to determine the problems encountered with various treatment protocols. Retrospective analysis. 127 consecutive fetuses with a tachycardia presenting between 1980 and 1996 to a single tertiary centre for fetal cardiology. The median gestational age at presentation was 32 weeks (range 18 to 42). 105 fetuses had a supraventricular tachycardia and 22 had atrial flutter. Overall, 52 fetuses were hydropic and 75 non-hydropic. Prenatal control of the tachycardia was achieved in 83% of treated non-hydropic fetuses compared with 66% of the treated hydropic fetuses. Digoxin monotherapy converted most (62%) of the treated non-hydropic fetuses, and 96% survived through the neonatal period. First line drug treatment for hydropic fetuses was more diverse, including digoxin (n = 5), digoxin plus verapamil (n = 14), and flecainide (n = 27). The response rates to these drugs were 20%, 57%, and 59%, respectively, confirming that digoxin monotherapy is a poor choice for the hydropic fetus. Response to flecainide was faster than to the other drugs. Direct fetal treatment was used in four fetuses, of whom two survived. Overall, 73% (n = 38) of the hydropic fetuses survived. Postnatally, 4% of the non-hydropic group had ECG evidence of pre-excitation, compared with 16% of the hydropic group; 57% of non-hydropic fetuses were treated with long term anti-arrhythmics compared with 79% of hydropic fetuses. Non-hydropic fetuses with tachycardias have a very good prognosis with transplacental treatment. Most arrhythmias associated with fetal hydrops can be controlled with transplacental treatment, but the mortality in this group is 27%. At present, there is no ideal treatment protocol for these fetuses and a large prospective multicentre trial is required to optimise treatment of both hydropic and non-hydropic fetuses.


The drug treatment of premature ejaculation.
The management recommendation for both acquired premature ejaculation (APE) and lifelong PE (LPE) are similar, such as a behavioral/psychotherapy, a pharmacotherapy and a combination of these treatments. For the drug treatment for PE, gold standard is selective serotonin reuptake inhibitors (SSRIs) including dapoxetine or paroxetine. The drug treatment for PE is still developing and some new promising therapeutic options have been proposed. Topical anesthetics, tramadol, and alpha-1 blockers will be the next strategies of the drug treatment for PE in the future.


The human SNARE protein Ykt6 mediates its own palmitoylation at C-terminal cysteine residues.
The yeast SNARE (soluble N-ethylmaleimide-sensitive fusion protein attachment protein receptor) protein Ykt6 was shown to mediate palmitoylation of the fusion factor Vac8 in a reaction essential for the fusion of vacuoles. Here I present evidence that hYkt6 (human Ykt6) has self-palmitoylating activity. Incubation of recombinant hYkt6 with [3H]Pal-CoA ([3H]palmitoyl-CoA) leads to covalent attachment of palmitate to C-terminal cysteine residues. The N-terminal domain of human Ykt6 contains a Pal-CoA binding site and is required for the reaction.


The neurology resident as teacher: evaluating and improving our role.
There is a need to improve the quality of teaching done by neurology residents because neurology residents are intimately involved in medical student education. This article reviews the available literature on techniques to improve the teaching ability of resident physicians. Eight randomized prospective studies were identified from health and education databases. The outcomes measured were student ratings of residents or objective ratings of interactions between residents and students. The skills curriculum provided a more robust response, and the objective standardized teaching examination (OSTE) provided a standardized outcome. There continues to be a need for studies specifically addressing the teaching by neurology residents and fellows.


Essential fatty acid supplementation during early alcohol abstinence.
Interactions between ethanol, prostaglandins, and essential fatty acids (EFA) have led to the hypothesis that acute alcohol withdrawal and the sequelae of chronic alcoholism may be related to an EFA/prostaglandin deficiency. To test this hypothesis, EFA profiles in blood-lipid fractions, serum liver enzymes, cognitive function, and alcohol craving were measured in 27 acutely abstinent alcoholics before and after a 3-week double-blind trial of EFA supplementation. Upon entry into the study, alcoholics had significant differences in EFA levels as compared to normal controls, and serum levels of liver enzymes tended to correlate with these EFA levels. After 21 days, cognitive function, alcohol craving, and liver enzymes all improved in both the EFA and placebo groups; most EFA levels also approached normal values. There were no treatment effects of EFA supplementation at the dose used.


[Heart Failure - A Model for Multimorbidity].
Heart failure frequently is the consequence of different cardiac diseases and is associated with multiple cardiac and non-cardiac co-morbidities. It may be exemplary for multi-morbidity in the elderly, has negative impact on various organ systems and may induce further comorbidities. The following article addresses heart failure as a multisystem disorder.


Development of the 'Sigue la Huella' physical activity intervention for adolescents in Huesca, Spain.
Engaging in physical activity (PA) on a regular and adequate basis generates considerable benefits for health. In developed countries, the time spent doing PA is decreasing, whilst sedentary time (ST) is increasing. A multicomponent school-based intervention programme, called 'Sigue la Huella' (Follow the Footprint), was developed to reduce sedentary lifestyles and increase PA levels. This programme has proven to be effective in increasing the daily levels of moderate to vigorous PA, in decreasing ST and in improving motivational outcomes in secondary education students, in the city of Huesca (Spain). The study design was quasi-experimental, longitudinal and by cohorts, and it was carried out in four schools, two as an experimental group (n = 368) and two as a control group (n = 314). During the 25 months' intervention, this programme adopted a holistic approach aiming to create favourable environments to engage in PA, and the empowerment of students to get actively involved in the design and execution of the activities, assuming responsibility for managing and optimizing their own PA. The programme is theoretically based on the social-ecological model and self-determination theory, and it provided evidence for four actions or components that can be used in school-based PA promotion: tutorial action, Physical Education at school, dissemination of information and participation in institutional programmes and events. The aim of this article is to describe the main characteristics of the intervention programme that have proved to be effective with respect to the objectives proposed.


Oxidative stress induced in tobacco leaves by chloroplast over-expression of maize plastidial transglutaminase.
As part of a project aiming to characterize the role of maize plastidial transglutaminase (chlTGZ) in the plant chloroplast, this paper presents results on stress induced by continuous chlTGZ over-expression in transplastomic tobacco leaves. Thylakoid remodelling induced by chlTGZ over-expression in young leaves of tobacco chloroplasts has already been reported (Ioannidis et al. in Biochem Biophys Acta 1787:1215-1222, 2009). In the present work, we determined the induced alterations in the photosynthetic apparatus, in the chloroplast ultrastructure, and, particularly, the activation of oxidative and antioxidative metabolism pathways, regarding ageing and functionality of the tobacco transformed plants. The results revealed that photochemistry impairment and oxidative stress increased with transplastomic leaf age. The decrease in pigment levels in the transformed leaves was accompanied by an increase in H(2)O(2) and lipid peroxidation. The rise in H(2)O(2) correlated with a decrease in catalase activity, whereas there was an increase in peroxidase activity. In addition, chlTGZ over-expression lead to a drop in reduced glutathione, while Fe-superoxide dismutase activity was higher in transformed than in wild-type leaves. Together with the induced oxidative stress, the over-expressed chlTGZ protein accumulated progressively in chloroplast inclusion bodies. These traits were accompanied by thylakoid scattering, membrane degradation and reduction of thylakoid interconnections. Consequently, the electron transport between photosystems decrease in the old leaves. In spite of these alterations, transplastomic plants can be maintained and reproduced in vitro. These results are discussed in line with chlTGZ involvement in chloroplast functionality.


A hybrid linear/nonlinear training algorithm for feedforward neural networks.
This paper presents a new hybrid optimization strategy for training feedforward neural networks. The algorithm combines gradient-based optimization of nonlinear weights with singular value decomposition (SVD) computation of linear weights in one integrated routine. It is described for the multilayer perceptron (MLP) and radial basis function (RBF) networks and then extended to the local model network (LMN), a new feedforward structure in which a global nonlinear model is constructed from a set of locally valid submodels. Simulation results are presented demonstrating the superiority of the new hybrid training scheme compared to second-order gradient methods. It is particularly effective for the LMN architecture where the linear to nonlinear parameter ratio is large.


Insertion of transposons through the major cotransduction gap of Escherichia coli K-12.
The major cotransduction gap of the Escherichia coli chromosome extends from mini 31 to 34. We have inserted transposons through this gap which, by sequential transduction, link sbcA (min 29.8) with manA (min 35.7) and thus eliminate the gap. These results indicate that the length of DNA in the region, as measured by transduction, is not significantly different from the length obtained by conjugational time of entry. Since this segment of the E. coli chromosome has few known genes, these transposon insertions will be useful for genetic manipulations in the region of the gap. We describe the usefulness of these markers for rapidly mapping mutations which may be isolated in the region from min 27 to 37.


Regional colon transit in patients with dys-synergic defaecation or slow transit in patients with constipation.
To differentiate dys-synergic defaecation (DD) from normal function and slow transit constipation (STC). The medical records of 1411 patients evaluated by a single gastroenterologist over a 16-year period at a tertiary medical centre were reviewed. DD was characterised by anorectal manometry and balloon expulsion test. There were 390 patients with DD, and 61 with STC without DD. Transit data from 211 healthy individuals served as controls. The primary endpoints were overall colonic transit (geometric centre) at 24 h and 48 h (GC24 and GC48). Regional transit was measured as ascending colon half-emptying time (AC t(1/2)) and residual content in descending rectosigmoid colon and stool (DRS). Age and body mass index were similar in the STC and DD groups. DD was associated with smaller perineal descent and a greater difference in rectoanal pressure than STC. Both STC and DD were associated with lower GC24 and GC48 and slower AC t(1/2) than controls. GC48 differentiated DD from healthy controls (p<0.001) and DD from STC (p=0.007). AC t(1/2) values differentiated healthy controls from DD (p=0.006) and STC (p<0.001) and were associated with constipation (DD vs STC, p=0.007). The regional content of DRS at 48 h discriminated DD from STC (AUC=0.82) and stool content at 48 h, increasing the odds for DD over STC (OR per 5% in stool 2.4, 95% CI 1.1 to 5.5, p=0.03). DD is associated with delayed overall colonic transit at 48 h and AC t(1/2) compared with healthy controls. Regional scintigraphic transit profiles differentiate DD from STC and facilitate identification of a subgroup of patients with constipation.


