Multidisciplinary Care of Patients with Inherited Metabolic Diseases and Epilepsy: Current Perspectives.
More than 650 inherited metabolic diseases may present with epilepsy or seizures. These diseases are often multisystem, life-long and induce complex needs of patients and families. Multidisciplinary care involves all stages of disease management: diagnostics, specific or symptomatic, acute and chronic treatments, and integrated care that takes into account not only medical, but also manifold psychosocial, educational, vocational and other needs of patients and their caregivers. Care coordination is indispensable to ensure smooth transitions of care across life and disease stages, including management of emergencies, transition from pediatric to adult services and palliative care. Care pathways are highly diverse and have to find the right balance between highly specialized and locally provided services. While multidisciplinary teams consist of many professionals, a named supervising physician in a highly specialized healthcare setting and a care coordinator are highly important. As the greatest burden of care always falls onto the shoulders of patients and/or families, patient empowerment should be a part of every care pathway and include provision of required information, involvement into common decision-making, patient's and family's education, support for self-management, liaison with peer support groups and emotional/ psychological support. Due to the rarity and complexity of these diseases, sufficient expertise may not be available in a national healthcare system and cross-border services (virtual or physical) in the recently developed European Reference Networks should be ensured through the proper organization of referral systems in each EU and EEA country. Finally, digital technologies are particularly important in the provision of services for patients with rare diseases and can significantly increase the availability of highly specialized services and expertise.


Reshaping the path of vascular cognitive impairment with resistance training: a study protocol for a randomized controlled trial.
Subcortical ischemic vascular cognitive impairment (SIVCI) is the most common form of vascular cognitive impairment. Importantly, SIVCI is considered the most treatable form of cognitive impairment in older adults, due to its modifiable risk factors such as hypertension, diabetes mellitus, and hypercholesterolemia. Exercise training is a promising intervention to delay the progression of SIVCI, as it actively targets these cardiometabolic risk factors. Despite the demonstrated benefits of resistance training on cognitive function and emerging evidence suggesting resistance training may reduce the progression of white matter hyperintensities (WMHs), research on SIVCI has predominantly focused on the use of aerobic exercise. Thus, the primary aim of this proof-of-concept randomized controlled trial is to investigate the efficacy of a 12-month, twice-weekly progressive resistance training program on cognitive function and WMH progression in adults with SIVCI. We will also assess the efficiency of the intervention. Eighty-eight community-dwelling adults, aged > 55 years, with SIVCI from metropolitan Vancouver will be recruited to participate in this study. SIVCI will be determined by the presence of cognitive impairment (Montreal Cognitive Assessment < 26) and cerebral small vessel disease using computed tomography or magnetic resonance imaging. Participants will be randomly allocated to a twice-weekly exercise program of (1) progressive resistance training or (2) balance and tone training (i.e., active control). The primary outcomes are cognitive function measured by the Alzheimer's Disease Assessment Scale-Cognitive-Plus (ADAS-Cog-13 with additional cognitive tests) and WMH progression. The burden of SIVCI is immense, and to our knowledge, this will be the first study to quantify the effect of progressive resistance training on cognitive function and WMH progression among adults with SIVCI. Slowing the rate of cognitive decline and WMH progression could preserve functional independence and quality of life. This could lead to reduced health care costs and avoidance of early institutional care. ClinicalTrials.gov NCT02669394 . Registered on February 1, 2016.


Real-time analysis of G protein-coupled receptor signaling in live cells.
Seven transmembrane-spanning receptors, widely referred to as G protein-coupled receptors (GPCRs), mediate a broad spectrum of extracellular signals at the plasma membrane through G proteins, thereby modulating a variety of biological processes. In addition to G proteins, they also interact with a number of other cytoplasmic proteins. Thus, methods to understand GPCR signaling and their interactions with intracellular proteins in real time in live cells are of importance. Recent developments in microscopy methods and the availability of fluorescent proteins facilitated the development of techniques to unravel these interactions more precisely. This chapter describes the methodology for sequential capturing of images of membrane and cytoplasmic proteins fused to different fluorescence probes to understand GPCR interaction with cytosolic proteins and their colocalization.


