Perinatal outcome in relation to fetal sex in offspring to mothers with pre-gestational and gestational diabetes--a population-based study.
The objective of the present study was to investigate if perinatal outcome differs with fetal sex in pregnancies with maternal Type 1 diabetes, Type 2 diabetes or gestational diabetes. This was a population-based cohort study, with data from the Medical Birth Registry in Sweden throughout the period 1998-2007. Singleton pregnancies with maternal Type 1 diabetes (n = 4092), Type 2 diabetes (n = 412) and gestational diabetes (n = 8602) were identified based on the International Classification of Diseases, 10th edition code. For comparison, 905 565 pregnancies without diabetes were included. The primary outcome was a composite outcome, consisting of any of the following diagnoses: perinatal mortality rate, major malformation, preterm delivery, acute respiratory disorders and neonatal hypoglycaemia. Logistic regression was used to obtain odds ratios for adverse outcomes in male offspring within the diabetic and reference cohorts, respectively. In pregnancies with diabetes, maternal characteristics did not differ with fetal sex, except for a higher rate of Caesarean delivery in male offspring of women with Type 1 diabetes. Male infants to mothers with Type 1 diabetes and gestational diabetes had significantly increased odds of respiratory disorders [adjusted odds ratio (confidence interval) Type 1 diabetes: 1.50 (1.12-2.02); gestational diabetes: 1.81 (1.27-2.57)]. Male infants to mothers with gestational diabetes also had significantly increased odds of major malformations [adjusted odds ratio: 1.44 (1.07-1.93)]. In offspring of mothers with Type 2 diabetes, odds ratios of most outcomes were higher in male infants; however, not significantly different from female infants. In pregnancies without diabetes, male infants had significantly higher odds of all adverse outcomes, except perinatal mortality rate. The risk of adverse perinatal outcome in offspring of mothers with Type 1 diabetes and gestational diabetes did not differ by sex, except for a higher risk in male infants for respiratory disorders. The risk of major malformations was also significantly increased in male offspring to mothers with gestational diabetes. In offspring of mothers with Type 2 diabetes, no significant differences between sexes were found.


Exploration of the forbidden regions of the Ramachandran plot (ϕ-ψ) with QTAIM.
A new QTAIM interpretation of the Ramachandran plot is formulated from the most and least facile eigenvectors of the second-derivative matrix of the electron density with a set of 29 magainin-2 peptide conformers. The presence of QTAIM eigenvectors associated with the most and least preferred directions of electronic charge density explained the role of hydrogen bonding, HH contacts and the glycine amino acid monomer in peptide folding. The highest degree of occupation of the QTAIM interpreted Ramachandran plot was found for the glycine amino acid monomer compared with the remaining backbone peptide bonds. The mobility of the QTAIM eigenvectors of the glycine amino acid monomer was higher than for the other amino acids and was comparable to that of the hydrogen bonding, explaining the flexibility of the magainin-2 backbone. We experimented with a variety of hybrid QTAIM-Ramachandran plots to highlight and explain why the glycine amino acid monomer largely occupies the 'forbidden' region on the Ramachandran plot. In addition, the new hybrid QTAIM-Ramachandran plots contained recognizable regions that can be associated with concepts familiar from the conventional Ramachandran plot whilst retaining the character of the QTAIM most and least preferred regions.


Self-sampling HPV test in women not undergoing Pap smear for more than 5 years and factors associated with under-screening in Taiwan.
Under-utilization of Papanicolaou (Pap) smear causes a gap in the prevention of cervical neoplasms. A prospective population-based study was conducted investigating whether a self-sampling human papillomavirus (HPV) test was feasible for under-users of Pap smear and factors associated with under-screening in Taiwan. Women not having Pap smear screening for > 5 years were invited to participate in this study. Invitation letters and educational brochures were mailed to 4% of randomly selected eligible women from Taoyuan City, Taiwan, and responders received an HPV self-sampling kit. Those with HPV-positive results were recalled for a Pap smear and colposcopy. Between March 2010 and June 2012, 10,693 women were invited, 354 responded (3.3%), and 282 (2.6%) gave valid informed consent, answered the questionnaire, and submitted HPV samples. The median age of enrolled women was 48.1 years. Forty-seven women (16.7%) had a positive HPV test, and 14 women accepted further survey to find two CIN2+. Another two cases of CIN2+ were identified from a national registry database. The cost of direct mailing self-samplers was less than that done on request (from NT$434,866 to NT$164,229, response rate of 5% to 15%, respectively, versus NT$683,957 for detecting 1 CIN2+). Reasons for not attending screening included lack of time, embarrassment, assumed low risk, fear of positive results, and perceived potential pain. Among the responders, 90.8% found the method acceptable. Our study indicated that different approaches (e.g., direct mailing self-samplers to under-users and/or various educational interventions) must be explored to improve coverage in populations with culture characteristics similar to Taiwan.


Excess mortality in northern Haiti during the 2010 cholera epidemic.
In the course of infectious disease outbreaks, barriers to accessing health care can contribute to preventable mortality. According to the Ministry of Health of Haiti (Ministère de la Santé Publique et de la Population [MSPP]), the 2010 cholera epidemic caused 7,936 deaths from October 2010 to December 2012 in Haiti alone. We seek to quantify the excess mortality attributable to patients not seeking care during the cholera outbreak in the Nord Department in 2010-2012. Using data from a community-based retrospective survey conducted by Doctors Without Borders (Médecins Sans Frontières [MSF]) in Northern Haiti, we used logistic regression to examine the association between healthcare utilization and fatality among household members with watery diarrhea in the Communes of Borgne, Pilate, Plaisance, and Port-Margot in the Nord Department. We found that failing to seek care resulted in a 5-fold increase in the case fatality ratio among infected individuals (26%) versus those who sought care (5%). Common concerns noted for why care was not sought included travel distance to treatment centers, not attributing watery diarrhea episodes to cholera, and being unsure where to seek health care for their watery diarrhea episodes within their Communes. In conclusion, addressing transportation and information needs could increase healthcare utilization and reduce lives lost during an outbreak.


Helpful post-diagnostic services for young onset dementia: Findings and recommendations from the Angela project.
There is a significant lack of evidence regarding optimum models for service provision in young onset dementia (YOD). Our study aim was to gather detailed information about services experienced as helpful by those with YOD and family carers. The objective was to identify the core features of these services to inform service design, delivery and improvements. A qualitative approach based on appreciative inquiry was used, posing open-ended questions about services experienced as helpful, as part of a national UK survey of people with YOD and carers. We used inductive thematic analysis to analyse the free-text responses. The resulting template was used as a basis for analysis of in-depth follow-up interviews, conducted to acquire greater in-depth understanding. Two hundred and thirty-three survey respondents provided 856 examples of helpful support. Twenty-four follow-up interviews were conducted (two with dyads, so 26 participants in total: 8 with people with YOD, 14 with carers, 2 with dyads). Twelve themes capturing the features of helpful services were clustered into three super-ordinate themes. 'Person-centredness' reflects micro levels of person-professional interaction (positive attitude, flexibility, collaborative, user-friendly materials, and in-person). 'Functional consistency' captures the meso level, demonstrating that services were helpful when organised consistently with needs (age-appropriate, holistic, responsive, and accessible). 'Organisational coherence', at the macro level, emphasises the need for service integration, specialist services and service continuity. Key conclusions are that the needs for flexibility and a collaborative stance may be particularly important for those under 65 years with dementia, who have full lives and are used to being in control; to be age-appropriate, helpful services need to provide activities and opportunities suitable for active middle-aged people; and to be holistic, services need to provide for needs associated with rare dementias and be family-centred. Specialist services need to be commissioned and arrangements need to be stable over time to enable continuity.


Prophylactic Negative Pressure Wound Therapy in Obese Patients Following Cesarean Delivery.
Negative pressure therapy (NPT) offers the potential to reduce infection in obese patients. The goal of this study was to explore the association between NPT use and infection after cesarean delivery among obese women. We initiated a hospital protocol wherein women with a body mass index (BMI) of 40 kg/m2 or greater who delivered after January 1, 2011 were to receive NPT following cesarean section. A retrospective comparison of surgical site infection (SSI) in women receiving the intervention to a similar group with a BMI of 40 kg/m2 or greater, a historical control group of women who delivered before January 1, 2011. Incidence of SSI was compared between time periods using logistic regression models. A total of 233 patients in the preintervention (control) group and 234 patients in the intervention group were included in the analysis. In the control group, 23 (9.9%) developed SSI, compared with 13 (5.6%) in the intervention group. After adjustment for potential confounding factors, women in the postintervention period experienced a statistically significant reduction in SSI rates (adjusted odds ratio =0.45, 95% CI = 0.22-0.95); P = .04). Implementation of a hospital protocol of NPT following cesarean delivery in obese women resulted in reduced incidence of postoperative SSI. This study suggests that using NPT after cesarean delivery in women with a BMI ≥40 kg/m2 is an efficacious method to reduce incidence of postoperative wound infections.


Inhibition and role of let-7d in idiopathic pulmonary fibrosis.
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and usually lethal fibrotic lung disease characterized by profound changes in epithelial cell phenotype and fibroblast proliferation. To determine changes in expression and role of microRNAs in IPF. RNA from 10 control and 10 IPF tissues was hybridized on Agilent microRNA microarrays and results were confirmed by quantitative real-time polymerase chain reaction and in situ hybridization. SMAD3 binding to the let-7d promoter was confirmed by chromatin immunoprecipitation, electrophoretic mobility shift assay, luciferase assays, and reduced expression of let-7d in response to transforming growth factor-beta. HMGA2, a let-7d target, was localized by immunohistochemistry. In mice, let-7d was inhibited by intratracheal administration of a let-7d antagomir and its effects were determined by immunohistochemistry, immunofluorescence, quantitative real-time polymerase chain reaction, and morphometry. Eighteen microRNAs including let-7d were significantly decreased in IPF. Transforming growth factor-beta down-regulated let-7d expression, and SMAD3 binding to the let-7d promoter was demonstrated. Inhibition of let-7d caused increases in mesenchymal markers N-cadherin-2, vimentin, and alpha-smooth muscle actin (ACTA2) as well as HMGA2 in multiple epithelial cell lines. let-7d was significantly reduced in IPF lungs and the number of epithelial cells expressing let-7d correlated with pulmonary functions. HMGA2 was increased in alveolar epithelial cells of IPF lungs. let-7d inhibition in vivo caused alveolar septal thickening and increases in collagen, ACTA2, and S100A4 expression in SFTPC (pulmonary-associated surfactant protein C) expressing alveolar epithelial cells. Our results indicate a role for microRNAs in IPF. The down-regulation of let-7d in IPF and the profibrotic effects of this down-regulation in vitro and in vivo suggest a key regulatory role for this microRNA in preventing lung fibrosis. Clinical trial registered with www.clinicaltrials.gov (NCT 00258544).