The clinical spectrum of sport-related traumatic brain injury.
Acute and chronic sports-related traumatic brain injuries (TBIs) are a substantial public health concern. Various types of acute TBI can occur in sport, but detection and management of cerebral concussion is of greatest importance as mismanagement of this syndrome can lead to persistent or chronic postconcussion syndrome (CPCS) or diffuse cerebral swelling. Chronic TBI encompasses a spectrum of disorders that are associated with long-term consequences of brain injury, including chronic traumatic encephalopathy (CTE), dementia pugilistica, post-traumatic parkinsonism, post-traumatic dementia and CPCS. CTE is the prototype of chronic TBI, but can only be definitively diagnosed at autopsy as no reliable biomarkers of this disorder are available. Whether CTE shares neuropathological features with CPCS is unknown. Evidence suggests that participation in contact-collision sports may increase the risk of neurodegenerative disorders such as Alzheimer disease, but the data are conflicting. In this Review, the spectrum of acute and chronic sport-related TBI is discussed, highlighting how examination of athletes involved in high-impact sports has advanced our understanding of pathology of brain injury and enabled improvements in detection and diagnosis of sport-related TBI.


Myositis ossificans of infraorbital musculature in uncontrolled diabetic.
Myositis ossificans traumatica is a form of dystrophic calcification that leads to heterotopic ossification of intramuscular connective tissue. It is rare in the orofacial region. A history of trauma, conventional radiography and computed tomography, along with histopathological examination, can be used effectively to diagnose this condition. We present a unique case of infected myositis ossificans traumatica in the infraorbital region in an uncontrolled diabetic.


Changes in copper, zinc and cadmium distributions in the liver of Formosan squirrels with characteristic high copper accumulation.
We discovered previously that Formosan squirrels (Callosciurus erythraeus) accumulate copper (Cu) in their livers at levels averaging 1700 μg per dry g (approximately 420 μg per wet g). In the current study, we investigated the relationship between Cu accumulation and hepatic injury, and we determined the distribution and chemical form of Cu in the liver supernatant. In particular, we explored the role of metallothionein in the liver supernatant. We observed no significant differences in hepatic Cu concentration between squirrels that showed pathological changes in the liver and those that did not. Serum alanine aminotransferase activity did not increase with increasing hepatic Cu concentration. These results suggest that abnormal Cu accumulation in the livers of Formosan squirrels does not induce severe hepatic injury. We found that 26.7% of the Cu in the liver was distributed to the supernatant, and only 11.0% of the Cu in the liver was bound to metallothionein, suggesting that metallothionein in the hepatic supernatant does not contribute to detoxification of excess Cu in Formosan squirrels.


Stimulation in the dorsolateral prefrontal cortex changes subjective evaluation of percepts.
Nelson and Narens have proposed a metacognition model that dissociates the objective processing of information (object-level) and the subjective evaluation of the performance (i.e., the metalevel). Neurophysiological evidence also indicates that the prefrontal cortices (PFC) are the brain areas which perform the metalevel function [1]-[3]. A corresponding neural mechanism of Nelson and Narens's model, called dynamic filtering theory [4], [5], indicates that object-level processing is distributed in the posterior cortices and regulated by the prefrontal cortices with a filtering or gating mechanism to select appropriate signals and suppress inappropriate signals and noise. Based on this model, a hypothesis can be developed that, in the case of uncertainty or overloading of object-level processing, the prefrontal cortices will become more active in order to modulate signals and noise. This hypothesis is supported by a recent fMRI study [6] showing that the PFC (Brodmann area 9, BA9) was activated when subjects were overloaded in a bimodal attentional task, compared to a unimodal task. Here, we report a study showing that applying repetitive transmagnetic stimulation (rTMS) over the BA9 in order to interfere with its functional activity resulted in significant increas in guessed responses, compared to three other control conditions (i.e., no-TMS, sham TMS on BA9, and rTMS on Cz). The results are compatible with the dynamic filtering theory and suggest that a malfunction of the PFC would weaken the quality of meta-cognitive percepts and increase the number of guessed responses.


How technology-enhanced experiential e-learning can facilitate the development of person-centred communication skills online for health-care students: a qualitative study.
The COVID-19 pandemic brought a new challenge to medical education-health-care students had fewer opportunities to interact with and treat real patients in clinical settings. Interpersonal communication skills are often developed through human interaction and communication in person, and few studies have proposed feasible digital solutions to develop learners' communication skills. Consequently, understanding how medical teachers facilitate and implement online training programmes, with feasible instruments, to enhance students' learning effectiveness when in-person training is not possible is critical. By using a convenience sampling method, we recruited 26 health-care students from seven medical schools in Taiwan. Through semistructured interviews and the thematic analysis technique, we analysed the latent learning factors from the experience of implementing the technology-enhanced experiential e-learning tool 'mPath'. Three themes were generated: A) transferring theory into practice, B) increasing authenticity with analytical features, and C) maintaining autonomy with nondirective learning. The features accessibility, flexibility, intractability, and visualisation with the characteristics of remote accessibility and flexibility, repetition and retrospect, feedback requesting, and visualised analytical reports were considered to enhance learning outcomes. This study indicated how online training using technology could develop the participants' person-centred communication skills and what features influenced the learning outcomes of social distancing. mPath may be a feasible online learning approach and has provided inspiration for developing health-care students' communication skills when in-person training is not possible.


Noninvasive methods, including transient elastography, for the detection of liver disease in adults with cystic fibrosis.
Liver disease is the third leading cause of mortality in patients with cystic fibrosis (CF). However, detection of CF-associated liver disease (CFLD) is challenging. To evaluate the diagnostic performance of noninvasive methods for the detection of CFLD with a focus on transient elastography (TE). Patients at the Adult CF Clinic of Calgary and Southern Alberta (n=127) underwent liver stiffness measurement (LSM) by TE using the FibroScan (FS, Ecosens, France) M probe; aspartate aminotransferase to platelet ratio index (APRI) and FibroTest (FT) scores were also calculated. The diagnostic performance of these tools for the detection of CFLD (defined as two or more the following criteria: abnormal liver biochemistry, hepatomegaly or sonographic abnormalities other than steatosis) were compared using the area under ROC curves. Forty-seven percent of the cohort was male. The median age was 27 years (interquartile range [IQR] 22 to 37 years) and body mass index 21 kg⁄m(2) (IQR 19 kg⁄m(2) to 23 kg⁄m(2)); 25% of patients were on ursodeoxycholic acid and 12% had undergone lung transplantation. The prevalence of CFLD was 14% (n=18). FS was successful in all patients; one (0.8%) patient had poorly reliable results (IQR⁄M >30% and LSM ≥7.1 kPa). Compared with patients without CFLD (n=109), individuals with CFLD had higher median LSM according to FS (3.9 kPa [IQR 3.4 to 4.9 kPa] versus 6.4 kPa [IQR 4.4 to 8.0 kPa]), APRI (0.24 [IQR 0.17 to 0.31] versus 0.50 [IQR 0.22 to 1.18]) and FT scores (0.08 [IQR 0.05 to 1.5] versus 0.18 [IQR 0.11 to 0.35]; all P<0.05). Area under ROC curve for FS, APRI and FT for the detection of CFLD were 0.78 (95% CI 0.65 to 0.92), 0.72 (95% CI 0.56 to 0.87) and 0.76 (95% CI 0.62 to 0.90) (P not significant). At a threshold of >5.2 kPa, the sensitivity, specificity, positive and negative predictive values of LSM according to FS for detecting CFLD were 67%, 83%, 40% and 94%, respectively. FS, APRI and FT were useful noninvasive methods for detecting CFLD in adults.


Exploring the association between air pollution and Parkinson's disease or Alzheimer's disease: a Mendelian randomization study.
The correlation between air pollution and neurodegenerative diseases has garnered growing attention. Although observational studies have indicated a potential link between air pollution and neurodegenerative disease, establishing a causal relationship remains uncertain. To address this gap, we performed a two-sample Mendelian randomization analysis utilizing genetic instruments. This analysis aimed to investigate the causal connections between PM2.5, PM10, NO2, and NOX exposure and the occurrence of Parkinson's disease (PD) and Alzheimer's disease (AD). We implemented a series of filtering steps to identify suitable genetic instruments that demonstrated significant associations (P < 5 × 10-8) with PM2.5, PM10, NO2, and NOX. These instruments were derived from a comprehensive genome-wide association study (GWAS) encompassing up to 456,380 participants in the UK Biobank. To obtain summary statistics for PD (N = 482,730) and AD risk (N = 63,926), we utilized the most recent GWAS datasets available. For our primary analysis, we employed the inverse-variance weighted approach for two-sample MR. A multivariable MR (MVMR) was also performed to verify the impact of air pollution exposure on the risk of PD and AD. To ensure the robustness of our findings, sensitivity analyses and heterogeneity assessments were performed. In two-sample MR, by employing the inverse-variance weighted method, our result suggested that genetically NO2 exposure showed a significant association with an elevated risk of PD (OR = 4.07, 95% CI: 1.13 to 19.62, P = 0.034) and genetically PM10 exposure exhibited a significant association with a heightened risk of AD (OR = 1.93, 95% CI: 1.03-3.59, P = 0.040). Further MVMR analysis demonstrated that the causal effect between NO2 and PD disappeared (OR = 3.489, 95% CI: 0.01 to 2.1e + 03, P = 0.703), and only PM10 was associated with an increased risk of AD (OR = 6.500, 95% CI: 1.10 to 38.51, P = 0.039). Sensitivity analysis showed no detectable heterogeneity and pleiotropy (P > 0.05). Our findings demonstrate that NO2 and PM10 exposure may contribute to a risk of PD and AD, respectively. Future research is necessary to elucidate potential physiopathological mechanisms.