Diabetes mellitus in ataxia-telangiectasia, Fanconi anemia, xeroderma pigmentosum, common variable immune deficiency, and severe combined immune deficiency families.
The hypothesis that heterozygous carriers of genes for certain autosomal recessive syndromes may be predisposed to diabetes was tested by comparing diabetes incidence from age 20 to 69 yr in blood relatives to that in spouse controls among 7999 adult family members of patients with one of five autosomal recessive syndromes: ataxia-telangiectasia (A-T), Fanconi anemia (FA), xeroderma pigmentosum (XP), common variable immune deficiency (CVID), and severe combined immune deficiency (SCID). FA and A-T families were studied because earlier findings in family members and the frequency of diabetes in homozygotes suggested that heterozygotes might also be predisposed to diabetes. The XP, CVID, and SCID families were included to see what analysis of family data would reveal when there was no prior evidence for a gene-diabetes association. The diabetes rate ratios of 2.6 and 4.2 among FA and SCID females, respectively, were significantly elevated. For female FA heterozygotes specifically, the estimated relative risk of 5.1 for developing diabetes was also significantly elevated. Among males, the most pronounced, although not statistically significant, findings were an elevated rate ratio of 2.2 for A-T males and a low-rate ratio of 0.5 for CVID males. The results suggest that heterozygotes for some of the diabetes-associated autosomal recessive syndromes may themselves be predisposed to diabetes.


Tailored motivational message generation: A model and practical framework for real-time physical activity coaching.
This paper presents a comprehensive and practical framework for automatic generation of real-time tailored messages in behavior change applications. Basic aspects of motivational messages are time, intention, content and presentation. Tailoring of messages to the individual user may involve all aspects of communication. A linear modular system is presented for generating such messages. It is explained how properties of user and context are taken into account in each of the modules of the system and how they affect the linguistic presentation of the generated messages. The model of motivational messages presented is based on an analysis of existing literature as well as the analysis of a corpus of motivational messages used in previous studies. The model extends existing 'ontology-based' approaches to message generation for real-time coaching systems found in the literature. Practical examples are given on how simple tailoring rules can be implemented throughout the various stages of the framework. Such examples can guide further research by clarifying what it means to use e.g. user targeting to tailor a message. As primary example we look at the issue of promoting daily physical activity. Future work is pointed out in applying the present model and framework, defining efficient ways of evaluating individual tailoring components, and improving effectiveness through the creation of accurate and complete user- and context models.


A CYP3A4 phenotype-based dosing algorithm for individualized treatment of irinotecan.
Irinotecan, the prodrug of SN-38, is extensively metabolized by cytochrome P450-3A4 (CYP3A4). A randomized trial was done to assess the utility of an algorithm for individualized irinotecan dose calculation based on a priori CYP3A4 activity measurements by the midazolam clearance test. Patients were randomized to receive irinotecan at a conventional dose level of 350 mg/m(2) (group A) or doses based on an equation consisting of midazolam clearance, gamma-glutamyl-transferase, and height (group B). Pharmacokinetics and toxicities were obtained during the first treatment course. Demographics of 40 evaluable cancer patients were balanced between both groups, including UGT1A1*28 genotype and smoking status. The absolute dose of irinotecan ranged from 480 to 800 mg in group A and 380 to 1,060 mg in group B. The mean absolute dose and area under the curve of irinotecan and SN-38 were not significantly different in either group (P > 0.18). In group B, the interindividual variability in the area under the curve of irinotecan and SN-38 was reduced by 19% and 25%, respectively (P > 0.22). Compared with group A, the incidence of grades 3 to 4 neutropenia was >4-fold lower in group B (45 versus 10%; P = 0.013). The incidence of grades 3 to 4 diarrhea was equal in both groups (10%). Incorporation of CYP3A4 phenotyping in dose calculation resulted in an improved predictability of the pharmacokinetic and toxicity profile of irinotecan, thereby lowering the incidence of severe neutropenia. In combination with UGT1A1*28 genotyping, CYP3A4 phenotype determination should be explored further as a strategy for the individualization of irinotecan treatment.


Evaluating Animal-Based Foods and Plant-Based Alternatives Using Multi-Criteria and SWOT Analyses.
Global diets have transitioned in recent decades with animal and processed products increasing. Promoting a reversal in these trends towards plant-based diets could reduce the environmental impacts of food systems and reduce the prevalence of non-communicable diseases and malnutrition. In Spain, a reference point for the Mediterranean diet (predominantly plant-source based), plant-based alternatives to traditional animal-based products are receiving increased attention. However, limited focus has been given to the opinions of stakeholder groups on the potential of these novel products. We evaluate the opinions of stakeholders within the Spanish agri-food sector, using multicriteria and SWOT analyses, on traditional and novel food products. Stakeholders involved in the supply chain of food products (producers, processors, and distributors) were critical of novel plant-based foods, highlighting problems with their taste, processing technology, and high prices. These results contrast with the perspectives of policymakers, researchers, environmental NGOs, and consumers who see novel products more positively - healthier, more sustainable, and highly profitable. These results illustrate the more traditional mindset seen in Spanish production systems, contrasting with the rapidly shifting tastes and demands of consumers and the potential legislative orientation of policymakers. This study calls for improved understanding and collaboration between stakeholders to better manage complex choices that affect the future of food systems during their needed transformation.