Willingness to pay and moral stance: The case of farm animal welfare in Germany.
This study examines the impact of ethical attitude on the willingness to pay for farm animal welfare improvement in Germany. Little is known about the pluralism of moral attitudes that may exist behind farm animal welfare issues and its relationship to customers' willingness to pay for it. Via a large survey (n = 1334) we are able to identify different moral dimensions by employing validated scales. We find utilitarian alongside deontological attitudes as well as a mixture of both. Thus, presupposing a standard moral attitude is too simple. This has implications for decision-making on markets, since the implicit normative assumptions of a utilitarian position in economics has to be critically assessed. Furthermore, we asked for the willingness to pay for various aspects of farm animal welfare improvement. We find significant positive correlations between willingness to pay and environmental concern, altruism and less apathy. Measured in Euro, a higher environmental concern has the strongest effect on WTP for all five moral scales. Outliers with higher bids are willing to pay almost five times for any aspect of farm animal welfare than the rest of the sample. A more detailed analysis of outliers demonstrates that market-based approaches have restrictions in capturing certain moral values. Moreover, the motivations behind zero bids reveal that moral concerns outweigh indifference towards animal welfare by far. This has implications how policy can be designed to serve people's demand for higher animal welfare standards. Two other findings are of interest. First, we find a very high number of people assigning an intrinsic value to animals (90%). Second, zero bids and outlier treatment in WTP-studies deserves more careful consideration, since WTP-estimates are easily skewed by excluding these groups.


In vivo imaging of brain aromatase in female baboons: [11C]vorozole kinetics and effect of the menstrual cycle.
The aim of this work was to quantify the brain distribution of the enzyme aromatase in the female baboon with positron emission tomography and the tracer [11C]vorozole using three different quantification methods for estimating the total distribution volume (V(T)): a graphical method, compartment modeling, and a tissue to plasma ratio. The graphical model and the compartment modeling gave similar estimates to the data and similar values (correlation R = .988; p = .0001). [11C]Vorozole shows a rapid uptake by the brain followed by a relatively constant accumulation, suggesting the possibility of using the tissue to plasma ratio as an estimate of V(T). The highest uptake of [11C]vorozole in the baboon brain was measured in the amygdala, followed by the preoptic area and hypothalamus, basal ganglia, and cortical areas. Pretreatment studies with vorozole or letrozole showed a generalized decrease in brain accumulation and V(T). The results suggested that the physiologic changes in gonadal hormone levels accompanying the menstrual cycle had a significant effect on brain aromatase V(T).


Transcriptome analysis revealed that short-term stress in Blattella germanica to β-cypermethrin can reshape the phenotype of resistance adaptation.
Previous studies on insect resistance have primarily focused on resistance monitoring and the molecular mechanisms involved, while overlooking the process of phenotype formation induced by insecticide stress. In this study, we compared the expression profiles of a beta-cypermethrin (β-CYP) resistant strain (R) and a susceptible strain (S) of Blattella germanica after β-CYP induction using transcriptome sequencing. In the short-term stress experiment, we identified a total of 792 and 622 differentially expressed genes (DEGs) in the S and R strains. Additionally, 893 DEGs were identified in the long-term adaptation experiment. To validate the RNA-Seq data, we performed qRT-PCR on eleven selected DEGs, and the results were consistent with the transcriptome sequencing data. These DEGs exhibited down-regulation in the short-term stress group and up-regulation in the long-term adaptation group. Among the validated DEGs, CUO8 and Cyp4g19 were identified and subjected to knockdown using RNA interference. Subsequent insecticide bioassays revealed that the mortality rate of cockroaches treated with β-CYP increased by 69.3% and 66.7% after silencing the CUO8 and Cyp4g19 genes (P<0.05). Furthermore, the silencing of CUO8 resulted in a significant thinning of the cuticle by 59.3% and 53.4% (P<0.05), as observed through transmission electron microscopy and eosin staining, in the S and R strains, respectively. Overall, our findings demonstrate that the phenotypic plasticity in response to short-term stress can reshape the adaptive mechanisms of genetic variation during prolonged exposure to insecticides. And the identified resistance-related genes, CUO8 and Cyp4g19, could serve as potential targets for controlling these pest populations.


First-trimester aspiration abortion practices: a survey of United States abortion providers.
To assess whether first-trimester aspiration abortion practices of US providers agree with evidence-based policy guidelines. We sent surveys by mail or electronically to all abortion facilities in the United States identified via professional networks and websites from June through December 2013. Administrators reported on the volume of procedures performed at their site(s) through 13 weeks 6 days' gestation and on clinic services. Clinicians reported on personal demographic characteristics and abortion practices. We reviewed guidelines from key US professional organizations to determine how well reported practices aligned with available recommendations and the extent to which guidelines have changed since the time of the survey. We identified 703 clinical sites in the United States; 383 (54%) sites responded, 256 of which offer first-trimester aspiration abortions. Most providers identified as obstetrician-gynecologists (74%) and female (64%); 52% were less than 50 years old compared to 36% in 2002. Overall, reported practices follow evidence-based guidelines, including routine administration of periprocedure antibiotics (85%), use of misoprostol for cervical ripening in the late first trimester (94%), pain management practices, and same-day contraception provision (98%) including long-acting devices (76%). Less evidence-based practices include routine preprocedure ultrasound (99%), not providing abortion before 5 weeks' gestation (66%), restrictive fasting policies, and prolonged and postprocedure antibiotic provision. Overall, the first-trimester aspiration abortion practices revealed in our survey agree with professional evidence-based policy guidelines, though some related to preprocedure ultrasound use, very early abortion provision, preanesthesia fasting protocols, and antibiotic regimens deserve attention. In this third cross-sectional survey of US abortion practices (prior surveys 1997 and 2002), first-trimester aspiration abortion providers are younger than before, reflecting an improvement in the "graying" of the abortion provider workforce. Research and education are needed to further improve evidence-based practice in abortion care.


p53 and apoptosis.
Loss of function of the p53 tumour suppressor gene is a frequent and important event in the genesis or progression of many human malignancies. Loss of p53 dependent apoptosis is believed to be critical to carcinogenesis in many of these cases, suggesting the possibility to therapeutically restore this pathway and directly eliminate malignant cells or increase or restore their sensitivity to chemotherapeutic agents. The regulation of p53-dependent responses is complex and variable between cell types, and whether a cell undergoes apoptosis after activation of p53 is highly sensitive to signal context, including environmental and cell intrinsic influences. This article focuses upon p53-dependent apoptosis, considering current understanding of the biochemical steps involved, the factors determining selection of apoptosis over other p53-dependent responses, the significance of p53-dependent apoptosis for the genesis, progression and drug resistance of human cancers, and finally the prospects for clinical manipulation of this pathway in cancer therapy.


Predictors of personal continuity of care of patients with severe mental illness: A comparison across five European countries.
In Europe, at discharge from a psychiatric hospital, patients with severe mental illness may be exposed to one of two main care approaches: personal continuity, where one clinician is responsible for in- and outpatient care, and specialisation, where various clinicians are. Such exposure is decided through patient-clinician agreement or at the organisational level, depending on the country's health system. Since personal continuity would be more suitable for patients with complex psychosocial needs, the aim of this study was to identify predictors of patients' exposure to care approaches in different European countries. Data were collected on 7302 psychiatric hospitalised patients in 2015 in Germany, Poland, and Belgium (patient-level exposure); and in the UK and Italy (organisational-level exposure). At discharge, patients were exposed to one of the care approaches according to usual practice. Putative predictors of exposure at patients' discharge were assessed in both groups of countries. Socially disadvantaged patients were significantly more exposed to personal continuity. In all countries, the main predictor of exposure was the admission hospital, except in Germany, where having a diagnosis of psychosis and a higher education status were predictors of exposure to personal continuity. In the UK, hospitals practising personal continuity had a more socially disadvantaged patient population. Even in countries where exposure is decided through patient-clinician agreement, it was the admission hospital, not patient characteristics, that predicted exposure to care approaches. Nevertheless, organisational decisions in hospitals tend to expose socially disadvantaged patients to personal continuity.


Core-Satellite Nanoassemblies as SPR/SERS Dual-Mode Plasmonic Sensors for Sensitively Detecting Ractopamine in Complex Media.
Highly sensitive and reliable detection of β-adrenergic agonists is especially necessary due to the illegal abuse of growth-promoting feed additives. Here, we develop a novel surface plasmon resonance/surface-enhanced Raman scattering (SPR/SERS) dual-mode plasmonic sensor based on core-satellite nanoassemblies for the highly sensitive and reliable detection of ractopamine (RAC). The addition of RAC results in the decomposition of core-satellite nanoassemblies and consequently changes the Rayleigh scattering color of dark-field microscopy (DFM) images and the Raman scattering intensity of SERS spectra. The excellent sensitivity, specificity, and uniformity of this strategy were confirmed by detecting RAC in various complex media in the farm-to-table chain, and the limit of detection (LOD) was 0.03 ng/mL in an aqueous solution. In particular, the convenient access to livestock sewage not only ensures animal welfare but also provides great convenience for the market regulation of β-agonists. The success of our on-site strategy only with a portable Raman device promises great application prospects for β-agonist detection.