Efficient organic photovoltaics utilizing nanoscale heterojunctions in sequentially deposited polymer/fullerene bilayer.
A highly efficient sequentially deposited bilayer (SD-bilayer) of polymer/fullerene organic photovoltaic (OPV) device is developed via the solution process. Herein, we resolve two essential problems regarding the construction of an efficient SD-bilayer OPV. First, the solution process fabrication of the SD-bilayer is resolved by incorporating an ordering agent (OA) to the polymer solution, which improves the ordering of the polymer chain and prevents the bottom-layer from dissolving into the top-layer solution. Second, a non-planar heterojunction with a large surface area is formed by the incorporation of a heterojunction agent (HA) to the top-layer solution. Poly[[9-(1-octylnonyl)-9H-carbazole-2,7-diyl]-2,5-thiophenediyl-2,1,3-benzothiadiazole-4,7-diyl-2,5-thiophenediyl] (PCDTBT) is used for the bottom-layer and phenyl-C71-butyric-acid-methyl ester (PC70BM) is used for the top-layer. The SD-bilayer OPV produced utilizing both an OA and HA exhibits a power conversion efficiency (PCE) of 7.12% with a high internal quantum efficiency (IQE). We believe our bilayer system affords a new way of forming OPVs distinct from bulk heterojunction (BHJ) systems and offers a chance to reconsider the polymers that have thus far shown unsatisfactory performance in BHJ systems.


Loud speech in realistic environmental noise: phonetogram data, perceptual voice quality, subjective ratings, and gender differences in healthy speakers.
A new method for cancelling background noise from running speech was used to study voice production during realistic environmental noise exposure. Normal subjects, 12 women and 11 men, read a text in five conditions: quiet, soft continuous noise (75 dBA to 70 dBA), day-care babble (74 dBA), disco (87 dBA), and loud continuous noise (78 dBA to 85 dBA). The noise was presented over loudspeakers and then removed from the recordings in an off-line processing operation. The voice signals were analyzed acoustically with an automatic phonetograph and perceptually by four expert listeners. Subjective data were collected after each vocal loading task. The perceptual parameters press, instability, and roughness increased significantly as an effect of speaking loudly over noise, whereas vocal fry decreased. Having to make oneself heard over noise resulted in higher SPL and F0, as expected, and in higher phonation time. The total reading time was slightly longer in continuous noise than in intermittent noise. The women had 4 dB lower voice SPL overall and increased their phonation time more in noise than did the men. Subjectively, women reported less success making themselves heard and higher effort. The results support the contention that female voices are more vulnerable to vocal loading in background noise.


Differentiating Between Multiple Myeloma and Metastasis Subtypes of Lumbar Vertebra Lesions Using Machine Learning-Based Radiomics.
To determine whether machine learning based on conventional magnetic resonance imaging (MRI) sequences have the potential for the differential diagnosis of multiple myeloma (MM), and different tumor metastasis lesions of the lumbar vertebra. We retrospectively enrolled 107 patients newly diagnosed with MM and different metastasis of the lumbar vertebra. In total 60 MM lesions and 118 metastasis lesions were selected for training classifiers (70%) and subsequent validation (30%). Following segmentation, 282 texture features were extracted from both T1WI and T2WI images. Following regression analysis using the least absolute shrinkage and selection operator (LASSO) algorithm, the following machine learning models were selected: Support-Vector Machine (SVM), K-Nearest Neighbor (KNN), Random Forest (RF), Artificial Neural Networks (ANN), and Naïve Bayes (NB) using 10-fold cross validation, and the performances were evaluated using a confusion matrix. Matthews correlation coefficient (MCC), sensitivity, specificity, and accuracy of the models were also calculated. To differentiate MM and metastasis, 13 features in the T1WI images and 9 features in the T2WI images were obtained. Among the 10 classifiers, the ANN classifier from the T2WI images achieved the best performance (MCC = 0.605) with accuracy, sensitivity, and specificity of 0.815, 0.879, and 0.790, respectively, in the validation cohort. To differentiate MM and metastasis subtypes, eight features in the T1WI images and seven features in the T2WI images were obtained. Among the 10 classifiers, the ANN classifier from the T2WI images achieved the best performance (MCC = 0.560, 0.412, 0.449), respectively, with accuracy = 0.648; sensitivity 0.714, 0.821, 0.897 and specificity 0.775, 0.600, 0.640 for the MM, lung, and other metastases, respectively, in the validation cohort. Machine learning-based classifiers showed a satisfactory performance in differentiating MM lesions from those of tumor metastasis. While their value for distinguishing myeloma from different metastasis subtypes was moderate.


H-Mode operation in the START spherical tokamak
H-mode operation has been achieved in high current (I(p)>200 kA) plasmas in the START spherical tokamak for both neutral-beam-injection-heated and Ohmic discharges. The transition to H mode features the development of well-defined edge pedestals in density and temperature, which signifies the formation of an edge-transport barrier, and associated edge-localized modes. Recent operation at plasma currents exceeding 250 kA shows that these features are accompanied by increases in energy confinement time. This is the first clear demonstration of the H-mode regime in a spherical tokamak.


Matrix metalloproteinases as valid clinical targets.
The matrix metalloproteinase family of enzymes has been a pharmaceutical target for over 20 years. In that time, many drugs have been developed but none have successfully passed clinical trials. A significant problem has been development of dose-limiting side-effects that were revealed during long-term clinical trials in diseases such as arthritis and various cancers. There are, however, other clinical settings where evidence for MMP function contributing to the pathophysiology of disease is strong. A number of these settings will be discussed here together with evidence from animal models that MMP inhibition is a valid strategy to be considered. A major advantage with many of these settings is that drug exposure may not have to be long-term and/or systemic thus reducing the possibility that side-effects will stymie MMPI-based therapy.


Modelling inorganic and organic biocide leaching from CBA-amine (Copper-Boron-Azole) treated wood based on characterisation leaching tests.
Numerical simulation of the leaching behaviour of treated wood is the most pertinent and less expensive method for the prediction of biocides' release in water. Few studies based on mechanistic leaching models have been carried out so far. In this work, a coupled chemistry-mass transport model is developed for simulating the leaching behaviour of inorganic (Cu, B) and organic (Tebuconazole) biocides from CBA-amine treated wood. The model is based on experimental investigations (lab-scale leaching tests coupled with chemical and structural analysis). It considers biocides' interactions with wood solid components and with extractives (literature confirmed reactions), as well as transport mechanisms (diffusion, convection) in different compartments. Simulation results helped at identifying the main fixation mechanisms, like (i) direct complexation of Cu by wood-phenolic and -carboxylic sites (and not via monoethanolamine; complex) on lignin and hemicellulose and strong dependence on extractives' nature, (ii) pH dependent binding of tebuconazole on polarized OH moieties on wood. The role of monoethanolamine is to provide a pore-solution pH of about 7.5, when copper solubility is found to be weakest. The capability of the developed model to simulate the chemical and transport behaviour is the main result of this study. Moreover, it proved that characterization leaching tests (pH dependency and dynamic tests), combined with appropriate analytical methods are useful experimental tools. Due to its flexibility for representing and simulating various leaching conditions, chemical-transport model developed could be used to further simulate the leaching behaviour of CBA treated wood at larger scales.


Double-injection method for sequentially measuring cerebral blood flow with N-isopropyl-(123I)p-iodoamphetamine.
We investigated the accuracy of a double-injection method for sequentially measuring cerebral blood flow (CBF) with N-isopropyl-(123I)p-iodoamphetamine (IMP) in simulation studies based on patient data and in clinical studies. The unidirectional clearance of IMP from the blood to the brain (K1; nearly equal to CBF) in the first and second sessions was calculated by means of a microsphere model. The K1 values in the first session (K1I) were calculated from Cb(5)/Int_CaI, where Cb(5) and Int_CaI are values for brain radioactivity 5 min after the first injection and for arterial blood radioactivity obtained by 5-min continuous sampling. The K1 values in the second session (K1II) were calculated by means of the following four methods. Method 1: [Cb(tz + 5) - Cb(tz)]/[Int_CaII - Ca(tz) x 5], where Cb(tz+5) and Cb(tz) are the brain radioactivity levels 5 min after the second injection and at the time the second session was started (tz), respectively. Int_CaII and Ca(tz) are the arterial blood radioactivity levels obtained by 5-min continuous sampling after the second injection and at tz, respectively. Method 2: [Cb(tz + 5) - Cb(tz)]/[Int_CaI x R], where R is the injection dose ratio. Method 3: [Cb(tz + 5) - Cb(tz) x exp(- K1I x 5/lambda)]/Int_CaII, where lambda is the population averaged partition coefficient. Method 4: same as Method 3 except that K1I was replaced by K1II obtained by means of Method 2. Theoretically, Method 4 appeared to be the best of the four methods. The change in K1 during the second session obtained by Method 1 or 2 largely depended on R and tz, whereas Method 3 or 4 yielded a more reliable estimate than Method 1 or 2, without largely depending on R and tz. Since Method 2 was somewhat superior to other methods in terms of noninvasiveness and simplicity, it also had the potential for routine clinical use. The reproducibility of two sequential measurements of K1 was investigated with clinical data obtained without any intervention. The response of CBF to acetazolamide challenge was also assessed by the above four methods. The knowledge gained by this study may assist in selecting a method for sequentially measuring CBF with a double injection of IMP.