Comparative Efficacy of Methylprednisolone Acetate and Dexamethasone Disodium Phosphate in Lumbosacral Transforaminal Epidural Steroid Injections.
Transforaminal epidural steroid injection (TFESI) is an effective treatment for lumbosacral radicular pain. But in view of accidental intravascular injections and consequent neurological injuries, the safety profile of particulate steroids has been questioned. Dexamethasone (DEXA), being non-particulate, is presumed to be a safe replacement for earlier particulate agents. However, the efficacy of DEXA is still doubtful as compared to particulate steroids. The present study aims to determine the comparative efficacy of DEXA and methylprednisolone (MP) in terms of pain relief and improvement of disability. Seventy-six patients were sorted into two groups (MP and DEXA) to receive lumbar TFESI. A protocol of one-time single- or two-level TFESI with equipotent doses of MP or DEXA was followed. Numeric Rating Scale (NRS) and Roland-Morris Disability Questionnaire (RMDQ) scores were collected pre-treatment and at different times for a duration of 6 months at follow-up appointments. Overall, the extent of pain relief (determined from NRS) and quality of life (determined from RMDQ) were significantly better (p<0.01) in patients belonging to MP group following TFESI. NRS was 2.8±1.2, 3.3±1, 5.1±1.6 and 3.9±1.4, 4.5±1.3, 6.2±1.1 respectively in MP and DEXA group at 1 month, 3 months and 6months of follow-up, whereas RMDQ was 7.9±2.8, 7.4±2.3, 8.5±2.4 and 10±2.2, 11.4±2.6, 12.4±2.7 respectively in MP and DEXA group at similar time points. The immediate and short term pain relief following TFESI in lumbar radicular pain remained satisfactory and is comparable between MP and DEXA groups, but the long term benefit is significantly more with the use of MP, as evidenced by the NRS and RMDQ scores.


Royal jelly-like protein localization reveals differences in hypopharyngeal glands buildup and conserved expression pattern in brains of bumblebees and honeybees.
Royal jelly proteins (MRJPs) of the honeybee bear several open questions. One of them is their expression in tissues other than the hypopharyngeal glands (HGs), the site of royal jelly production. The sole MRJP-like gene of the bumblebee, Bombus terrestris (BtRJPL), represents a pre-diversification stage of the MRJP gene evolution in bees. Here we investigate the expression of BtRJPL in the HGs and the brain of bumblebees. Comparison of the HGs of bumblebees and honeybees revealed striking differences in their morphology with respect to sex- and caste-specific appearance, number of cells per acinus, and filamentous actin (F-actin) rings. At the cellular level, we found a temporary F-actin-covered meshwork in the secretory cells, which suggests a role for actin in the biogenesis of the end apparatus in HGs. Using immunohistochemical localization, we show that BtRJPL is expressed in the bumblebee brain, predominantly in the Kenyon cells of the mushroom bodies, the site of sensory integration in insects, and in the optic lobes. Our data suggest that a dual gland-brain function preceded the multiplication of MRJPs in the honeybee lineage. In the course of the honeybee evolution, HGs dramatically changed their morphology in order to serve a food-producing function.