Optimization of the activated sludge anoxic reactor configuration as a means to control nutrient removal kinetically.
Factors influencing the determination of optimum reactor configuration for activated sludge denitrification are investigated in this paper. A kinetic optimization method is presented to evaluate optimal pre- and post-denitrification bioreactor stages. Applying the method developed, simulation studies were carried out to investigate the impacts of the ratio of the influent readily biodegradable and slowly biodegradable substrates and the oxygen entering the denitrification zones on the optimal anoxic reactor configuration. In addition, the paper describes the effects of the slowly biodegradable substrate on the denitrification efficiency using external substrate dosing, and it demonstrates kinetic considerations concerning the hydrolysis process. It has been shown that as a function of the biodegradable substrate composition, the stage system design with three optimized reactor compartments can effectively increase reaction rates in the denitrification zones, and can provide flexibility for varying operation conditions.


A Novel Adenovirus Detected in Bering-Chukchi-Beaufort Seas Bowhead Whale (Balaena mysticetus): Epidemiologic Data and Phylogenetic Characterization.
Adenoviruses are common pathogens infecting a wide range of vertebrates. Few cetacean adenoviruses have been described in the literature, and their pathogenicity is still unclear. Using PCR-based viral and bacterial pathogen surveillance in Bering-Chukchi-Beaufort seas bowhead whales (Balaena mysticetus) legally harvested 2012-15 during Alaskan aboriginal subsistence hunts, six of 59 bowhead whales (10%) tested positive for adenovirus DNA in the spleen. We found a high degree of sequence divergence from other mastadenoviruses, suggesting these may represent a novel species, tentatively named bowhead whale adenovirus. The sequences detected are distinct from adenoviruses previously identified in bottlenose dolphins (Tursiops truncatus) and harbor porpoises (Phocoena phocoena), forming two distinct clades in the cetacean hosts. The clinical impact is unclear, since no histopathologic evidence of adenovirus-associated disease was found. Furthermore, detection of adenovirus DNA in the spleen, contrary to other cetacean adenoviruses detected in the intestinal tract, may suggest a broader tissue tropism. Our study demonstrates adenovirus infection in bowhead whales and the usefulness of molecular diagnostics to discover and genetically characterize novel viruses in marine mammals.


Cell biology. A universal bicarbonate sensor.
The life-span of sperm may be short but it is certainly busy. The three principal molecular events that prepare sperm for fertilization are all controlled by the intracellular nucleotide adenosine 3',5'-monophosphate (cAMP). One of these, capacitation, is also regulated by bicarbonate ions. The elusive connection between cAMP and bicarbonate ions now appears to be solved as Kaupp and Weyand explain in their Perspective. Bicarbonate ions enter sperm through the anion transporter in the sperm plasma membrane and activate the soluble form of adenylyl cyclase, the enzyme that synthesizes cAMP (Chen et al.)


Trends in Clostridium difficile infection and risk factors for hospital acquisition of Clostridium difficile among children with cancer.
To study the trend of Clostridium difficile infection (CDI) and risk factors for hospital acquired CDI (HA-CDI) among children with cancer. We analyzed 33 095 first pediatric hospitalizations for malignancy among 43 pediatric hospitals between 1999 and 2011. The effect of demographics, disease characteristics, and weekly drug exposure (antibiotics, antacids, and chemotherapy) on HA-CDI was assessed with multivariate Cox regression. CDI was defined by the combination of International Classification of Diseases, 9th edition-Clinical Modification (ICD-9CM), CDI diagnostic assay billing code, and concurrent administration of a CDI-active antibiotic. HA-CDI was defined as CDI with assay occurring after the sixth hospital day. A total of 1736 admissions with CDI were identified, of which 380 were HA-CDI. CDI incidence increased from 1999-2006 (P = .01); however, CDI testing frequency and disease decreased from 2006-2010 (P < .05). Admissions with HA-CDI had longer lengths of stay compared with those without HA-CDI (35 days vs 12 days, P < .01) and greater risk of inpatient mortality (relative risk 2.3, P < .01). Increased risk of HA-CDI (hazard ratio [95% CI]) was seen after exposure to the following drugs: aminoglycoside (1.357 [1.053-1.749]), third generation cephalosporin (1.518 [1.177-1.959]), cefepime (2.383 [1.839-3.089]), and proton pump inhibiting agent (1.398 [1.096-1.784]) in the prior week, and chemotherapy (1.942 [1.491-2.529]) in the 8-14 days prior to HA-CDI onset. Histamine-2 receptor antagonist exposure in the prior week was associated with decreased risk of HA-CDI (0.730 [0.584-0.912]). Despite an apparent decrease in CDI incidence from 2006-2010, HA-CDI remains prevalent and morbid among children with cancer. Recent exposure to chemotherapy, proton pump inhibitor, and certain antibiotics were independent risk factors for HA-CDI.


A Cross-Sectional Survey on Professionals to Assess Health Needs of Newly Arrived Migrants in Spain.
Heightened conflicts and lack of safety due to reasons related to economic, social, ethnic, religious, sexual orientation, political, or nationality matters have increased migratory movements during the last, few decades. Unfortunately, when migrants arrive in new territories, they can face many barriers. For example, in Spain, some migrants have difficulties in accessing health services. The main objective of this study was to describe, from the perspective of social and healthcare professionals, health needs and barriers faced among migrants who recently arrived in Spain when accessing the health system. To accomplish this aim, we carried out a cross-sectional descriptive study using a newly created self-administered questionnaire. Statistical analysis was done using the SPSS 23.00® program. Survey collection was from April 2018 to October 2018, and the cohort comprised a total of 228 professionals. Most participants were females (76%), with an average age of 35 years [interquartile range (IQR) 29.8-43.0]. The most represented profession in the cohort was physician (48%), followed by social care professionals (32%), nursing (11%), and other (8%). Of these individuals, 61% stated having either little or limited knowledge of international migrant health rights, and 94% believed migrants must overcome barriers to receive health services. The four most reported barriers were as follows: language, cultural differences, administrative issues, and fear of being undocumented. Additionally, by order of importance, professionals viewed mental health disorders and infectious diseases as the most common contributors to disease burden in this group. The four most popular strategies implemented by professionals to improve healthcare access further for migrants included intercultural competency training for professionals; access to community health agents; access to translators; and development of health system navigation skills among those newly arrived. Study results suggest that governments should make greater efforts to provide social and healthcare professionals with more effective tools that overcome communication barriers and cultural competence training modules.


Oral administration of Grifola frondosa polysaccharides improves memory impairment in aged rats via antioxidant action.
Grifola frondosa is an edible/medicinal mushroom with great nutritional value and bioactivity. The present study was performed to evaluate the beneficial effect of polysaccharides isolated from Grifola frondosa on memory impairment in aged rats. 20-month-old rats were gavaged with Grifola frondosa polysaccharides (GFP) for 8 weeks. Morris Water Maze test revealed that GFP administration significantly improved memory impairment in aged rats. GFP supply was also found to attenuate age-associated changes of brain histology and ultrastructure observed by light microscopy and transmission electron microscopy. Moreover, the increase of total antioxidant capacity (T-AOC), glutathione peroxidase (GPx) activity, superoxide dismutase (SOD) activity, catalase (CAT) activity, as well as the decreased nitric oxide (NO) and malondialdehyde (MDA) levels, were consistent with the behavioral results. These findings indicated that oral administration of GFP could improve memory impairment via antioxidant action, and dietary supplementation with GFP may provide potential benefits on brain aging.


Gaps in affiliation indexing in Scopus and PubMed.
The authors sought to determine whether unexpected gaps existed in Scopus's author affiliation indexing of publications written by the University of Nebraska Medical Center or Nebraska Medicine (UNMC/NM) authors during 2014. First, we compared Scopus affiliation identifier search results to PubMed affiliation keyword search results. Then, we searched Scopus using affiliation keywords (UNMC, etc.) and compared the results to PubMed affiliation keyword and Scopus affiliation identifier searches. We found that Scopus's records for approximately 7% of UNMC/NM authors' publications lacked appropriate UNMC/NM author affiliation identifiers, and many journals' publishers were supplying incomplete author affiliation information to PubMed. Institutions relying on Scopus to track their impact should determine whether Scopus's affiliation identifiers will, in fact, identify all articles published by their authors and investigators.


Drug therapy. Treatment of herpesvirus infections.
Guidelines for the prophylaxis or therapy of herpesvirus infections are shown in Table 1. Progress is so rapid in this area that frequent revisions of such guidelines will be necessary. Newer drugs or new formulations of older agents are constantly being developed. Combination therapies--e.g., interferon plus acyclovir--appear promising in laboratory models of herpesvirus infections and will undoubtedly receive clinical investigation in the years ahead. The problem of dealing with latent virus infections still eludes us, and major breakthroughs will be necessary before we can discuss cure of recurrent infections. Nevertheless, important strides have been made in the past few years, and further progress is predictable in the years ahead.


[How to Place Percutaneous Cardiopulmonary Support(PCPS)].
Cannulation for percutaneous cardiopulmonary support (PCPS) is usually performed percutaneously. However, cut down exposure of the vessels is needed if percutaneous cannulation is difficult. Once the vessels are exposed, cannulas can be placed either by a direct cut down cannulation or by a Seldinger technique. Vascular access is usually achieved through femoral vessels, but other large vessels can be used in specific patient conditions. For instance, neck vessels are commonly used for veno-venous extracorporeal membrane oxygenation (ECMO). In patients who cannot come off cardiopulmonary bypass, direct cannulation of the aorta and right atrium( central ECMO) is a simple way. Complications related to cannulation are bleeding, vascular injury, arterial embolism, and distal malperfusion. Thoracic surgeons must have up-to-date information and become proficient in these procedures.