Aspirin use associated with amyotrophic lateral sclerosis: a total population-based case-control study.
The association of aspirin use and nonsteroid anti-inflammatory drug (NSAID) use with amyotrophic lateral sclerosis (ALS) risk is unclear. This study determined whether use of any individual compound is associated with ALS risk by conducting a total population-based case-control study in Taiwan. A total of 729 patients with newly diagnosed ALS who had a severely disabling disease certificate between January 1, 2002, and December 1, 2008, comprised the case group. These cases were compared with 7290 sex-, age-, residence-, and insurance premium-matched controls. Drug use by each Anatomical Therapeutic Chemical code was analyzed using conditional logistic regression models. False discovery rate (FDR)-adjusted P values were reported in order to avoid inflating false positives. Of the 1336 compounds, only the 266 with use cases exceeding 30 in our database were included in the screening analysis. Without controlling for steroid use, the analysis failed to reveal any compound that was inversely associated with ALS risk according to FDR criteria. After controlling for steroid use, we found use of the following compounds to be associated with ALS risk: aspirin, diphenhydramine (one of the antihistamines), and mefenamic acid (one of the NSAIDs). A multivariate analysis revealed that aspirin was independently inversely associated with ALS risk after controlling for diphenhydramine, mefenamic acid, and steroid use. The inverse association between aspirin and ALS was present predominately in patients older than 55 years. The results of this study suggested that aspirin use might reduce the risk of ALS, and the benefit might be more prominent for older people.


Determining the Effects of Differential Expression of GRKs and β-arrestins on CLR-RAMP Agonist Bias.
Signalling of the calcitonin-like receptor (CLR) is multifaceted, due to its interaction with receptor activity modifying proteins (RAMPs), and three endogenous peptide agonists. Previous studies have focused on the bias of G protein signalling mediated by the receptor and receptor internalisation of the CLR-RAMP complex has been assumed to follow the same pattern as other Class B1 G Protein-Coupled Receptors (GPCRs). Here we sought to measure desensitisation of the three CLR-RAMP complexes in response to the three peptide agonists, through the measurement of β-arrestin recruitment and internalisation. We then delved further into the mechanism of desensitisation through modulation of β-arrestin activity and the expression of GPCR kinases (GRKs), a key component of homologous GPCR desensitisation. First, we have shown that CLR-RAMP1 is capable of potently recruiting β-arrestin1 and 2, subsequently undergoing rapid endocytosis, and that CLR-RAMP2 and -RAMP3 also utilise these pathways, although to a lesser extent. Following this we have shown that agonist-dependent internalisation of CLR is β-arrestin dependent, but not required for full agonism. Overexpression of GRK2-6 was then found to decrease receptor signalling, due to an agonist-independent reduction in surface expression of the CLR-RAMP complex. These results represent the first systematic analysis of the importance of β-arrestins and GRKs in CLR-RAMP signal transduction and pave the way for further investigation regarding other Class B1 GPCRs.


Effect of Delirium on Physical Function in Noncardiac Thoracic Surgery Patients.
The effect of delirium on physical function in patients undergoing noncardiac thoracic surgery has not been well described and may differ from that in other surgical populations. To determine the effects of delirium on muscle strength and functional independence. The primary end point was change in Medical Research Council sum score (MRC-SS) by delirium status. A secondary analysis of data from a clinical trial involving English-speaking adults aged 18 years or older who were undergoing major noncardiac thoracic surgery. Exclusion criteria were history of schizophrenia, Parkinson disease, dementia, alcohol abuse, or neuroleptic malignant syndrome; haloperidol allergy; being pregnant or nursing; QT prolongation; and taking levodopa or cholinesterase inhibitors. Delirium was assessed twice daily using the Confusion Assessment Method for the Intensive Care Unit. Preoperatively and postoperatively, muscle strength was assessed using the modified MRC-SS and functional independence was assessed using the Katz scale of activities of daily living. Changes in MRC-SS and Katz score by delirium status were analyzed using the Fisher exact test. Seventy-three patients were included in the analysis. Median (interquartile range) MRC-SS and Katz score before surgery did not differ significantly between patients without and with delirium (MRC-SS: 30 [30-30] vs 30 [30-30], P > .99; Katz score: 6 [6-6] vs 6 [6-6], P = .63). The percentage of patients with a change in MRC-SS was similar in patients without and with delirium (17% vs 13%, respectively; P > .99). More patients in the delirium group had a change in Katz score (13% vs 0%, P = .04). Postoperative delirium was not associated with change in muscle strength. Follow-up studies using other muscle measures may be needed.


Thickness mapping of individual retinal layers and sectors by Spectralis SD-OCT in Autosomal Dominant Optic Atrophy.
To assess layer- and location-specific retinal thickness deficits in autosomal dominant optic atrophy (ADOA) using Spectralis SD-OCT. This cross-sectional study included 41 ADOA patients with OPA1 exon 28 (2826delT) mutation [age, 8.6-83.5 years; best-corrected visual acuity (BCVA), 8-89 Early Treatment Diabetic Retinopathy Study (ETDRS) letters] and 55 mutation-free first-degree relatives as healthy controls (age, 8.9-68.7; BCVA, 80-99). Participants underwent routine examination and optical coherence tomography (OCT) with segmentation of the whole retina, inner retinal layers (IRL) and outer retinal layers (ORL). Individual segmentation was performed of the perifoveal retinal nerve fibre layer (RNFL), ganglion cell layer (GCL), inner plexiform layer (IPL), inner nuclear layer (INL), outer plexiform layer (OPL), outer nuclear layer (ONL), retinal pigment epithelium (RPE) and the peripapillary RNFL. Combinations of layers and sectors were tested for their diagnostic significance. Only right eye data are presented. Statistical analysis was adjusted for age, gender, spherical equivalent, axial length and family clustering in a mixed model analysis. The perifoveal RNFL, GCL, IPL and the peripapillary RNFL were all significantly thinner in ADOA patients than in healthy controls (p < 0.0001). No statistical difference was found for other layers. The most prominent and diagnostically most valuable deficit was found in the GCL (-49.9%) in the 'nasal inner macula' (NIM) sector (-63%). Attenuation of the peripapillary RNFL was most significant in the temporal sector (-58.4%). In ADOA, retinal ganglion cells are most prominently reduced in the nasal perifoveal area of the GCL, which together with the temporal peripapillary RNFL area serves as the strongest diagnostic OCT marker.


Anti-obesity activity of human gut microbiota Bacteroides stercoris KGMB02265.
Obesity is a global health threat that causes various complications such as type 2 diabetes and nonalcoholic fatty liver disease. Gut microbiota is closely related to obesity. In particular, a higher Firmicutes to Bacteroidetes ratio has been reported as a biomarker of obesity, suggesting that the phylum Bacteroidetes may play a role in inhibiting obesity. Indeed, the genus Bacteroides was enriched in the healthy subjects based on metagenome analysis. In this study, we determined the effects of Bacteroides stercoris KGMB02265, a species belonging to the phylum Bacteroidetes, on obesity both in vitro and in vivo. The cell-free supernatant of B. stercoris KGMB02265 inhibited lipid accumulation in 3T3-L1 preadipocytes, in which the expression of adipogenic marker genes was repressed. In vivo study showed that the oral administration of B. stercoris KGMB02265 substantially reduced body weight and fat weight in high-fat diet induced obesity in mice. Furthermore, obese mice orally administered with B. stercoris KGMB02265 restored glucose sensitivity and reduced leptin and triglyceride levels. Taken together, our study reveals that B. stercoris KGMB02265 has anti-obesity activity and suggests that it may be a promising candidate for treating obesity.


Comparative assessment of erbium fiber ring lasers and reflective SOA linear lasers for fiber Bragg grating dynamic strain sensing.
Fiber Bragg grating (FBG) dynamic strain sensors using both an erbium-based fiber ring laser configuration and a reflective semiconductor optical amplifier (RSOA)-based linear laser configuration are investigated theoretically and experimentally. Fiber laser models are first presented to analyze the output characteristics of both fiber laser configurations when the FBG sensor is subjected to dynamic strains at high frequencies. Due to differences in the transition times of erbium and the semiconductor (InP/InGaAsP), erbium-doped fiber amplifier (EDFA)- and RSOA-based fiber lasers exhibit different responses and regimes of stability when the FBG is subjected to dynamic strains. The responses of both systems are experimentally verified using an adaptive photorefractive two-wave mixing (TWM) spectral demodulation technique. The experimental results show that the RSOA-FBG fiber linear cavity laser is stable and can stably respond to dynamic strains at high frequencies. An example application using a multiplexed TWM interferometer to demodulate multiple FBG sensors is also discussed.


[Vertical vestibulo-ocular interaction in unilateral labyrinth lesion (communication II)].
Vertical vestibuloocular reflex (VVOR) suppression was studied in 25 patients with unilateral labyrinthine disorders and 22 healthy individuals. The method of the suppression investigation was based on stimulation of the internal semicircular channels of the labyrinth by active sagittal nodding with glance fixation of the object moving with the head. VVOR suppression by glance reflex in patients with unilateral labyrinthine lesion is characterized by reduced reflex suppression effectiveness, especially on the side of the affected labyrinth, via a significant VVOR phase shift down.