Identification of a Novel Small RNA srvg23535 in Vibrio alginolyticus ZJ-T and Its Characterization With Phenotype MicroArray Technology.
Small non-coding RNAs (sRNAs) are important modulators of gene expression and are involved in the pathogenesis and survival of prokaryotes. However, few studies have been conducted with Vibrio alginolyticus, which limits our ability to probe the regulation of virulence and environmental adaptation by sRNAs in this opportunistic pathogen. In this study, the sRNA candidate srvg23535 was identified in V. alginolyticus ZJ-T. The precise transcript end, secondary structure, and sequence conservation were determined. A srvg23535 null mutant was constructed and characterized by using Phenotype MicroArray (PM) technology. In silico target prediction was conducted by IntaRNA and TargetRNA2. Subsequently, a 107 nt transcript was validated with a sigma70 promoter at the 5' end and a Rho-independent terminator at the 3' end. The sRNA srvg23535 had four stem-loop structures and was conserved among Vibrio harveyi, Vibrio parahaemolyticus, and Vibrio splendidus. Deletion of srvg23535 in V. alginolyticus ZJ-T led to a weaker utilization of D-mannose, D-melibiose, lactulose, and inosine as carbon sources but stronger utilization of L-cysteine as nitrogen source. Moreover, the srvg2353 mutant showed stronger resistance to osmotic stress but weaker resistance to pH stress. Additionally, a total of 22 common targets were identified and several were related to the observed phenotype of the mutant. This study indicated that the novel sRNA, srvg23535, is conserved and restricted to Vibrio spp., affecting the utilization of several carbon and nitrogen sources and the response to osmotic and pH stress. These results extend our understanding of sRNA regulation in V. alginolyticus and provide a significant resource for the further study of the precise target mRNAs of srvg23535, which may provide targets for antibacterial therapeutic or attenuated vaccines against Vibrio spp.


Introducing a standard method for experimental determination of the solvent response in laser pump, X-ray probe time-resolved wide-angle X-ray scattering experiments on systems in solution.
In time-resolved laser pump, X-ray probe wide-angle X-ray scattering experiments on systems in solution the structural response of the system is accompanied by a solvent response. The solvent response is caused by reorganization of the bulk solvent following the laser pump event, and in order to extract the structural information of the solute, the solvent response has to be treated. Methodologies capable of doing so include both theoretical modelling and experimental determination of the solvent response. In the work presented here, we have investigated how to obtain a reproducible solvent response-the solvent term-experimentally when applying laser pump, X-ray probe time-resolved wide-angle X-ray scattering. The solvent term describes difference scattering arising from the structural response of the solvent to changes in the hydrodynamic parameters: pressure, temperature and density. We present results based on NIR and dye mediated solvent heating, and demonstrate that the solvent response is independent of the heating method. The NIR heating is shown to be rendered unusable by higher order effects under certain experimental conditions, while the dye mediated solvent heating is demonstrated to exhibit first order behaviour with respect to the amount of energy deposited in the solution. We introduce a standardized method for recording solvent responses in laser pump, X-ray probe time-resolved X-ray wide-angle scattering experiments by using dye mediated solvent heating. Furthermore, we have generated a library of solvent terms, which can be used to describe the solvent term in any TRWAXS experiment, and made it available online.


Children with medical complexities: their distinct vulnerability in health systems' Covid-19 response and their claims of justice in the recovery phase.
In this paper, we discuss the lack of consideration given to children in the COVID-19 health systems policy response to the pandemic. We do this by focusing on the case of children with complex medical needs. We argue that, in broad terms, health systems policies that were implemented during the pandemic failed adequately to meet our obligations to both children generally and those with complex medical needs by failing to consider those needs and so to give them fair protection against harm and disadvantage. We argue that justice requires that the distinct needs and vulnerabilities of children with medical complexities are explicitly integrated and prioritised in decisions concerning healthcare and operational planning in the recovery phase and beyond.


The role of nutritional status in the outcome of peritoneal dialysis patients.
Abnormalities in nutritional status of peritoneal dialysis (PD) patients include too high body mass (overweight, obesity), too low body mass (underweight, starvation) or changes in body composition (malnutrition) without or with normal body weight. In vivo neutron activation analysis is considered the reference gold standard for the determination of protein malnourishment in end-stage renal disease patients, but body mass index (BMI) is the most frequently used parameter in nutritional assessment surveys. The association between BMI and outcome of PD patients is controversial, but so-called obesity paradox (the higher BMI the longer survival) remains frequently reported. The use of metabolic syndrome with high BMI as a crucial component is not more predictable in the prognosis of outcome in PD patients than using separately each risk factor of metabolic syndrome. Underweight/starvation is univocally underlined as associated with morbidity and mortality, but prevalence of severe undernutrition is decreasing over last decades, at least in well developed countries. PD patients may also present features of malnutrition without decreased body mass or even with increased body weight. It mainly concerns to deficiencies of vitamins, minerals and trace elements. Serum albumin concentration has serious limitations as a marker of nutritional status, because is influenced by volemic status and inflammation. Nutritional interventions in undernourished patients (oral, intestinal or intravenous feeding, amino acid peritoneal solution, supplementation of vitamins and trace elements) may correct deficiencies, but their influence on PD patients survival remains unclear.