Physiological adaptations of small mammals to desert ecosystems.
Adaptations of animals to the xeric environment have been studied in various taxonomic groups and across several deserts. Despite the impressive data that have been accumulated, the focus in most of these studies is mainly on the significance of one variable at a time. Here, we attempt to integrate between responses of several physiological systems, challenged by increasing diet and water salinity and extreme temperatures, acquired in different studies of thermo and osmo-regulatory adaptations, of small rodents, to the xeric environment. Studies have shown differential thermoregulatory responses to increased dietary salinity, which were attributed to habitat and habits of the relevant species. In the thermoregulatory studies, a potential adaptive significance of low metabolic rate was demonstrated. From an evolutionary point of view, the most important adaptation is in the timing of reproduction, as it enables the transfer of genetic properties to the next generation in an unpredictable ecosystem, where reproduction might not occur every year. Results in this aspect show that increased dietary salinity, through an increase in vasopressin plasma levels, plays an important role as a regulator of the reproductive system. We assume that the amount of food existing in the habitat and the amount of reserves in the animal in the form of white adipose tissue are important for reproduction. Photoperiod affects all studied physiological responses, emphasizing the importance of pre-acclimation to seasonal characteristics. We summarize the existing data and suggest neuro-endocrine pathways, which have a central role in these adaptations by affecting thermoregulation, osmoregulation and reproduction to create the optimal response to xeric conditions. These hypotheses can be used as the basis for future studies.


The impact of carbon to nitrogen ratios and pH on the microbial prevalence and polyhydroxybutyrate production levels using a mixed microbial starter culture.
Growth conditions have been frequently studied in optimizing polyhydroxybutyrate (PHB) production, while few studies were performed to unravel the dynamic mixed microbial consortia (MMCs) in the process. In this study, the relationship between growth conditions (C/N ratios and pH) and the corresponding key-microbes were identified and monitored during PHB accumulation. The highest PHB level (70 wt% of dry cell mass) was obtained at pH 9, C/N 40, and acetic acid 10 g/L. Linking the dominant genera with the highest point of PHB accumulation, Thauera was the most prevalent species in all MMCs of pH 9, except when a C/N ratio of 1 was applied. Notably, dominant bacteria shifted at pH 7 (C/N 10) from Thauera (0 h) to Paracoccus, and subsequently to Alcaligenes following the process of PHB accumulation and consumption. Further understanding of the relationship between the structure of the microbial community and the performance will be beneficial for regulating and obtaining high PHB accumulation within an MMC. Our study illustrates the impact of C/N ratios and pH on microbial prevalence and PHB production levels using a mixed microbial starter culture. This knowledge will broaden industrial perspectives for regulating high PHB production and timely harvesting.


[Willis and his circle].
Thomas Willis (1621-1675) grew up in Wiltshire and studied medicine in Oxford, at a time when the city was besieged and then occupied by Parliamentarian troops. He started his career as a country doctor while concurrently taking part in informal gatherings with other scientists (William Petty, Christopher Wren and, later on, Robert Hooke, Richard Lower and Robert Boyle). They performed physical and chemical experiments and carried out a variety of tests on animals. After the restoration of the monarchy in 1660 Willis combined his practice with academic teaching. From then on he focused his studies on the structure and function of the brain, dissecting brains after removal from the skull and fixation in 'spirit of wine'. In his 'Cerebri anatome' of 1664, illustrated by Wren, he drew attention to the arterial circle at the base of the brain, including its physiological advantages. This arterial circle had been incompletely described by others in the past and fully, but only in writing, by Wepfer in 1658.


Comprehensive identification of protein disulfide bonds with pepsin/trypsin digestion, Orbitrap HCD and Spectrum Identification Machine.
Disulfide bonds (SS) are post-translational modifications important for the proper folding and stabilization of many cellular proteins with therapeutic uses, including antibodies and other biologics. With budding advances of biologics and biosimilars, there is a mounting need for a robust method for accurate identification of SS. Even though several mass spectrometry methods have emerged for this task, their practical use rests on the broad effectiveness of both sample preparation methods and bioinformatics tools. Here we present a new protocol tailored toward mapping SS; it uses readily available reagents, instruments, and software. For sample preparation, a 4-h pepsin digestion at pH 1.3 followed by an overnight trypsin digestion at pH 6.5 can maximize the release of SS-containing peptides from non-reduced proteins, while minimizing SS scrambling. For LC/MS/MS analysis, SS-containing peptides can be efficiently fragmented with HCD in a Q Exactive Orbitrap mass spectrometer, preserving SS for subsequent identification. Our bioinformatics protocol describes how we tailored our freely downloadable and easy-to-use software, Spectrum Identification Machine for Cross-Linked Peptides (SIM-XL), to minimize false identification and facilitate manual validation of SS-peptide mass spectra. To substantiate this optimized method, we've comprehensively identified 14 out of 17 known SS in BSA. SIGNIFICANCE: Comprehensive and accurate identification of SS in proteins is critical for elucidating protein structures and functions. Yet, it is far from routine to accomplish this task in many analytical or core laboratories. Numerous published methods require complex sample preparation methods, specialized mass spectrometers and cumbersome or proprietary software tools, thus cannot be easily implemented in unspecialized laboratories. Here, we describe a robust and rapid SS mapping approach that utilizes readily available reagents, instruments, and software; it can be easily implemented in any analytical core laboratories, and tested for its impact on the research community.


Redundancy-weighting for better inference of protein structural features.
Structural knowledge, extracted from the Protein Data Bank (PDB), underlies numerous potential functions and prediction methods. The PDB, however, is highly biased: many proteins have more than one entry, while entire protein families are represented by a single structure, or even not at all. The standard solution to this problem is to limit the studies to non-redundant subsets of the PDB. While alleviating biases, this solution hides the many-to-many relations between sequences and structures. That is, non-redundant datasets conceal the diversity of sequences that share the same fold and the existence of multiple conformations for the same protein. A particularly disturbing aspect of non-redundant subsets is that they hardly benefit from the rapid pace of protein structure determination, as most newly solved structures fall within existing families. In this study we explore the concept of redundancy-weighted datasets, originally suggested by Miyazawa and Jernigan. Redundancy-weighted datasets include all available structures and associate them (or features thereof) with weights that are inversely proportional to the number of their homologs. Here, we provide the first systematic comparison of redundancy-weighted datasets with non-redundant ones. We test three weighting schemes and show that the distributions of structural features that they produce are smoother (having higher entropy) compared with the distributions inferred from non-redundant datasets. We further show that these smoothed distributions are both more robust and more correct than their non-redundant counterparts. We suggest that the better distributions, inferred using redundancy-weighting, may improve the accuracy of knowledge-based potentials and increase the power of protein structure prediction methods. Consequently, they may enhance model-driven molecular biology.


LGI1 mutations in autosomal dominant and sporadic lateral temporal epilepsy.
Autosomal dominant lateral temporal epilepsy (ADLTE) or autosomal dominant partial epilepsy with auditory features (ADPEAF) is an inherited epileptic syndrome with onset in childhood/adolescence and benign evolution. The hallmark of the syndrome consists of typical auditory auras or ictal aphasia in most affected family members. ADTLE/ADPEAF is associated in about half of the families with mutations of the leucine-rich, glioma-inactivated 1 (LGI1) gene. In addition, de novo LGI1 mutations are found in about 2% of sporadic cases with idiopathic partial epilepsy with auditory features, who are clinically similar to the majority of patients with ADLTE/ADPEAF but have no family history. Twenty-five LGI1 mutations have been described in familial and sporadic lateral temporal epilepsy patients. The mutations are distributed throughout the gene and are mostly missense mutations occurring in both the N-terminal leucine rich repeat (LRR) and C-terminal EPTP (beta propeller) protein domains. We show a tridimensional model of the LRR protein region that allows missense mutations of this region to be divided into two distinct groups: structural and functional mutations. Frameshift, nonsense and splice site point mutations have also been reported that result in protein truncation or internal deletion. The various types of mutations are associated with a rather homogeneous phenotype, and no obvious genotype-phenotype correlation can be identified. Both truncating and missense mutations appear to prevent secretion of mutant proteins, suggesting a loss of function effect of mutations. The function of LGI1 is unclear. Several molecular mechanisms possibly leading to lateral temporal epilepsy are illustrated and briefly discussed.


On the diversity of ideas in academic spaces.
Universities and other academic spaces are social institutions that exist primarily for ideas-to generate, curate, and transmit ideas to students and to the world. Academic spaces cannot carry out that function without supporting a diversity of perspectives. At the same time, universities must reckon-as must all social institutions-with changing norms around how to engage with ideas that challenge, provoke, even anger members of the communities dedicated to their discussion. It is on these institutions to listen to and learn from these ideas, consistent with their core function, while engaging pragmatically with the challenges and controversies that can arise whenever ideas are regularly and freely aired. While there should indeed be limits to the range of tolerable expression within universities, the imposition of these limits should happen rarely, with caution and humility. It is important that academic institutions recognize that while contemporary preoccupations that influence our engagement with speech may change, the secret to universities' durability over the centuries is that our core purpose-the generation and exploration of ideas-does, and should, not. This inherent value for societies is worth preserving, even, and particularly, in the face of societal pressure and change.


Systematic review and model-based analysis to identify whether renal safety risks of URAT1 inhibitors are fully determined by uric acid-lowering efficacies.
Renal safety risk is currently an important factor that hinders the development of uric acid transporter 1 (URAT1) inhibitors. This study aimed to compare the renal safety and uric acid-lowering efficacy of different URAT1 inhibitors and clarify the association between them. A systematic review of published randomized controlled trials on URAT1 inhibitors was conducted to investigate the incidence of renal safety events. A model-based analysis was performed to predict the uric acid-lowering efficacy of representative URAT1 inhibitors. The overall renal safety event incidences of lesinurad, verinurad, dotinurad, SHR4640, and benzbromarone in patients with hyperuricemia were 11.2 % (142/1264), 12.0 % (34/284), 0.5 % (2/421), 2.3 % (5/213), and 1.3 % (5/393), respectively. A semi-mechanistic pharmacokinetic/pharmacodynamic model was used to establish the dose-exposure-effect relationship of lesinurad, verinurad, dotinurad, and SHR4640 with or without the combination of xanthine oxidase inhibitors (XOIs). The efficacy ranking of the intermediate dose of URAT1 inhibitors with once-daily dosing was 2 mg dotinurad > 10 mg verinurad > 5 mg SHR4640 > 400 mg lesinurad. The combination of 80 mg febuxostat and 600 mg allopurinol reduced the 24-h cumulative renal uric acid excretion by 48.4 % and 48.3 %, respectively. Uric acid-lowering efficacy is not an independent factor for the renal safety risk of different URAT1 inhibitors, and structural differences could be responsible for the difference. The adverse renal effects of URAT1 inhibitors are dose-dependent, and the combination with high doses of XOIs can significantly reduce the renal safety risk by reducing uric acid excretion by the kidneys.