Neuroprotective effects of crocin against traumatic brain injury in mice: Involvement of notch signaling pathway.
This study investigated the protective effects and mechanisms of crocin, an extract of saffron, on brain damage after traumatic brain injury (TBI) in mice. C57BL/6 mice were subjected to controlled cortical impact (CCI)-induced TBI. Pretreatment with crocin (20mg/kg) had protective effects against TBI, demonstrated by improved neurological severity score (NSS) and brain edema, decreased microglial activation and release of several pro-inflammatory cytokines, and decreased cell apoptosis. TBI activated Notch signaling, as shown by upregulated levels of Notch intracellular domain (NICD) and Hes1 mRNA, and pretreatment with crocin further increased Notch activation. However, pretreatment with DAPT (100mg/kg), a gamma-secretase inhibitor, significantly suppressed crocin-induced activation of Notch signaling and attenuated the ability of crocin to protect mice against TBI-induced inflammation and apoptosis. Therefore, these results suggest that crocin has neuroprotective effects against TBI in mice, and these effects are at least partially dependent on activation of Notch signaling.


Acute respiratory infections among individuals seeking outpatient care in the states of Washington and Michigan by pregnancy status, 2011-2016.
Acute respiratory infections (ARIs) during pregnancy are associated with poor maternal and fetal outcomes. Using U.S. Flu Vaccine Effectiveness Network data (2011-2016) from Washington and Michigan, we tested for respiratory viruses among pregnant and non-pregnant outpatients matched on age, site, and season (n = 191). Among all participants, detection of human coronaviruses and rhinovirus was common. We also observed differences in virus detection by pregnancy status; human coronaviruses and respiratory syncytial virus (RSV) were detected more frequently among pregnant and non-pregnant participants, respectively. The role of respiratory viruses in maternal ARI morbidity should be further characterized to inform implementation of prevention interventions including maternal vaccines.


Arsenic accumulation in edible vegetables and health risk reduction by groundwater treatment using an adsorption process.
The heavy metals transfer from the soil, where they accumulate, to the edible parts of the plants, and then, their entrance in the food chain can represent a source of concern for human health. Among heavy metals, arsenic is one of the most widespread in the soil of Lazio (central region of Italy), where the phytoavailable geogenic arsenic enters the food chain, with a dangerous exposition of the local population. In the first part of this work, plants of radish (Raphanus sativus L.) and lettuce (Lactuca sativa L.) were grown in protected culture in the experimental farm of CREA-AA, where they were daily treated with different concentrations of sodium arsenate dibasic heptahydrate in order to investigate differences in their arsenic accumulation capacities. In order to confirm the results achieved, in the second part of this study, the arsenic concentration was determined in commercial products obtained from contaminated areas of Lazio, and the potential exposition risk for human health through consumption of these widely consumed vegetables was estimated. The highest arsenic concentrations were found in the samples of lettuce. To evaluate the potential health risk from consumption of L. sativa and R. sativus, the estimated daily intake (EDI) for adults, adolescents, and elderly was calculated, finding that HRI (health risk index) index value for arsenic was low (< 1) in the case of chronic consumptions for all samples of radishes, and for the lettuces grown in the area of Viterbo. On the contrary, the lettuces obtained from Tuscania and Tarquinia presented very high concentrations of arsenic and a worrying HRI value. In order to reduce the risk of As toxicity in the people through consumption of the vegetables, the irrigation water should contain less than 0.1 mg As L-1. For this reason, the authors tested the application of red mud (RM) to remove As from groundwater before using it for the irrigation of radish and lettuce in greenhouse production.


[Composition of volatile thermo-destruction components of automobile brake straps].
The air contamination content was studied of the air samples taken from the driver's cabs of different vehicles at the time of sharp braking. The air samples contained: CO (0.7-9.7 mg/m3); n-hydrocarbons + divinyl (6.4-130.0 mg/m3); aromatic hydrocarbons (3.6-26.8 mg/m3); acrylonitrile (0.5-1.0 mg/m3) H2S (0.23-0.9 mg/m3); SO2 (1.5-7.05 mg/m3).


Drug disposition during pregnancy.
This review examines the literature on drug disposition during human pregnancy. Drugs are considered on the basis of their mode of excretion and hepatic extraction ratio in order to assess the general effects of pregnancy on drug disposition. Pregnancy increases clearance of drugs whose excretion is predominantly renal and related to creatinine clearance but fails to change clearance of parenterally administered drugs that are extensively metabolized by liver and have a high hepatic extraction ratio. The data are unclear as to how pregnancy influences the disposition of drugs extensively metabolized by liver with a low to intermediate hepatic extraction ratio.


The vertical gracilis myocutaneous flap for breast reconstruction in a massive weight loss patient.
The number of patients undergoing bariatric surgery is increasing worldwide. Different types of free flaps are often used for breast reconstruction following mastectomy. We present a not previously described case using a vertical myocutaneous gracilis flap for breast reconstruction in a massive weight loss patient. The patient was a 61 year-old woman who previously had a lumpectomy for an in situ ductile carcinoma of her left breast. Subsequently the patient underwent a full mastectomy in 2020 due to a recurrence. The massive weight loss population poses a challenge in reconstructive surgery, due to their higher risk of complications. However, we still believe free flaps should be considered as a valid option for breast reconstruction in these patients. Due to the often increased size of perforator vessels in these patients, other flaps may prove more suitable than the usually preferred ones.


Templated nanocarbons for energy storage.
The template carbonization method is a powerful tool for producing carbon materials with precisely controlled structures at the nanometer level. The resulting templated nanocarbons exhibit extraordinarily unique (often ordered) structures that could never be produced by any of the conventional methods for carbon production. This review summarizes recent publications about templated nanocarbons and their composites used for energy storage applications, including hydrogen storage, electrochemical capacitors, and lithium-ion batteries. The main objective of this review is to clarify the true significance of the templated nanocarbons for each application. For this purpose, the performance characteristics of almost all templated nanocarbons reported thus far are listed and compared with those of conventional materials, so that the advantages/disadvantages of the templated nanocarbons are elucidated. From the practical point of view, the high production cost and poor mass-producibility of the templated nanocarbons make them rather difficult to utilize; however, the study of their unique, specific, and ordered structures enables a deeper insight into energy storage mechanisms and the guidelines for developing energy storage materials. Thus, another important purpose of this work is to establish such general guidelines and to propose future strategies for the production of carbon materials with improved performance for energy storage applications.


Origin and effect of high-order dispersion in ultrashort pulse multiphoton microscopy in the 10 fs regime.
Short pulses can induce high nonlinear excitation, and thus they should be favorable for use in multiphoton microscopy. However, the large spectral dispersion can easily destroy the advantages of the ultrashort pulse if there is no compensation. The group delay dispersion (GDD), third-order dispersion, and their effects on the intensity and bandwidth of second-harmonic generation (SHG) signal were analyzed. We found that the prism pair used for compensating the GDD of the two-photon microscope actually introduces significant negative high-order dispersion (HOD), which dramatically narrowed down the two-photon absorption probability for ultrashort pulses. We also investigated the SHG signal after GDD and HOD compensation for different pulse durations. Without HOD compensation, the SHG efficiency dropped significantly for a pulse duration below 20 fs. We experimentally compared the SHG and two-photon excited fluorescence (TPEF) signal intensity for 11 fs versus 50 fs pulses, a pulse duration close to that commonly used in conventional multiphoton microscopy. The result suggested that after adaptive phase compensation, the 11fs pulse can yield a 3.2- to 6.0-fold TPEF intensity and a 5.1-fold SHG intensity, compared to 50 fs pulses.


Periapical Lesions Increase Macrophage Infiltration and Inflammatory Signaling in Muscle Tissue of Rats.
Our previous studies have shown that periapical lesions (PLs) in rats cause systemic disorders such as increased tumor necrosis factor-α plasma levels, insulin resistance, and impairment in insulin signal transduction in muscle tissue. However, the mechanisms involved in these alterations are not fully understood. Under chronic inflammatory conditions such as obesity, it has been shown that the skeletal muscle is affected by inflammation, and the number of resident macrophages that are associated with impairments of insulin action and sensitivity is increased. This study aimed to investigate the presence of macrophages, activation of inflammatory pathways in muscle tissue, glycemia, and insulinemia of rats with PLs. Sixty Wistar rats were distributed into a control group; a group with 1 PL (1PL), which was induced in the right maxillary first molar; and a group with 4 PLs (4PL), which were induced in the right upper and lower first and second molars. We quantified macrophage content by immunohistochemistry for the F4/80 protein. We evaluated Jun N-terminal kinase and IKKα/β phosphorylation status in the muscle tissue by Western blotting. Serum levels of lipopolysaccharide (LPS) and HSP70 and plasma levels of glucose and insulin were assessed by using commercial kits. The 1PL and 4PL groups showed increase in macrophage content, IKKα/β, and Jun N-terminal kinase phosphorylation status, serum LPS and HSP70 levels, and insulin resistance and no changes in glycemia and insulinemia compared with the control group. There was no difference in these parameters between the 1PL and 4PL groups. PLs promoted an increase in macrophage infiltration, activation of inflammatory pathways in muscle tissue, and serum concentrations of HSP70 and LPS in rats. The present study improves the knowledge on the impact of oral inflammations on the development of systemic alteration, which can induce insulin resistance.