Short run effects of a price on carbon dioxide emissions from U.S. electric generators.
The price of delivered electricity will rise if generators have to pay for carbon dioxide emissions through an implicit or explicit mechanism. There are two main effects that a substantial price on CO2 emissions would have in the short run (before the generation fleet changes significantly). First, consumers would react to increased price by buying less, described by their price elasticity of demand. Second, a price on CO2 emissions would change the order in which existing generators are economically dispatched, depending on their carbon dioxide emissions and marginal fuel prices. Both the price increase and dispatch changes depend on the mix of generation technologies and fuels in the region available for dispatch, although the consumer response to higher prices is the dominant effect. We estimate that the instantaneous imposition of a price of $35 per metric ton on CO2 emissions would lead to a 10% reduction in CO2 emissions in PJM and MISO at a price elasticity of -0.1. Reductions in ERCOT would be about one-third as large. Thus, a price on CO2 emissions that has been shown in earlier workto stimulate investment in new generation technology also provides significant CO2 reductions before new technology is deployed at large scale.


Pyruvate Dehydrogenase Complex Deficiency: An Unusual Cause of Recurrent Lactic Acidosis in a Paediatric Critical Care Unit.
Pyruvate dehydrogenase complex deficiency (PDCD) is a rare neurodegenerative disorder associated with abnormal mitochondrial metabolism. Structural brain abnormalities are common in PDCD. A case of a patient with PDCD with an unusual presentation is described. A 20-month-old boy with hypotonia and developmental delay, presented with hypoxia and respiratory distress due to bronchiolitis. During hospitalisation, he was prescribed PediaSure® feeds. Two days after starting these feeds, he developed respiratory arrest requiring intubation. His blood gas before arrest revealed lactate of 8.9 mmol/L despite normal haemodynamics. After stabilisation and a period of compulsory fasting, subsequent feeding with PediaSure® resulted in the recurrence of lactic acidosis. A metabolic workup revealed an elevated serum pyruvate level. Brain MRI was normal. Skeletal muscle biopsy confirmed PDCD. The most common cause of PDCD is a mutation in the X-linked PDHA1 gene. The severity of PDCD can range from neonatal death to more delayed onset of symptoms as in our index case. Normal brain MRI is reported in only 2% of patients with PDCD. There is no effective treatment for PDCD. In patients with proximal muscle weakness and feeding intolerance with glucose-containing feeds, the presence of lactic acidosis should raise the suspicion of PDCD irrespective of the patient's age and normal MRI.


Role of the Cj1371 periplasmic protein and the Cj0355c two-component regulator in the Campylobacter jejuni NCTC 11168 response to oxidative stress caused by paraquat.
Campylobacter jejuni is a microaerophilic pathogen representing one of the major causes of bacterial enteritis in humans. The oxidative stress response after exposure to paraquat, a strong oxidising agent, was analysed by two-dimensional protein electrophoresis and Maldi-ToF mass spectrometry. Oxidative stress and redox-related proteins were overexpressed: FldA flavodoxin and a pyruvate-flavodoxin oxidoreductase encoded by cj1476c. No increase in SodB expression was observed. An additional quantitative RT-PCR analysis showed an increase in katA but not in sodB expression. However, the sodB mutant was very sensitive to paraquat, its basal expression level being essential for oxidative stress resistance. Proteins related to iron homeostasis (Cft and a non-haem iron protein encoded by cj0012c) and general stress response (FusA and MreB) were found overexpressed. Interestingly, a two-component regulator encoded by cj0355c was differentially expressed in the presence of paraquat and could play a role in induction of the C. jejuni oxidative stress response. Virulence factors (CadF, FlaA and a VacJ homolog encoded by cj1371) were also found overexpressed under oxidative stress conditions and a cj1371 mutant showed increased sensitivity to paraquat, suggesting that the Cj1371 periplasmic protein could play a role in C. jejuni oxidative stress resistance.