Conserved main-chain peptide distortions: a proposed role for Ile203 in catalysis by dihydrodipicolinate synthase.
In recent years, dihydrodipicolinate synthase (DHDPS, E.C. 220.127.116.11) has received considerable attention from a mechanistic and structural viewpoint. DHDPS catalyzes the reaction of (S)-aspartate-beta-semialdehyde with pyruvate, which is bound via a Schiff base to a conserved active-site lysine (Lys161 in the enzyme from Escherichia coli). To probe the mechanism of DHDPS, we have studied the inhibition of E. coli DHDPS by the substrate analog, beta-hydroxypyruvate. The K (i) was determined to be 0.21 (+/-0.02) mM, similar to that of the allosteric inhibitor, (S)-lysine, and beta-hydroxypyruvate was observed to cause time-dependent inhibition. The inhibitory reaction with beta-hydroxypyruvate could be qualitatively followed by mass spectrometry, which showed initial noncovalent adduct formation, followed by the slow formation of the covalent adduct. It is unclear whether beta-hydroxypyruvate plays a role in regulating the biosynthesis of meso-diaminopimelate and (S)-lysine in E. coli, although we note that it is present in vivo. The crystal structure of DHDPS complexed with beta-hydroxypyruvate was solved. The active site clearly showed the presence of the inhibitor covalently bound to the Lys161. Interestingly, the hydroxyl group of beta-hydroxypyruvate was hydrogen-bonded to the main-chain carbonyl of Ile203. This provides insight into the possible catalytic role played by this peptide unit, which has a highly strained torsion angle (omega approximately 201 degrees ). A survey of the known DHDPS structures from other organisms shows this distortion to be a highly conserved feature of the DHDPS active site, and we propose that this peptide unit plays a critical role in catalysis.


Cocaine and the AP-1 Transcription Factor Complex.
Cocaine addiction in humans develops gradually with repeated administrations and persists long after cocaine has cleared the body. The mechanisms underlying this persistent form of neuroplasticity are not understood and can involve both structural and biochemical mechanisms. The long time course for cocaine addiction in humans and for development of cocaine self-administration in animal models suggests the involvement of alterations in gene expression leading to altered signaling in the brain. In the striatum (Str) and nucleus accumbens (NAc) of rats, pretreatment with repeated cocaine administrations downregulates the induction of various immediate early genes (IEGs) by a subsequent acute challenge with cocaine. Some of these downregulated IEGs encode Fos-related components of the activator protein-1 (AP-1) complex, which is likely to regulate a number of genes important for neuronal function. Interestingly, repeated cocaine administration induces novel delta FosB-related proteins (called chronic Fos-related antigens (Fras)) in the NAc and Str that replace the downregulated isoforms of Fos. Unlike the acutely induced, short-lasting isoforms of Fos and FosB, the chronic Fras persist long after the last cocaine administration. The known form of delta FosB per se lacks the domain required to activate transcription. If the chronic Fras are similar in structure to delta FosB, then the induction of chronic Fras likely leads to a blockade of AP-1-dependent transcription resulting in altered gene expression. We are presently purifying the chronic Fras to obtain amino acid sequence in order to directly examine our hypothesis about the effects of repeated cocaine administration on AP-1-dependent transcription and gene expression in the brain.


Sexual pain in women: quality of sex life and marital relations.
Common gynecological and dermatological conditions resulting in sexual pain are often observed in gynecological practice and are easily diagnosed with visual observation and laboratory tests. The lower genital tract diseases we are referring to are vaginitis, vaginoses, dermatoses, hypoestrogenism and endometriosis. All of them affect the vaginal mucosa with diverse mechanisms, their effects lasting for only few days or many months. Furthermore, they change the women's sense of wellbeing sometimes significantly and for a long period. The conditions we mentioned above are recognized promptly with basic gynecological interventions but when burning or sharp pain occurs with light pressure (as in case of penetration attempts) without physical signs we must suspect the genitopelvic pain penetration disorder. This condition was defined for the first time in the Diagnostic and Statistical Manual of Mental Disorders-5 and its dimensions include difficulty or pain at penetration associated with fear, anxiety, and pelvic floor hypertonus. Pain is most often localized at the vulvar vestibule and described as burning, pressure, and itching. These dimensions are iconic of sexual pain associated with vulvodyina and vaginismus but are common also in fibromyalgia, a syndrome of widespread chronic pain of unknown origin; sexual pain in fibromyalgia is mostly attributed both to the joint pathology and to the lower sensitive threshold that are the pathognomonic signs of this condition. In our study we analyzed the characteristics of pain as reported for each disease to evaluate its influence on sexuality and marital relations.


Assessment of prescribing, dispensing, and patient use pattern of antihypertensive drugs for patients attending outpatient department of Hiwot Fana Specialized University Hospital, Harar, Eastern Ethiopia.
Hypertension is a global concern and is one of the key preventable risk factors for cardiovascular events, resulting in unnecessary morbidity and mortality. The aim of this study was to assess the prescribing, dispensing and patient use pattern of antihypertensive drugs among patients attending Hiwot Fana Specialized University Hospital outpatient department. A hospital-based cross-sectional study was conducted in Hiwot Fana Specialized University Hospital on assessment of the prescribing, dispensing, and patient use pattern of antihypertensive drugs among patients who were above the age of 18 years and attending outpatient department from April 1-May 31, 2013. Data collection was conducted by reviewing the record of patients and direct observation of the dispensing process of randomly selected patients to measure average dispensing time, and direct interview with the patients. A total of 400 patients met the inclusion criteria; out of the 400 patients studied, 63.5% were females. Most of the patients had Stage 1 hypertension (69%), followed by Stage 2 hypertension (31%). Out of the total number of patients, 264 were with different comorbid conditions: diabetes mellitus (64.3%), followed by congestive heart failure (15.1%) and ischemic heart disease (2.3%). The most frequently prescribed class of antihypertensive drugs was diuretics, of which hydrochlorothiazide was the most frequently prescribed drug, both in single (55%), followed by enalapril (22.3%), methyl dopa (11.2%), atenolol (6.9%), and nifedipine (4.6%), and in combination with other antihypertensive drugs. The average dispensing time was 1.2 minutes, and 75% of the patients left the counter with inadequate information about the dosage. All antihypertensive drugs prescribed were in compliance with the Ethiopian Standard Treatment Guidelines. This study showed that most outpatients with hypertension in our hospital received monotherapy. Diuretics and angiotensin converting enzyme inhibitors were the most frequently prescribed classes of antihypertensive drugs in both monotherapy and combination therapy.


AA-PMe, a novel asiatic acid derivative, induces apoptosis and suppresses proliferation, migration, and invasion of gastric cancer cells.
Asiatic acid (AA; 2α,3β,23-trihydroxyurs-12-ene-28-oic acid) is widely used for medicinal purposes in many Asian countries due to its various bioactivities. A series of AA derivatives has been synthesized in attempts to improve its therapeutic potencies. Herein we investigated the anti-tumor activities of N-(2α,3β,23-acetoxyurs-12-en-28-oyl)-l-proline methyl ester (AA-PMe), a novel AA derivative. AA-PMe exhibited a stronger anti-cancer activity than its parent compound AA. AA-PMe inhibited the proliferation of SGC7901 and HGC27 human gastric cancer cells in a dose-dependent manner but had no significant toxicity in human gastric mucosa epithelial cells (GES-1). AA-PMe induced cell cycle arrest in G0/G1 phase and blocked G1-S transition, which correlated well with marked decreases in levels of cyclin D1, cyclin-dependent kinase CKD4, and phosphorylated retinoblastoma protein, and increase in cyclin-dependent kinase inhibitor P15. Further, AA-PMe induced apoptosis of human gastric cancer cells by affecting Bcl-2, Bax, c-Myc, and caspase-3. Moreover, AA-PMe suppressed the migration and invasion of human gastric cancer cells (SGC7901 and HGC27) cells by downregulating the expression of MMP-2 and MMP-9. Overall, this study investigated the potential anti-cancer activities of AA-PMe including inducing apoptosis and suppressing proliferation, migration and invasion of gastric cancer cells, as well as the underlying mechanisms, suggesting that AA-PMe is a promising anti-cancer drug candidate in gastric cancer therapy.


Efficacy and safety of oral silymarin in comparison with oral doxycycline and their combination therapy in the treatment of acne vulgaris.
Two factors of oxidative stress and inflammatory processes are implicated in pathogenesis of acne vulgaris. Silymarin has antioxidant and anti-inflammatory activities. This study was done to evaluate the effect of oral silymarin in the treatment of acne vulgaris compared to doxycycline and also their combination therapy. This randomized controlled trial was performed on 60 patients with acne vulgaris were divided into three groups of 20 patients, including: Silymarin (Group 1), Doxycycline (Group 2), and both compounds (Group 3). The patients' response was monitored every month and the lesions were evaluated using photography and two methods of Global Acne Grading system (GAGS) and Acne Severity Index (ASI). According to the results, the response to silymarin was not significantly different with doxycycline in the GAGS index (p = .260), but was lower in the ASI (p = .021). In this study, the synergistic effects of silymarin and doxycycline combination have been investigated in comparison with doxycycline. Although the improvement was more favorable in combination group, there was no statistically significant difference (p = .9 in ASI and p = .5 in GAGS). The results of our study suggest that although the silymarin monotherapy is not as effective as doxycycline for the treatment of acne vulgaris, it can be a therapeutic option.