Endophthalmitis after Cataract Surgery in the United States: A Report from the Intelligent Research in Sight Registry, 2013-2017.
To determine recent incidence and visual outcomes for acute-onset endophthalmitis after cataract surgery performed in the United States. Retrospective cohort study. United States cataract surgery patients, 2013-2017 (5 401 686 patients). Cases of acute-onset postoperative endophthalmitis occurring within 30 days after cataract surgery were identified using diagnosis codes in the American Academy of Ophthalmology IRIS (Intelligent Research in Sight) Registry database, drawn from electronic health records in ophthalmology practices across the nation. Annual and aggregate 5-year incidences were determined for all cataract surgeries and specifically for standalone procedures versus those combined with other ophthalmic surgeries. Patient characteristics were compared. Mean and median visual acuity was determined at 1 month preoperative as well as 1 week, 1 month, and 3 months postoperative among patients with and without endophthalmitis. Incidence of acute-onset postoperative endophthalmitis after cataract surgery. A total of 8 542 838 eyes underwent cataract surgery, 3629 of which developed acute-onset endophthalmitis (0.04%; 95% confidence interval, 0.04%-0.04%). Endophthalmitis incidence was highest among patients aged 0 to 17 years (0.37% over 5 years), followed by patients aged 18 to 44 years (0.18% over 5 years; P < 0.0001). Endophthalmitis occurred 4 times more often after combined cases (cataract with other ophthalmic procedures) than after standalone cataract surgeries (0.20% vs. 0.04% of cases), and occurred in 0.35% of patients receiving anterior vitrectomy. Mean 3-month postoperative visual acuity was 20/100 (median, 20/50) among endophthalmitis patients, versus a mean of approximately 20/40 (median, 20/30) among patients without endophthalmitis. However, 4% of endophthalmitis patients still achieved 20/20 or better visual acuity, and 44% achieved 20/40 or better visual acuity at 3 months. Acute-onset endophthalmitis occurred in 0.04% of 8 542 838 cataract surgeries performed in the United States between 2013 and 2017. Risk factors may include younger age, cataract surgery combined with other ophthalmic surgeries, and anterior vitrectomy. Visual acuity outcomes vary; however, patients can recover excellent vision after surgery. Big data from clinical registries like the IRIS Registry has great potential for evaluating rare conditions such as endophthalmitis, including developing benchmarks, longer-term time trend investigation, and comprehensive analysis of risk factors and prophylaxis.


The interaction of highly helical structural mutants with the NOP receptor discloses the role of the address domain of nociceptin/orphanin FQ.
Nociceptin is a heptadecapeptide whose sequence is similar to that of Dynorphin A, sharing a message domain characterized by two glycines and two aromatic residues, and a highly basic C-terminal address domain but, in spite of these similarities, displays no opioid activity. Establishing the relative importance of the message and address domains of nociceptin has so far been hampered by its extreme conformational flexibility. Here we show that mutants of this peptide, designed to increase the helical content in the address domain, can be employed to explain the mode of interaction with the NOP receptor. Nociceptin analogues in which Ala residues are substituted with aminoisobutyric acid (Aib) show a substantial increment of activity in their interaction with the NOP receptor. The increment of biological activity was attributed to the well-documented ability of Aib to induce helicity. Here we have verified this working hypothesis by a conformational investigation extended to new analogues in which the role of Aib is taken up by Leu. The NMR conformational analysis confirms that all Ala/Aib peptides as well as [Leu(7,11)]-N/OFQ-amide and [Leu(11,15)]-N/OFQ-amide mutants (N/OFQ=nociceptin/orphanin FQ) have comparable helix content in helix-promoting media. We show that the helical address domain of nociceptin can place key basic residues at an optimal distance from complementary acidic groups of the EL(2) loop of the receptor. Our structural data are used to rationalize pharmacological data which show that although [Leu(11,15)]-N/OFQ-amide has an activity comparable to those of Ala/Aib peptides, [Leu(7,11)]-N/OFQ-amide is less active than N/OFQ-amide. We hypothesize that bulky residues cannot be hosted in or near the hinge region (Thr(5)-Gly(6)-Ala(7)) without severe steric clash with the receptor. This hypothesis is also consistent with previous data on this hinge region obtained by systematic substitution of Thr, Gly, and Ala with Pro.


Health effects of adverse childhood events: Identifying promising protective factors at the intersection of mental and physical well-being.
Research documents how exposure to adversity in childhood leads to negative health outcomes across the lifespan. Less is known about protective factors - aspects of the individual, family, and community that promote good health despite exposure to adversity. Guided by the Resilience Portfolio Model, this study examined protective factors associated with physical health in a sample of adolescents and adults exposed to high levels of adversity including child abuse. A rural community sample of 2565 individuals with average age of 30 participated in surveys via computer assisted software. Participants completed self-report measures of physical health, adversity, and a range of protective factors drawn from research on resilience. Participants reporting a greater burden of childhood victimization and current financial strain (but not other adverse life events) had poorer physical health, but those with strengths in emotion regulation, meaning making, community support, social support, and practicing forgiveness reported better health. As hypothesized, strengths across resilience portfolio domains (regulatory, meaning making, and interpersonal) had independent, positive associations with health related quality of life after accounting for participants' exposure to adversity. Prevention and intervention efforts for child maltreatment should focus on bolstering a portfolio of strengths. The foundation of the work needs to begin with families early in the lifespan.


The relationship between lactose tolerance test results and symptoms of lactose intolerance.
A standard for the assessment of lactose malabsorption does not exist. As measured by lactose tolerance tests, insufficient increase in blood glucose or increased breath hydrogen (H2) excretion after lactose ingestion is regarded as pathological. In this study, we have tried to elucidate the relationship between lactose tolerance test results and symptoms after a lactose challenge. This relationship might be an indicator for the validity of the test. In a prospective study, 309 consecutive patients with suspected lactose malabsorption underwent a lactose tolerance test. After consumption of 50 g of lactose, blood glucose and breath H2 concentrations were measured. During the test (240 min), the severity of bloating, flatulence, abdominal distention, and diarrhea were semiquantitatively scored as 0, 1, or 2. The individual sum of these four scores was calculated and denoted as the total symptom score (TSS). All subjects were classified according to their TSS to compare symptoms with peak breath-H2 concentration and change in blood glucose concentration, respectively. The glucose and breath H2 response were pathological in 51.1 and 39.5% of cases, respectively. A stepwise increase in TSS of 1 point was associated with a significant increase (p < 0.05) in mean peak H2 concentration. However, a significantly lower glucose increment compared with patients with a TSS of 0 was found only in patients with a TSS of 2 or 4. The mean symptom score differed significantly between the positive and negative breath tests (p < 0.001), but did not differ between the positive and negative glucose response results. This study shows that GI symptoms after a lactose challenge are strongly associated with the amount of H2 excretion. The relationship between the increase in glucose concentration and symptoms after a lactose load is less evident. Thus, the H2 breath test seems to be superior to the measurement of blood glucose increment as a diagnostic tool in lactose malabsorption, although the true predictive value of this test only can be determined after a period of dietary treatment.


Efficacy of amlodipine/olmesartan medoxomil ± hydrochlorothiazide in patients aged ≥ 65 or < 65 years with uncontrolled hypertension on prior monotherapy.
Our subanalysis evaluated the efficacy of an amlodipine/olmesartan medoxomil (AML/OM)-based titration regimen to achieve blood pressure (BP) goals among patients aged ≥ 65 years. In this dose-titration study, 999 patients (228 of whom were aged ≥ 65 years) with uncontrolled BP after ≥ 1 month of monotherapy were switched to fixed-dose AML/OM 5/20 mg and uptitrated every 4 weeks to AML/OM 5/40 and 10/40 mg to achieve BP < 120/70 mm Hg. Patients were subsequently uptitrated every 4 weeks to AML/OM 10/40 mg + hydrochlorothiazide (HCTZ) 12.5 mg and AML/OM 10/40 mg + HCTZ 25 mg to achieve BP < 125/75 mm Hg. The primary efficacy endpoint (ie, the cumulative percentage of patients achieving the seated cuff systolic BP goal of < 140 mm Hg [or < 130 mm Hg for patients with type 2 diabetes mellitus] during first 12 weeks of treatment) was achieved by 76.7% and 75.6% of patients aged ≥ 65 (ie, 65-80) years and < 65 (ie, 18-64) years, respectively. For patients aged ≥ 65 and < 65 years, mean seated cuff BP changes from baseline during the titration periods ranged from -14.5/-7.8 mm Hg and -14.1/-7.7 mm Hg, respectively, for AML/OM 5/20 mg, to -28.5/-12.4 and -24.5/-14.0 mm Hg for AML/OM 10/40 mg + HCTZ 25 mg (all P < 0.0001). By week 20, the cumulative BP threshold of < 140/90 mm Hg was achieved by 86.8% and 84.2% of patients aged ≥ 65 and < 65 years, respectively. Among patients aged ≥ 65 years who underwent ambulatory BP monitoring, mean 24-hour, daytime, and nighttime ambulatory BP all decreased from baseline at weeks 12 and 20 (all P < 0.0001). At weeks 12 and 20, the mean 24-hour American Heart Association-recommended ambulatory BP target of < 130/80 mm Hg was achieved in 80.4% and 97.4% of patients aged ≥ 65 years, respectively, and in 71.3% and 88.8% of patients aged < 65 years, respectively. The majority of adverse events were mild to moderate in intensity and the incidence of treatment-emergent adverse events determined by clinical laboratory evaluation was low. The incidence of drug-related hypotension and orthostatic hypotension in patients aged ≥ 65 years was 2.2% and 0.0%, respectively, and in patients aged < 65 years, was 2.3% and 0.3%, respectively. Fixed-dose AML/OM ± HCTZ combination therapy effectively lowered BP and achieved BP goals in patients aged ≥ 65 and < 65 years with hypertension previously uncontrolled on monotherapy. The treatment regimen was well tolerated irrespective of patient age.