Imported human brucellosis in Belgium: Bio and molecular typing of bacterial isolates, 1996-2015.
The aim of this study was to characterize by classical biotyping and Multi-Locus variable number tandem repeats (VNTR) Analysis (MLVA) all Brucella spp. derived from human cases in Belgium from 1996 to 2015. Final goals were to determine the species and biovar, to trace-back on genetic grounds the origin of each strain when patient history and risk factors were missing, and to survey for particular trends at the national level. A total of 37 Brucella strains, isolated from 37 patients in Belgium, were analyzed by both classical biotyping and MLVA, and the genetic patterns compared to those of human strains isolated worldwide. Classical biotyping revealed that isolates were mainly Brucella melitensis. Most of them belonged to biovar 3, the most abundant biovar in the Mediterranean region. MLVA confirmed that Brucella melitensis is too diverse in VNTRs to be able to make clusters associated to each biovar, but it allowed retrieving precious epidemiological information. The analysis highlighted the imported nature of the strains from all over the world with a dominant part from the Mediterranean countries. Findings of the MLVA11 testing were in line with the travel history of patients coming from Italy, Turkey, Lebanon and Peru. The analysis was particularly useful because it suggested the geographical origin of the infection for 12/16 patients for whom no case history was available. Classical biotyping and MLVA analysis are not exclusive but remain complementary tools for Brucella melitensis strain surveillance. MLVA11 is sufficient for Brucella-free countries such as Belgium to trace the geographical origin of infection, but complete MLVA16 is needed to search for links with endemic areas.


Nonfermentative bacilli: evaluation of three systems for identification.
Three systems for the identification of nonfermentative bacilli were evaluated for their rapidity and accuracy of identification of 217 strains. Two of the systems, API 20E (API) and Oxi/Ferm tube (OxiF), are available as kits; the oxidative attack (OA) system is not commerically available. The overall accuracies of the OA, API, and OxiF systems were 91, 69, and 50%, respectively. Identification within 48 h was achieved for 98% of the strains by OA, for 50% by API, and for 18% by OxiF. Most of the organisms that were either misidentified or not identified by API and OxiF were those nonfermentative bacilli which are relatively more fastidious or rarely encountered or both. All three systems accurately identified nonfermentative bacilli commonly isolated at Olive View Medical Center, namely, Pseudomonas aeruginosa, Acinetobacter anitratus, Pseudomonas maltophilia, Acinetobacter lwoffi, saccharolytic flavobacteria (CDC IIb), moraxellae, Pseudomonas fluorescens, and Pseudomonas putida. The OA system identified 100% of the above organisms correctly, API identified 99.4%, and OxiF identified 99.3%. Since these organisms comprise 92% of the total number of nonfermentative bacilli isolated at Olive View Medical Center, we conclude that both API and OxiF may be useful alternatives to conventional methods, based on accuracy of identification alone. These two systems were considered substantially inferior to the OA system when both accuracy and rapidity of identification were taken into account.


Exercise for osteoarthritis of the knee: a Cochrane systematic review.
To determine whether land-based therapeutic exercise is beneficial for people with knee osteoarthritis (OA) in terms of reduced joint pain or improved physical function and quality of life. Five electronic databases were searched, up until May 2013. Randomised clinical trials comparing some form of land-based therapeutic exercise with a non-exercise control were selected. Three teams of two review authors independently extracted data and assessed risk of bias for each study. Standardised mean differences immediately after treatment and 2-6 months after cessation of formal treatment were separately pooled using a random effects model. In total, 54 studies were identified. Overall, 19 (35%) studies reported adequate random sequence generation, allocation concealment and adequately accounted for incomplete outcome data. However, research results may be vulnerable to selection, attrition and detection bias. Pooled results from 44 trials indicated that exercise significantly reduced pain (12 points/100; 95% CI 10 to 15) and improved physical function (10 points/100; 95% CI 8 to 13) to a moderate degree immediately after treatment, while evidence from 13 studies revealed that exercise significantly improved quality of life immediately after treatment with small effect (4 points/100; 95% CI 2 to 5). In addition, 12 studies provided 2-month to 6-month post-treatment sustainability data which showed significantly reduced knee pain (6 points/100; 95% CI 3 to 9) and 10 studies which showed improved physical function (3 points/100; 95% CI 1 to 5). Among people with knee osteoarthritis, land-based therapeutic exercise provides short-term benefit that is sustained for at least 2-6 months after cessation of formal treatment.


A global representation of vitamin D status in healthy populations.
This paper visualizes the available data on vitamin D status on a global map, examines the existing heterogeneities in vitamin D status and identifies research gaps. A graphical illustration of global vitamin D status was developed based on a systematic review of the worldwide literature published between 1990 and 2011. Studies were eligible if they included samples of randomly selected males and females from the general population and assessed circulating 25-hydroxyvitamin D [25(OH)D] levels. Two different age categories were selected: children and adolescents (1-18 years) and adults (>18 years). Studies were chosen to represent a country based on a hierarchical set of criteria. In total, 200 studies from 46 countries met the inclusion criteria, most coming from Europe. Forty-two of these studies (21 %) were classified as representative. In children, gaps in data were identified in large parts of Africa, Central and South America, Europe, and most of the Asia/Pacific region. In adults, there was lack of information in Central America, much of South America and Africa. Large regions were identified for which the mean 25(OH)D levels were below 50 nmol/L. This study provides an overview of 25(OH)D levels around the globe. It reveals large gaps in information in children and adolescents and smaller but important gaps in adults. In view of the importance of vitamin D to musculoskeletal growth, development, and preservation, and of its potential importance in other tissues, we strongly encourage new research to clearly define 25(OH)D status around the world.