[Alcohol dependent subjects with psychiatric comorbidity: a heterogeneous group].
In a sample of 161 alcohol dependent outpatients, we carry out three comparative analysis between alcohol dependent subjects with and without associated affective disorders (n= 72); with and without associated personality disorders (n= 60) and with and without associated substance abuse disorders (n= 26) based on sociodemographic, clinical characteristics, treatment response and long-term evolution variables. As for associated affective disorders, the only difference is that there are more female. As for associated personality disorders, we find that they are younger, there are more female, they have previous treatment background and worse short-term response. As for the group with associated substance abuse disorders, they are younger, have lower educational and social economic level, alcohol dependence onset earlier, more legal complications and worse half-term treatment response. The alcohol dependent patients with comorbidity are a heterogeneous group which makes the use of it difficult to categorize alcohol dependence.


[Mutual adaptation of elderly patients with schizophrenia and mentally healthy persons in a family (socio-psychological analysis)].
Clinical and psychosocial examinations of 70 families of senile schizophrenic patients and 40 families of healthy persons showed that in the patients' and controls' families, the identical events were caused by the subjects' age itself: lower status and adaptation of senile persons, rationalistic attitude of the relatives toward them, conflicts, disintegrated families, dysharmonic relations. In line with the schizophrenic process, the patients have less frequently higher status, enjoy more care of siblings, more rationalistic attitude of the relatives, higher conflict rate, larger variety of familial cooperation disorders and adaptations.


Induction of cross-reactive serum neutralizing antibody to human rotavirus in calves after in utero administration of bovine rotavirus.
Sera from calves infected in utero or postnatally with bovine rotavirus NCDV or postnatally with human rotavirus D (serotype 1) were tested by plaque reduction neutralization assay for antibody to bovine rotavirus and to three serotypes of human rotavirus. Homologous antibody developed in all animals, but antibody to heterologous rotaviruses developed mainly in animals exposed in utero to bovine rotavirus. The development of heterologous antibody may explain the immunological implications for cross-protection, previously observed between bovine and human rotavirus in experimentally infected calves.


Information theory-based analysis of CYP2C19, CYP2D6 and CYP3A5 splicing mutations.
Several mutations are known or suspected to affect mRNA splicing of CYP2C19, CYP2D6 and CYP3A5 genes; however, little experimental evidence exists to support these conclusions. The present study applies mathematical models that measure changes in information content of splice sites in these genes to demonstrate the relationship between the predicted phenotypes of these variants to the corresponding genotypes. Based on information analysis, the CYP2C19*2 variant activates a new cryptic site 40 nucleotides downstream of the natural splice site. CYP2C19*7 abolishes splicing at the exon 5 donor site. The CYP2D6*4 allele similarly inactivates splicing at the acceptor site of exon 4 and activates a new cryptic site one nucleotide downstream of the natural acceptor. CYP2D6*11 inactivates the acceptor site of exon 2. The CYP3A5*3 allele activates a new cryptic site 236 nucleotides upstream of the exon 4 natural acceptor site. CYP3A5*5 inactivates the exon 5 donor site and CYP3A5*6 strengthens a site upstream of the natural donor site, resulting in skipping of exon 7. Other previously described missense and nonsense mutations at terminal codons of exons in these genes affected splicing. CYP2D6*8 and CYP2D6*14 both decrease the strength of the exon 3 donor site, producing transcripts lacking this exon. The results of information analysis are consistent with the poor metabolizer phenotypes observed in patients with these mutations, and illustrate the potential value of these mathematical models to quantitatively evaluate the functional consequences of new mutations suspected of altering mRNA splicing.


Microinjection of cytoplasm as a test of complementation in Paramecium.
Mutants in Paramecium tetraurelia, unable to generate action potentials, have been isolated as cells which show no backward swimming in response to ionic stimulation. These "pawn" mutants belong to at least three complementation groups designated pwA, pwB, and pwC. We have found that microinjection of cytoplasm from a wild-type donor into a pawn recipient of any of the three complementation groups restores the ability of the pawn to generate action potentials and hence swim backward. In addition, the cytoplasm from a pawn cannot restore a recipient of the same complementation group, but that from a pawn of a different group can. Electrophysiological analysis had demonstrated that the restoration of backward swimming is not due to a simple addition of ions but represents a profound change in the excitable membrane of the recipient pawn cells. Using known pawn mutants and those which had previously been unclassified, we have been able to establish a perfect concordance of genetic complementation and complementation by cytoplasmic transfer through microinjection. This method has been used to classify pawn mutants that are sterile or hard-to-mate and to examine the ability of cytoplasms from different species of ciliated protozoa to restore the ability to swim backward in the pawn mutants of P. tetraurelia. A cell homogenate has also been fractionated by centrifugation to further purify the active components. These results demonstrate that transfer of cytoplasm between cells by microinjection can be a valid and systematic method to classify mutants. This test is simpler to perform than the genetic complementation test and can be used under favorable conditions in mutants that are sterile and in cells of different species.


PPiClust: efficient clustering of 3D protein-protein interaction interfaces.
The biological mechanisms through which proteins interact with one another are best revealed by studying the structural interfaces between interacting proteins. Protein-protein interfaces can be extracted from three-dimensional (3D) structural data of protein complexes and then clustered to derive biological insights. However, conventional protein interface clustering methods lack computational scalability and statistical support. In this work, we present a new method named "PPiClust" to systematically encode, cluster, and analyze similar 3D interface patterns in protein complexes efficiently. Experimental results showed that our method is effective in discovering visually consistent and statistically significant clusters of interfaces, and at the same time sufficiently time-efficient to be performed on a single computer. The interface clusters are also useful for uncovering the structural basis of protein interactions. Analysis of the resulting interface clusters revealed groups of structurally diverse proteins having similar interface patterns. We also found, in some of the interface clusters, the presence of well-known linear binding motifs which were noncontiguous in the primary sequences. These results suggest that PPiClust can discover not only statistically significant, but also biologically significant, protein interface clusters from protein complex structural data.


[Comparative physiological studies of Candida spec. H and its mutant H 13 during nitrogen starvation].
With Candida spec. H and the mutant H13 during nitrogen starvation we studied the changes occurring in the macromolecular cell composition. In the absence of nitrogen, but in the presence of n-alkanes as carbon source, both the nucleic acid and protein levels of the dried yeasts rapidly decreased. At the same time carbohydrates and lipids were accumulated. Candida spec. H predominantly increased carbohydrate content, whereas the mutant accumulated significantly higher amounts of lipids. The main components of the cellular carbohydrates and the fatty acid content were analyzed, and the results were discussed.


Two-year outcomes for children with autism after the cessation of early intensive behavioral intervention.
Evidence from recent meta-analytic and narrative review suggests that early intensive behavioral intervention (EIBI) may improve life chances of preschool children with autism. Unfortunately, there are few data indicating whether early gains are maintained after intervention ceases. The purpose of the present study was to establish the 2-year follow-up outcome for children with autism (N = 41) who had participated in an earlier 2-year controlled comparison of EIBI. Twenty-three children in the intervention group (100% of original sample) and 18 in the treatment-as-usual comparison group (86% of original sample) were located and retested. Group differences favoring intervention substantially diluted in this period but varied significantly between subgroups who had received university-supervised and parent-commissioned interventions, favoring the latter. These groups differed in terms of their baseline characteristics and intensity of intervention. Results strongly suggest a need for better characterization of those children who would benefit from more active maintenance programs.


Positive predictive value estimates for cell-free noninvasive prenatal screening from data of a large referral genetic diagnostic laboratory.
Since its debut in 2011, cell-free fetal DNA screening has undergone rapid expansion with respect to both utilization and coverage. However, conclusive data regarding the clinical validity and utility of this screening tool, both for the originally included common autosomal and sex-chromosomal aneuploidies as well as the more recently added chromosomal microdeletion syndromes, have lagged behind. Thus, there is a continued need to educate clinicians and patients about the current benefits and limitations of this screening tool to inform pre- and posttest counseling, pre/perinatal decision making, and medical risk assessment/management. The objective of this study was to determine the positive predictive value and false-positive rates for different chromosomal abnormalities identified by cell-free fetal DNA screening using a large data set of diagnostic testing results on invasive samples submitted to the laboratory for confirmatory studies. We tested 712 patient samples sent to our laboratory to confirm a cell-free fetal DNA screening result, indicating high risk for a chromosome abnormality. We compiled data from all cases in which the indication for confirmatory testing was a positive cell-free fetal DNA screen, including the common trisomies, sex chromosomal aneuploidies, microdeletion syndromes, and other large genome-wide copy number abnormalities. Testing modalities included fluorescence in situ hybridization, G-banded karyotype, and/or chromosomal microarray analysis performed on chorionic villus samples, amniotic fluid, or postnatally obtained blood samples. Positive predictive values and false-positive rates were calculated from tabulated data. The positive predictive values for trisomy 13, 18, and 21 were consistent with previous reports at 45%, 76%, and 84%, respectively. For the microdeletion syndrome regions, positive predictive values ranged from 0% for detection of Cri-du-Chat syndrome and Prader-Willi/Angelman syndrome to 14% for 1p36 deletion syndrome and 21% for 22q11.2 deletion syndrome. Detection of sex chromosomal aneuploidies had positive predictive values of 26% for monosomy X, 50% for 47,XXX, and 86% for 47,XXY. The positive predictive values for detection of common autosomal and sex chromosomal aneuploidies by cell-free fetal DNA screening were comparable with other studies. Identification of microdeletions was associated with lower positive predictive values and higher false-positive rates, likely because of the low prevalence of the individual targeted microdeletion syndromes in the general population. Although the obtained positive predictive values compare favorably with those seen in traditional screening approaches for common aneuploidies, they highlight the importance of educating clinicians and patients on the limitations of cell-free fetal DNA screening tests. Improvement of the cell-free fetal DNA screening technology and continued monitoring of its performance after introduction into clinical practice will be important to fully establish its clinical utility. Nonetheless, our data provide valuable information that may aid result interpretation, patient counseling, and clinical decision making/management.