Biomolecular Corona Stability in Association with Plasma Cholesterol Level.
Biomolecular corona is spontaneously formed on the surface of nanoparticles (NPs) when they are in contact with biological fluids. It plays an important role in the colloidal stability of NPs, which is of importance for most of their medical applications and toxicity assessment. While typical studies use either blood plasma or serum from a pooled biobank, it is unclear whether differences in the media, such as cholesterol level or protein concentration, might affect the NP colloidal stability and corona composition. In this study, the silica corona was prepared at particularly low plasma concentrations (3%, v/v-1.98 mg/mL) to identify the critical roles of the protein mass/NP surface ratio and the level of plasma cholesterol on the corona protein pattern and particle stability. While depending on the plasma dilution factor, the corona protein composition could be controlled by keeping the protein/NP constant. The NP colloidal stability was found to strongly correlate with the level of cholesterol in human plasma, particularly due to the high enrichment of high-density lipoprotein (HDL) and low-density lipoprotein (LDL) in the corona. A cohort study on plasma samples from individuals with known cholesterol levels was performed to highlight that association, which could be relevant for all corona systems enriched with the LDL.


[Clinical and epidemiological behavior of human leptospirosis in Los Palacios municipality, Pinar del Rio, Cuba].
A descriptive-retrospective study was performed to find out some epidemiological aspects of leptospirosis in Los Palacios municipality in the period January 1996 to December 1998. Data were obtained from an epidemiological survey of leptospirosis cases, which was made y the Municipal Hygiene and Epidemiological Center. The results were 94% of cases were males; the most affected aged group was 14-19y (21,8%). Fever (100%), myalgia(84%) and arthralgia (62%) were the most common clinical findings. Rice harvesting work (87,5%) was significantly associated to the onset of disease.


First evidence of TRPV5 and TRPV6 channels in human parathyroid glands: possible involvement in neoplastic transformation.
The parathyroid glands play an overall regulatory role in the systemic calcium (Ca(2+)) homeostasis. The purpose of the present study was to demonstrate the presence of the Ca(2+) channels transient receptor potential vanilloid (TRPV) 5 and TRPV6 in human parathyroid glands. Semi-quantitative and quantitative PCR was carried out to evaluate the presence of TRPV5 and TRPV6 mRNAs in sporadic parathyroid adenomas and normal parathyroid glands. Western blot and immunocytochemical assays were used to assess protein expression, cellular localization and time expression in primary cultures from human parathyroid adenoma. TRPV5 and TRPV6 transcripts were then identified both in normal and pathological tissues. Predominant immunoreactive bands were detected at 75-80 kD for both vanilloid channels. These channels co-localized with the calcium-sensing receptor (CASR) on the membrane surface, but immunoreactivity was also detected in the cytosol and around the nuclei. Our data showed that western blotting recorded an increase of protein expression of both channels in adenoma samples compared with normal glands suggesting a potential relation with the cell calcium signalling pathway and the pathological processes of these glands.


Truncated ETV1, fused to novel tissue-specific genes, and full-length ETV1 in prostate cancer.
In this study, we describe the properties of novel ETV1 fusion genes, encoding N-truncated ETV1 (dETV1), and of full-length ETV1, overexpressed in clinical prostate cancer. We detected overexpression of novel ETV1 fusion genes or of full-length ETV1 in 10% of prostate cancers. Novel ETV1 fusion partners included FOXP1, an EST (EST14), and an endogenous retroviral repeat sequence (HERVK17). Like TMPRSS2, EST14 and HERVK17 were prostate-specific and androgen-regulated expressed. This unique expression pattern of most ETV1 fusion partners seems an important determinant in prostate cancer development. In transient reporter assays, full-length ETV1 was a strong transactivator, whereas dETV1 was not. However, several of the biological properties of dETV1 and full-length ETV1 were identical. On stable overexpression, both induced migration and invasion of immortalized nontumorigenic PNT2C2 prostate epithelial cells. In contrast to dETV1, full-length ETV1 also induced anchorage-independent growth of these cells. PNT2C2 cells stably transfected with dETV1 or full-length ETV1 expression constructs showed small differences in induced expression of target genes. Many genes involved in tumor invasion/metastasis, including uPA/uPAR and MMPs, were up-regulated in both cell types. Integrin beta3 (ITGB3) was clearly up-regulated by full-length ETV1 but much less by dETV1. Based on the present data and on previous findings, a novel concept of the role of dETV1 and of full-length ETV1 overexpression in prostate cancer is proposed.


[Social representations and history: theoretical and methodological principles for public health].
This article discusses the concept of social representations on health and illness from a social/historical point of view, to provide the means for developing research in the public health care domain. To situate this discussion, the analysis was based on field research health issues, attempting to demarcate a theoretical frame of reference with the help of reference literature in sociology and cultural history, while also contemplating cultural anthropological studies conducted in the medical field.


Sudden cardiac death: a modern pathology approach to hypertrophic cardiomyopathy.
Hypertrophic cardiomyopathy is one of the most common causes of sudden cardiac death among young adults and adolescents. Unfortunately, the first manifestation of the condition may be sudden death during exertion, such as sporting activities. Other clinical symptoms include exertional dyspnea, angina, and syncope. Postmortem examination often reveals asymmetrical septal thickening and mural plaque formation in the left ventricular outflow tract. Histologic analysis shows cardiac myocyte hypertrophy, myofiber disarray, and interstitial and replacement fibrosis. Molecular analysis for known genetic abnormalities is essential to genetic counseling of living relatives of decedents to assess and reduce the risk of sudden cardiac death from hypertrophic cardiomyopathy.


Position statement on the non-invasive diagnosis of Patients with ATTR Cardiac Amyloidosis, endorsed by the Hellenic Society of Nuclear Cardiology, for the Nuclear Medicine practitioners.
Cardiac amyloidosis is a rare condition characterized by the accumulation of abnormal proteins called amyloids in the heart tissue. These amyloids can disrupt the normal functioning of the heart and lead to a variety of symptoms and complications.


Phlebotomine sand flies and Leishmania species in a focus of cutaneous leishmaniasis in Algeria.
Cutaneous leishmaniasis is a disease caused by various Leishmania spp., which are transmitted by phlebotomine sand flies. Algeria is one of the most affected countries, with thousands of cutaneous leishmaniasis cases registered every year. From March to November of 2016 and 2017, sand flies were collected in 12 municipalities in Setif province, North-Eastern Algeria. Sand flies were identified and females were tested by PCR for detecting Leishmania DNA. Additionally, cutaneous leishmaniasis cases notified during the study period were analysed. Out of 1804 sand flies collected, 1737 were identified as belonging to seven species, with Phlebotomus perniciosus (76.2%), Ph. papatasi (16.7%) and Ph. sergenti (5.0%) being the most common species, representing together 97.9% of the collected specimens. The remaining specimens were identified as Sergentomyia minuta, Se. fallax, Ph. longicuspis and Ph. perfiliewi. The number of sand flies collected monthly was positively correlated with temperature. Out of 804 females tested, nine Ph. perniciosus (1.1%) scored positive for Leishmania infantum (n = 5), L. major (n = 3) and L. tropica (n = 1), respectively. During the study period, 34 cutaneous leishmaniasis cases were notified in Setif, of which 58.8% were patients residing in two urban and peri-urban municipalities and 41.2% in rural areas. The finding of Ph. perniciosus as the most abundant species in Setif suggests that this sand fly may be adapted to different biotopes in the North-East region of Algeria. The detection of different Leishmania spp. in Ph. perniciosus suggests a complex epidemiological picture of cutaneous leishmaniasis in Setif, with the involvement of different etiological agents and possibly with different reservoir hosts and vectors.


Dysregulated light/dark cycle impairs sleep and delays the recovery of patients in intensive care units: A call for action for COVID-19 treatment.
Exposure to an adequate light-dark cycle is important for the speedy recovery of hospitalized and institutionalized patients. Light exposure, including natural light, offers several health benefits to both patients and nursing staff. This includes physical (e.g., decreased confusion and disorientation) and mental health benefits (e.g., prevention of depression) and a reduction in the hospital stay. Improved alertness and performance can also be noted among hospital staff. In this commentary, we discuss disrupting factors that include light during the nighttime along with noise and physical procedures on the patient and others. We then address some of the important steps that can be undertaken to restore a more normal environment for patients in the intensive care unit, which can be particularly important for COVID-19 patients.


Antagonistic roles for phospholipase D activities in B cell signaling: while the antigen receptors transduce mitogenic signals via a novel phospholipase D activity, phosphatidylcholine-phospholipase D mediates antiproliferative signals.
Cross-linking of the Ag receptors on B cells induces DNA synthesis and proliferation. Butanol trap experiments suggest that one or more phospholipase D activities play a key role in this process. Although phosphatidylcholine-phospholipase D has been shown to play a central role in the transduction of proliferative responses for a wide variety of calcium-mobilizing receptors, we show that the Ag receptors are not coupled to this phospholipase. In addition, phosphatidylcholine-phospholipase D is not stimulated under conditions that mimic T cell-dependent B cell activation. In contrast, ATP, which inhibits surface Ig (sIg)-mediated DNA synthesis in murine B cells via P2-purinoceptors, activates phosphatidylcholine-phospholipase D. Phosphatidylcholine-phospholipase D is therefore associated with antiproliferative signal transduction in mature B cells, but it does not transduce early signals associated with sIg-mediated growth arrest or apoptosis in immature B cells. Mitogenic stimulation of sIg is, however, coupled to a novel nonphosphatidylcholine-hydrolyzing phospholipase D activity. The resultant sIg-generated phosphatidic acid, unlike the phosphatidylcholine-derived phosphatidic acid generated via the purinoceptors, is converted to diacylglycerol. These data provide the first evidence that while the novel sIg-coupled phospholipase D and resultant diacylglycerol generation may play a role in B cell survival and proliferation, phosphatidylcholine-phospholipase D may transduce, via phosphatidic acid, negative immunomodulatory signals in mature B lymphocytes.