Effects of dietary interventions on neonatal and infant outcomes: a systematic review and meta-analysis.
Nutrition plays a fundamental role in fetal growth and birth outcomes. We synthesized effects of dietary interventions before or during pregnancy on neonatal and infant outcomes. Randomized controlled trials that assessed the whole diet or dietary components and neonatal or infant outcomes were included. Two authors independently identified articles to be included and assessed the methodologic quality. A meta-analysis was conducted separately for each outcome by using a random-effects model. Results were reported by dietary intervention as follows: 1) counseling, 2) food and fortified food products, or 3) a combination (counseling plus food) intervention, and 4) collectively for all dietary interventions. Results were subanalyzed by the nutrient of interest, country income, and BMI. Of 2326 abstracts screened, a total of 29 randomized controlled trials (31 publications) were included in this review. Food and fortified food products were effective in increasing birth weight [standardized mean difference (SMD): 0.27; 95% CI: 0.14, 0.40; P < 0.01] and reducing the incidence of low birth weight (SMD: -0.22; 95% CI: -0.37, -0.06; P < 0.01). All dietary interventions and those focused on macronutrient intake also increased birth weight (P < 0.01) and length (P < 0.05) and reduced the incidence of low birth weight (P < 0.01). Dietary interventions in low-income countries and underweight or nutritionally at-risk populations increased birth weight (P < 0.05) and reduced the incidence of low birth weight (P = 0.01). No effects were seen for the following other outcomes: placental weight, head circumference, macrosomia, Apgar score, small for gestational age, large for gestational age, and perinatal mortality. Additional high-quality randomized controlled trials that test different dietary interventions are required to identify maternal diet intakes that optimize neonatal and infant outcomes.


Derivation of high-purity definitive endoderm from human parthenogenetic stem cells using an in vitro analog of the primitive streak.
Human parthenogenetic stem cells (hpSCs) are pluripotent stem cells with enormous potential as cell sources for cell-based therapies: hpSCs may have histocompatibilty advantages over human embryonic stem cells (hESCs) and derivation of hpSCs does not require viable blastocyst destruction. For translation of all pluripotent stem cell-based therapies, derivation of differentiated cell products that are not contaminated with undifferentiated cells is a major technical roadblock. We report here a novel method to derive high-purity definitive endoderm (DE) from hpSCs, based on reproducing features of the normal human embryonic microenvironment. The method mimics the developmental process of transition through a primitive streak, using a differentiation device that incorporates a three-dimensional extracellular matrix (ECM) combined with a porous membrane. Treatment of undifferentiated hpSCs above the membrane results an epithelial-to-mesenchymal transition (EMT); thus, responsive cells acquire the ability to migrate through the membrane into the ECM, where they differentiate into DE. Importantly, the resultant DE is highly purified, and is not contaminated by undifferentiated cells, as assessed by OCT4 expression using immunocytochemistry and flow cytometry. The functional properties of the DE are also preserved by the process: DE differentiated in the device can generate a highly enriched population of hepatocyte-like cells (HLCs) characterized by expression of hepatic lineage markers, indocyanine green clearance, glycogen storage, cytochrome P450 activity, and engraftment in the liver after transplantation into immunodeficient mice. The method is broadly applicable and we obtained purified DE using hESCs, as well as several hpSC lines. The novel method described here represents a significant step toward the efficient generation of high-purity cells derived from DE, including hepatocytes and pancreatic endocrine cells, for use in regenerative medicine and drug discovery, as well as a platform for studying cell fate specification and behavior during development.