No increase in the CTG repeat size during transmission from parent with expanded allele: false suspicion of contraction phenomenon.
Myotonic dystrophy type 1 (DM1), also known as Steinert's disease, is a chronic, progressive and disabling multisystemic disorder with a broad spectrum of severity that arises from an autosomal-dominant expansion of the Cytosine-Thymine-Guanine (CTG) triplet repeat in the 3' untranslated region of the DMPK gene (19q13.3). In this study, we report the case of a family with several intergenerational expansions of the CTG repeat, with an additional case of a false suspicion of contraction phenomenon due to TP-PCR limitations. The meiotic instability of the (CTG)n repeats leads to genetic anticipation where increased size of DM1 mutation and a more severe phenotype have been reported in affected individuals across generations. Even if extremely rare, a decrease in the CTG repeat size during transmission from parents to child can also occur, most frequently during paternal transmissions.


[Determination of 49 pesticide residues in tobacco by gas chromatography-tandem mass spectrometry].
A method was developed for rapid determination of 49 pesticide residues in tobacco based on gas chromatography-tandem mass spectrometry (GC-MS/MS). Tobacco was extracted with 0.1% acetic acid-acetonitrile solution. The supernatant was quantitatively transferred and dried with nitrogen. The concentrated extract was dissolved with acetonitrile-ethyl acetate (1 : 1, v/v) solution and cleaned up by primary secondary amine (PSA) sorbents, MgSO4 and C18 sorbents, then determined by GC-MS/MS with mirex as internal standard. The ranges of spiked recoveries of 49 pesticides at 0.05 microg/L and 5 microg/L were 60.4%-104.8% and 70%-115% , respectively. The relative standard deviations were below 15%. The detection limits of 16 pesticides were 0.01-0.03 microg/kg and those of the other 33 pesticides were less than 0.01 microg/kg; the correlation coefficients were larger than 0.991. This method is simple, rapid and characterized with acceptable sensitivity and accuracy to meet the requirements for the analysis of multiple pesticide residues in tobacco.


Selective tissue uptake of agouti-related protein(82-131) and its modulation by fasting.
The blood concentration of agouti-related protein (AgRP), a protein related to hyperphagia and obesity, is increased in obese human and fasted lean subjects. Because there is no saturable transport system at the blood-brain barrier for circulating AgRP to reach its central nervous system target, uptake of AgRP by peripheral organs might be physiologically meaningful. Using the biologically active fragment AgRP(82-131), we determined the pharmacokinetics of its radioactively labeled tracer after iv bolus injection and compared it with that of the vascular marker albumin. AgRP enters peripheral organs at different influx rates, all of which were higher than into brain and spinal cord. At 10 min after iv injection, the radioactivity recovered in the liver, which had the fastest influx rate for AgRP, represented intact (125)I-AgRP. The adrenal gland had a moderately fast uptake (but the highest initial volume of distribution), followed by the heart, lungs, and skeletal muscle. By comparison, epididymal fat, testis, and pancreas had low permeability to AgRP. Saturation of influx was determined by coadministration of excess unlabeled AgRP and was shown to be present in the liver and adrenal gland. The influx rate and initial volume of distribution did not show a linear correlation with vascular permeability or regional blood flow. AgRP uptake by the liver and epididymal fat was significantly increased by overnight fasting, whereas that by the adrenal gland was significantly decreased in fasted mice. Thus, the differential uptake of AgRP by peripheral organs could be a regulated process that is modulated by food deprivation.


Ethics, EBM, and hospital management.
Matters of hospital management do not figure prominently on the medical ethics agenda. However, management decisions that have to be taken in the area of hospital care are in fact riddled with ethical questions and do have significant impact on patients, staff members, and the community being served. In this decision making process evidence based medicine (EBM) plays an increasingly important role as a tool for rationalising as well as rationing health care resources. In this article, ethical issues of hospital management and the role of EBM will be explored, with particular reference to disease management programs, diagnosis related groups, and clinical pathways as recent developments in the German health care system.


Electroporation facilitates introduction of reporter transgenes and virions into schistosome eggs.
The schistosome egg represents an attractive developmental stage at which to target transgenes because of the high ratio of germ to somatic cells, because the transgene might be propagated and amplified by infecting snails with the miracidia hatched from treated eggs, and because eggs can be readily obtained from experimentally infected rodents. We investigated the utility of square wave electroporation to deliver transgenes and other macromolecules including fluorescent (Cy3) short interference (si) RNA molecules, messenger RNAs, and virions into eggs of Schistosoma mansoni. First, eggs were incubated in Cy3-labeled siRNA with and without square wave electroporation. Cy3-signals were detected by fluorescence microscopy in eggs and miracidia hatched from treated eggs. Second, electroporation was employed to introduce mRNA encoding firefly luciferase into eggs. Luciferase activity was detected three hours later, whereas luciferase was not evident in eggs soaked in the mRNA. Third, schistosome eggs were exposed to Moloney murine leukemia virus virions (MLV) pseudotyped with vesicular stomatitis virus glycoprotein (VSVG). Proviral transgenes were detected by PCR in genomic DNA from miracidia hatched from virion-exposed eggs, indicating the presence of transgenes in larval schistosomes that had been either soaked or electroporated. However, quantitative PCR (qPCR) analysis determined that electroporation of virions resulted in 2-3 times as many copies of provirus in these schistosomes compared to soaking alone. In addition, relative qPCR indicated a copy number for the proviral luciferase transgene of approximately 20 copies for 100 copies of a representative single copy endogenous gene (encoding cathepsin D). Square wave electroporation facilitates introduction of transgenes into the schistosome egg. Electroporation was more effective for the transduction of eggs with pseudotyped MLV than simply soaking the eggs in virions. These findings underscore the potential of targeting the schistosome egg for germ line transgenesis.


Mold colonization of fiberglass insulation of the air distribution system: effects on patients with hematological malignancies.
We investigated mold colonization of air handling units (AHUs) of heating, ventilating, and air conditioning (HVAC) systems and its effects, including invasive pulmonary mycoses and febrile neutropenia, in patients with hematological malignancies. Sample collection with transparent adhesive tape and culture swabs revealed that AHUs were heavily colonized with molds, including thermotolerant, variously distributed Penicillium spp. Cases of nosocomial invasive pulmonary mycosis were not clustered in specific patient rooms but did occur frequently when the HVAC systems were not in use, prior to intervention (i.e., sealing and disuse of AHUs in private room), and during construction of a new hospital building. Multivariate logistic regression analysis of initial episodes of febrile neutropenia showed that the rate of febrile neutropenia was significantly associated with the duration of neutropenia (odds ratio [OR]: 1.16; 95% confidence interval [CI]: 1.07-1.27) and with sex (OR: 0.469; CI: 0.239-0.902). An evaluation of private rooms showed that female patients also had a lower rate of fever after intervention (OR: 0.0016; 95% CI: 0.000-0.209). The reduced rate of febrile neutropenia after intervention suggests that mold colonization of AHUs had adverse effects on patients with hematological malignancies.


Why the elderly could bankrupt Canada and how demographic imperatives will force the redesign of acute care service delivery.
Canada's aging population poses a significant challenge for the existing healthcare system. While individuals 65 and older accounted for 13.7% of the population in 2005, they accounted for 60% of all acute care service spending. This paper further illustrates how the heterogeneity of the older population and its impact on patterns of healthcare use demonstrate the failings of our current care systems. Our outdated acute care models frequently disadvantage the system's highest users, who are often characterized by factors such as poly-morbidity, functional impairment and social frailty. Understanding how implementing innovative models that challenge deeply ingrained ways of providing care has proven to be a significant challenge, this paper highlights one hospital's mission to transform current traditional paradigms of care by developing and implementing an elder-friendly hospital integrated service delivery model. This hospital aims to demonstrate wide-ranging benefits of this model that can contribute toward optimizing the outcomes of hospitalization for older adults and the system as a whole. The establishment of a national agency that could support the development of a national aging strategy to promote best practice dissemination and implementation could also ensure that the significant health, social and economic benefits that better care models can realize could be more easily achieved.


How I do it: a novel method that provides simultaneous coronary artery occlusion and retraction for beating heart bypass surgery.
Coronary artery stabilization and retraction have been a crucial problem in beating heart bypass surgery. Conventional methods such as looping and suspension of the target artery carry risk of coronary artery damage. Above all, these methods do not aid in retraction in coronary arteriotomy. Five mongrel dogs were used in this study. After intratracheal general anesthesia, median sternotomy was performed, and the left anterior descending coronary artery (LAD) and right coronary artery (RCA) were chosen as target vessels. To stabilize epicardium we passed the proximal portion of each coronary artery with a pledgeted suture parallel to the orientation of the coronary artery through the arteriotomy. After a similar suture was passed on the distal side, pledgets were placed on both sides of the incised coronary artery, and tourniquets were applied and snared just after opening of the target coronary artery for occlusion of proximal and distal flow. The tourniquets also were pulled up at an angle of 45 degrees on both sides for stabilization of the epicardium and retraction of the arteriotomy edges. All instances of snare-induced coronary occlusion and retraction were analyzed (10 coronary snares in 5 dogs, the RCA and the LAD of each dog being used). Flow in the coronary artery was stopped, and visualization of the arteriotomy was successful. We described a novel technique of temporary coronary artery stabilization and occlusion that provided simultaneous retraction in coronary arteriotomy. This procedure resulted in a clean and retracted operative field for suitable anastomosis even in the arteriotomy edges.


Inferring ancestral sequences in taxon-rich phylogenies.
Statistical consistency in phylogenetics has traditionally referred to the accuracy of estimating phylogenetic parameters for a fixed number of species as we increase the number of characters. However, it is also useful to consider a dual type of statistical consistency where we increase the number of species, rather than characters. This raises some basic questions: what can we learn about the evolutionary process as we increase the number of species? In particular, does having more species allow us to infer the ancestral state of characters accurately? This question is particularly important when sequence evolution varies in a complex way from character to character, as methods applicable for i.i.d. models may no longer be valid. In this paper, we assemble a collection of results to analyse various approaches for inferring ancestral information with increasing accuracy as the number of taxa increases.