Climate-dependent effectiveness of nonpharmaceutical interventions on COVID-19 mitigation.
Environmental factors have a significant impact on the transmission of infectious diseases. Existing results show that the novel coronavirus can persist outside the host. We propose a susceptible-exposed-presymptomatic-infectious-asymptomatic-recovered-susceptible (SEPIARS) model with a vaccination compartment and indirect incidence to explore the effect of environmental conditions, temperature and humidity, on the transmission of the SARS-CoV-2 virus. Using climate data and daily confirmed cases data in two Canadian cities with different atmospheric conditions, we evaluate the mortality rates of the SARS-CoV-2 virus and further estimate the transmission rates by the inverse method, respectively. The numerical results show that high temperature or humidity can be helpful in mitigating the spread of COVID-19 during the warm summer months. Our findings verify that nonpharmaceutical interventions are less effective if the virus can persist for a long time on surfaces. Based on climate data, we can forecast the transmission rate and the infection cases up to four weeks in the future by a generalized boosting machine learning model.


The effect of polysorbate 20 on solubility and stability of candesartan cilexetil in dissolution media.
The addition of polysorbate 20 (T20) is required to achieve "sink" conditions during a dissolution test for tablets with candesartan cilexetil (CC). Polysorbate 20 (0.35%-0.7% w/w) added to 0.05 mol/L of phosphate buffer pH 6.5 dramatically increased the apparent solubility of the drug from 0.8 μg/ml even to 353 μg/ml, while its effect in lower pH or in water was much smaller (20 μg/ml in pH 4.5). The increased concentration of phosphate salts (0.2 mol/l) at pH 6.5 in the presence of 0.7% of polysorbate 20, resulted in further increase of candesartan cilexetil solubility to 620 μg/ml. The change of pH from 1.2 to 7.4 resulted in a 1.5-fold increase of the activation energy and, depending on temperature, 8-14-fold decrease of the degradation rate. When polysorbate 20 increased the activation energy 2-fold, independent of pH, it protected candesartan cilexetil from degradation; however, this effect was temperature dependent and was very small at 310 K-the degradation rate in pH 6.5 decreased by 13% only. It was calculated that in the phosphate buffer pH 6.5 with polysorbate, one can expect during 24 h the degradation at the level of 9.3%, thus a flow-through dissolution apparatus was recommended for testing prolonged release dosage forms.


Near-Infrared Illumination of Native Tissues for Image-Guided Surgery.
Our initial efforts to prepare tissue-specific near-infrared (NIR) fluorescent compounds generated successful correlation between physicochemical properties and global uptake in major organs after systemic circulation and biodistribution. Herein, we focus on the effects on biodistribution based on modulating electronic influencing moieties from donating to withdrawing moieties at both the heterocyclic site and through meso-substitution of pentamethine cyanine fluorophores. These selected modifications harnessed innate biodistribution pathways through the structure-inherent targeting, resulting in effective imaging of the adrenal glands, pituitary gland, lymph nodes, pancreas, and thyroid and salivary glands. These native-tissue contrast agents will arm surgeons with a powerful and versatile arsenal for intraoperative NIR imaging in real time.


[Reaction of rat pulmonary macrophages to stimulation by zymosan].
Female Wistar rats weighing 200-250 g received 0.1 mg/g of zymosan particles intravenously. 2 days later the foci consisting of accumulated mononuclears developed in the lungs. On day 5 after zymosan injection they assumed granulocyte-like appearance. This coincided with more than three-fold increase of interstitial lung macrophages over-loaded with colloidal carbon particles. The delivery of cells into alveolar space also increased two-fold on the 2nd and three-fold on the 5th day after stimulation due to an influx of monocyte-macrophage elements. The clearance rate of inert colloidal particles through mononuclear phagocyte system increased more than two-fold on the 2nd and three-fold on the 5th day following stimulation. The initial figures were restored by day 14. Thus, activated macrophages play an essential role in mononuclear infiltration of the lung. The specificity of infiltrate development may be evaluated by the cellular content of bronchoalveolar washouts.


Enzymatic hydrolysis of cellulose: Visual characterization of the process.
Cellulose from the Gram-negative bacterium Acetobacter xylinum has been used as a model substrate for visualizing the action of cellulase enzymes from the fungus Trichoderma reesei. High-resolution electron microscopy reveals that A. xylinum normally produces a ribbon of cellulose that is a composite of bundles of crystalline microfibrils. Visual patterns of the process of cellulose degradation have been established. Enzymes are initially observed bound to the cellulose ribbon. Within 10 min, the ribbon is split along its long axis into bundles of microfibrils which are subsequently thinned until they are completely dissolved within 30 min. Incubations with purified components of the cellulase enzyme system produced less dramatic changes in ribbon structure. Purified 1,4-beta-D-glucan cellobiohydrolase I (D) (EC 22.214.171.124) produced no visible change in cellulose structure. Purified endo-1,4-beta-D-glucanase IV (EC 22.214.171.124) produced some splaying of ribbons into microfibril bundles. In both cases, whole ribbons were present even after 60 min of incubation, visually confirming the synergistic mode of action of these enzymes.


Microsatellites for the marsh fritillary butterfly: de novo transcriptome sequencing, and a comparison with amplified fragment length polymorphism (AFLP) markers.
Until recently the isolation of microsatellite markers from Lepidoptera has proved troublesome, expensive and time-consuming. Following on from a previous study of Edith's checkerspot butterfly, Euphydryas editha, we developed novel microsatellite markers for the vulnerable marsh fritillary butterfly, E. aurinia. Our goal was to optimize the process in order to reduce both time and cost relative to prevailing techniques. This was accomplished by using a combination of previously developed techniques: in silico mining of a de novo assembled transcriptome sequence, and genotyping the microsatellites found there using an economic method of fluorescently labelling primers. In total, we screened nine polymorphic microsatellite markers, two of which were previously published, and seven that were isolated de novo. These markers were able to amplify across geographically isolated populations throughout Continental Europe and the UK. Significant deviations from Hardy-Weinberg equilibrium were evident in some populations, most likely due to the presence of null alleles. However, we used an F(st) outlier approach to show that these markers are likely selectively neutral. Furthermore, using a set of 128 individuals from 11 populations, we demonstrate consistency in population differentiation estimates with previously developed amplified fragment length polymorphism (AFLP) markers (r = 0.68, p<0.001). Rapid development of microsatellite markers for difficult taxa such as Lepidoptera, and concordant results with other putatively neutral molecular markers, demonstrate the potential of de novo transcriptional sequencing for future studies of population structure and gene flow that are desperately needed for declining species across fragmented landscapes.


Treatment of pediatric uveitis with adalimumab: the MERSI experience.
To evaluate adalimumab therapy in children with uveitis. The electronic health records of pediatric patients diagnosed with uveitis and treated with adalimumab therapy were reviewed retrospectively. Demographic information, site and degree of intraocular inflammation, visual acuity, underlying systemic disorders, duration of therapy, side effects, and ability to obtain steroid-free remission were recorded. A total of 17 patients were included, 16 patients with anterior uveitis and 1 with panuveitis; 14 patients had bilateral disease. Juvenile idiopathic arthritis had been diagnosed in 14 patients, sarcoidosis in 1 patient, and idiopathic etiology in 2 patients. Of the 17 patients, 13 (about 77%) achieved steroid-free remission, and 4 did not. Six patients flared after discontinuation of adalimumab, with evidence of inflammation noted 3-7 months later. Adalimumab therapy was of 12-64 months' duration (mean, 36 months). At the time of initiation, 14 patients were using other agents concomitantly with adalimumab; 3 patients were on adalimumab monotherapy. At 1 year's follow-up, 12 patients were using combination therapy, and 3 patients were on adalimumab monotherapy: 11 patients had no evidence of inflammation. Side effects included pain at site of injection in 3 patients, anemia in 1 patient, and depression in 1 patient. In our study cohort, adalimumab was effective in inducing steroid-free remission. It was well tolerated, especially in combination with other immunomodulatory agents. The dosing and the interval can be adjusted to further improve inflammation control.


Thinking beyond new clinical guidelines: update in hypertension.
Hypertension is one of the most common conditions managed by generalists and is a major risk factor for multiple conditions. Surrounded by great debate, the committee appointed to the Eighth Joint National Committee published their suggestions for new hypertension treatment guidelines in early 2014. We suggest a new target blood pressure (BP) for the general population older than 60 years of less than 150/90 mm Hg, up from less than 140/90 mm Hg as recommended by the Seventh Joint National Committee, and in diabetic patients, a goal of less than 140/90 mm Hg, up from the Seventh Joint National Committee recommendation of less than 130/80 mm Hg. Regardless of the BP target recommendations suggested by the Eighth Joint National Committee and other organizations, obtaining accurate BP readings and recognizing white-coat and masked hypertension is imperative. Home and ambulatory BP monitoring are useful tools in addition to proper in-office BP readings. The optimal care of the hypertensive patient involves accurate BP characterization, careful use of guidelines, and good clinical judgment.