Controlling propulsive forces in gait initiation in transfemoral amputees.
During prosthetic gait initiation, transfemoral (TF) amputees control the spatial and temporal parameters that modulate the propulsive forces, the positions of the center of pressure (CoP), and the center of mass (CoM). Whether their sound leg or the prosthetic leg is leading, the TF amputees reach the same end velocity. We wondered how the CoM velocity build up is influenced by the differences in propulsive components in the legs and how the trajectory of the CoP differs from the CoP trajectory in able bodied (AB) subjects. Seven TF subjects and eight AB subjects were tested on a force plate and on an 8 m long walkway. On the force plate, they initiated gait two times with their sound leg and two times with their prosthetic leg. Force measurement data were used to calculate the CoM velocity curves in horizontal and vertical directions. Gait initiated on the walkway was used to determine the leg preference. We hypothesized that because of the differences in propulsive components, the motions of the CoP and the CoM have to be different, as ankle muscles are used to help generate horizontal ground reaction force components. Also, due to the absence of an active ankle function in the prosthetic leg, the vertical CoM velocity during gait initiation may be different when leading with the prosthetic leg compared to when leading with the sound leg. The data showed that whether the TF subjects initiated a gait with their prosthetic leg or with their sound leg, their horizontal end velocity was equal. The subjects compensated the loss of propulsive force under the prosthesis with the sound leg, both when the prosthetic leg was leading and when the sound leg was leading. In the vertical CoM velocity, a tendency for differences between the two conditions was found. When initiating gait with the sound leg, the downward vertical CoM velocity at the end of the gait initiation was higher compared to when leading with the prosthetic leg. Our subjects used a gait initiation strategy that depended mainly on the active ankle function of the sound leg; therefore, they changed the relative durations of the gait initiation anticipatory postural adjustment phase and the step execution phase. Both legs were controlled in one single system of gait propulsion. The shape of the CoP trajectories, the applied forces, and the CoM velocity curves are described in this paper.


Spatial navigation in autism spectrum disorders: a critical review.
On the basis of relative strengths that have been attributed to the autistic cognitive profile, it has been suggested by a number of theorists that people with autism spectrum disorders (ASD) excel at spatial navigational tasks. However, many of these claims have been made in the absence of a close inspection of extant data in the scientific literature, let alone anecdotal reports of daily navigational experiences. The present review gathers together published studies that have attempted to explicitly address functional components of navigation in ASD populations, including assays of wayfinding, large-scale search, and path integration. This inspection reveals a pattern of apparent strengths and weaknesses in navigational abilities, thus illustrating the necessity for a more measured and comprehensive approach to the understanding of spatial behavior in ASD.


Increases in plasma levels of atrial and brain natriuretic peptides after running a marathon: are their effects partly counterbalanced by adrenocortical steroids?
Long-distance running results in considerable stress. Little evidence exists about the role of the atrial and brain natriuretic peptides, ANP and BNP, deriving from the myocardium. The aim of our study was to investigate the influence of running 42.195 km on changes in circulating natriuretic propeptides and adrenocortical steroids. We studied 17 male and 2 female runners (age: 28-62 Years) participating in a marathon. Blood samples were obtained before and immediately after the competition. proANP(1-98) and proANP(1-30) as well as Nt-proBNP(8-29) were determined by enzyme immunoassays. Runners finished the competition between 2 h 58 min and 4 h 25 min. We observed a more pronounced increase in proANP(1-98) (+58%) and proANP(1-30) (+99%, both P<0.001) compared with Nt-proBNP(8-29) (+6%; P=0.005). Increases in proANP(1-30) positively correlated with runners' age (r=0.53; P=0.02). We also observed a marked increase in cortisol (+73%) and especially in aldosterone (+431%, both P<0.001). Cardiac strain during long-distance running may explain the pronounced increase in proANP. Other explanations for the observed rise in plasma levels might be a change in the permeability of myocardial cells and an impaired clearance. A rise in adrenocortical steroids may compensate for the negative influence of ANP on natriuresis and blood pressure. Positive effects of ANP during a marathon could be the regulation of body temperature by influencing sweat glands as well as the stimulation of lipolysis compensating for the enormous energy demand.


Optical modulation transfer and contrast sensitivity with decentered small pupils in the human eye.
Human observers experience a large decrement in visual acuity when a small artificial pupil is displaced from the center to the edge of the dilated natural pupil. This decrement in visual resolution, called the Campbell effect, has been attributed to the retina, the ocular optics, or a combination of the two. Given the uncertainty about the relative magnitudes of these two components over the range of spatial frequencies used in normal vision, we have obtained objective measurements of the retinal image quality and psychophysical measurements of visual performance, with decentered pupils. The contributions of monochromatic aberrations were determined by using double pass measurements of the modulus of the optical transfer function (MTF). For all of the observers, there was a substantial decrement in the MTF with decentering, showing that even when using a 1.5 mm pupil and appropriate spherical/cylindrical refractive corrections, there is a considerable contribution of monochromatic aberrations to the effect. We have compared these optical MTFs with the psychophysical contrast sensitivity functions (CSFs) measured under exactly the same conditions using green gratings generated on the screen of a color monitor. At the low and intermediate spatial frequencies considered (2-16 c/deg), we find the fall in the CSF is much greater than the fall in the monochromatic MTF, with the difference becoming greater as the spatial frequency increases. We show that this discrepancy can be mostly attributed to the effect of transverse chromatic aberration due to the bandwidth of the green stimulus used for the CSF measurements. In conclusion, the combination of the ocular transverse chromatic aberration and monochromatic aberrations accounts for the loss in visual sensitivity found with a decentered small pupil at low and intermediate spatial frequencies.


Healthcare costs of colorectal cancer screening and events following colonoscopy among commercially insured average-risk adults in the United States.
To examine the healthcare costs associated with colorectal cancer (CRC) screening and the frequency and costs of events potentially related to colonoscopy among average-risk adults. In this cohort study, adults (ages 50-75 years) with CRC screening between 1/1/2014 and 6/30/2019 (index = earliest test) were selected from the IBM MarketScan Research databases. Individuals at above-average risk for CRC or with prior CRC screening were excluded. Frequency of utilization was reported by screening type: colonoscopy, fecal immunochemical test (FIT), fecal occult blood test (FOBT), multi-target stool DNA (mt-sDNA). For colonoscopy, frequency and costs of potential events were reported overall, by event type, and by an individual event in the 30 days after colonoscopy. Among the 333,306 average-risk adults, colonoscopy was the most common CRC screening modality (70.6%), followed by FIT (17.7%), FOBT (8.1%), and mt-sDNA (3.2%). The mean cost of a colonoscopy procedure was $2,125 and the mean out-of-pocket costs were $79. Serious gastrointestinal (GI) events were observed in 1.3% of individuals with colonoscopy, 1.9% had other GI events, and 1.2% had an incident cardiovascular event. Mean event-related costs were $2,631 among individuals with a serious GI event, $1,774 among individuals with any other GI event, and $4,234 among individuals with a cardiovascular event. This study provides updated and more detailed information regarding the costs of CRC screening and potential colonoscopy events based on a comprehensive review of a robust claims dataset.


Development and Feasibility of Self-Management Application in Left-Ventricular Assist Devices.
Despite major advancements in mechanical circulatory support, the self-management (SM) for patients with a left-ventricular assist device (LVAD) remains complex and challenging for patients and their caregivers. We have developed a mobile phone application (VAD Care App) to organize and simplify the LVAD SM process. This article describes the development and feasibility study of the app as an SM tool for LVAD patients and caregivers requiring support from ventricular assist device (VAD) coordinators. The specific aim was to evaluate the app's acceptability and usability and the users' competency. App features included an automated alert, data collection/reporting, and dynamic real-time interaction systems embedded in the LVAD SM process. Beta-testing of the prototype was completed by five adults. For the feasibility study, we employed a mixed-method descriptive research design involving nine patients and nine caregivers from two VAD centers in the Midwest. We asked them to use the app daily for more than 30 days and complete an app Evaluation Questionnaire and an interview. The questionnaire uses a five-point rating scale (1 = strongly disagree to 5 = strongly agree) evaluating usability, acceptability, and competency domains. Data generated from the questionnaires and interviews were analyzed with descriptive statistics and content analytic procedures. A total of 16 users (eight patients [all male] and eight caregivers [seven female]) aged 22 to 68 years completed the 30 day study. Median acceptability, usability, and competency scores were 4.6, 4.5, and 4.7, respectively. Based on the data, it is feasible for patients and caregivers to use an app as an LVAD SM tool warranting further research.


Probing the topography of free and polymeric Ig-bound human secretory component with monoclonal antibodies.
Secretory component (SC), an integral membrane protein expressed on basolateral surfaces of secretory epithelial cells, mediates the transport of polymeric Ig (PIg) into external secretions. The ectoplasmic segment of SC is released into secretions either in a free form (FSC) or bound to PIg as secretory IgA or IgM. The topography of human SC in its free and PIgA-bound form was studied by using mAb directed against each form of SC. Competition experiments identified a minimum of nine SC epitopes, one of which was dependent on an N-glycosidic moiety. Three of the polypeptide-derived epitopes were displayed on denatured, reduced, and alkylated SC, whereas the others were fully or partially dependent on the native conformation of SC. Epitopes recognized by the latter class of antibodies were mapped to discrete domains of SC, based on amino acid sequence and antibody-binding analysis of limited proteolytic fragments. One of the mAb (6G11), which was directed against an epitope on domain I of SC, inhibited the binding of FSC to PIgA. Overall, our results provide evidence that a region within domain I, as well as protease-sensitive interdomain regions of FSC, become masked or altered when SC binds to PIgA. Furthermore, the binding of SC to PIgA results in conformational changes, or formation of combinatorial epitopes, involving regions within domains II and III of SC but not domain V.