Solvation and hydrogen bonding aided efficient non-radiative deactivation of polar excited state of 5-aminoquinoline.
The fluorescence of 5-aminoquinoline (5AQ) is quenched strongly in alcoholic solvents, in stark contrast to the enhancement in fluorescence observed earlier for its positional isomer, 3-aminoquinoline (3AQ). This phenomenon has been explained by the involvement of a highly dipolar excited state, which is manifested in the solvatochromism of 5AQ. A marked wavelength dependence of fluorescence decays of 5AQ in alcoholic solvents is ascribed to the ultrafast solvation of the highly dipolar excited state in these solvents. The resultant stabilization of this state leads to a decrease in the gap between its energy and lower lying triplet as well as ground singlet states, resulting in an efficient non-radiative relaxation and consequently, fluorescence quenching. Solvation dynamics reported for 5AQ is somewhat slower than earlier reports with coumarin probes, due to the involvement of solute-solvent hydrogen bonds, especially in the excited state of the solute. At lower temperatures, solvation is slowed down. An extreme case of this phenomenon is the absence of solvent relaxation at liquid nitrogen temperature. The fluorescence lifetime increases from tens of picoseconds at room temperature to tens of nanoseconds at cryogenic temperature, lending credence to the proposed model.


Expression and function of TNF-family proteins and receptors in human osteoblasts.
We studied how tumor necrosis-factor (TNF)-family proteins interact with osteoblasts to resolve several controversial points. We measured expression of TNFs, TNF-receptors, and nonsignaling (decoy) TNF receptors in human osteoblasts derived from mesenchymal stem cells and in MG63 human osteosarcoma cells using unamplified mRNA screening, with secondary Western or PCR analysis where indicated, and studied the effects of TNFs on osteoblasts in cell culture. Expression of TNFs and receptors was similar in MG63 cells and osteoblasts. TNF-R1 (p55), TRAIL receptor 1 and 2 (DR4 and 5), and Fas were expressed; RANK was undetectable. TNF-family ligands RANKL, TRAIL, and TNFalpha were expressed, but mRNAs were typically at low levels relative to receptors, suggesting that osteoblastic TNF signals, including RANKL, require specific stimuli. Flow cytometry of MG63 cells confirmed TNFalpha receptors and identified subpopulations with high surface-bound TNFalpha. Decoy receptors expressed included a novel soluble form of TNFRSF25 (formerly DR3 or Apo3), implicated in rheumatoid-arthritis linkage studies, as well as osteoprotegerin, a well-characterized osteoblast protein that binds TRAIL and RANKL, and DcR2, which binds TRAIL. Osteoblast apoptosis was studied using terminal deoxynucleotidyl transferase labeling and annexin V binding. MG63 cells were resistant to apoptosis by exogenous TNFalpha except when grown in media promoting osteoblast-like growth or matrix nodules. However, in media supporting osteoblast-like phenotype, apoptosis was induced by anti-Fas or TNF, in contrast to other studies with human osteoblasts. TRAIL caused cell retraction, supporting functional TRAIL response in cell differentiation, but did not cause apoptosis. We conclude that human osteoblasts have functional receptors for FasL, TNFalpha, TRAIL, but not RANKL, and that osteoblasts are protected by multiple nonsignaling TNF receptors against destruction by TNF-family proteins under conditions favoring cell growth.


Regional and temporal trends in malaria commodity costs: an analysis of Global Fund data for 79 countries.
Although procurement consumes nearly 40% of Global Fund's money, no analyses have been published to show how costs vary across regions and time. This paper presents an analysis of malaria-related commodity procurement data from 79 countries, as reported through the Global Fund's price and quality reporting (PQR) system for the 2005-2012 period. Data were analysed for the three most widely procured commodities for prevention, diagnosis and treatment of malaria. These were long-lasting insecticide-treated nets (LLINs), malaria rapid diagnostic tests (RDTs) and the artemether/lumefantrine (AL) combination treatment. Costs were compared across time (2005-2012), regions, and between individual procurement reported through the PQR and pooled procurement reported through the Global Fund's voluntary pooled procurement (VPP) system. All costs were adjusted for inflation and reported in US dollars. The data included 1,514 entries reported from 79 countries over seven years. Of these, 492 entries were for LLINs, 330 for RDTs and 692 for AL. Considerable variations were seen by commodity, although none showed an increase in cost. The costs for LLINs, RDTs and AL all dropped significantly over the period of analysis. Regional variations were also seen, with the cost for all three commodities showing significant variations. The median cost for a single LLIN ranged from USD 4.3 in East Asia to USD 5.0 in West and Central Africa. The cost of a single RDT was lowest in West and Central Africa at US$ 0.57, and highest in the Latin American region at US$ 1.1. AL had the narrowest margin of between US$ 0.06 per tablet in sub-Saharan Africa and South Asia, and US$ 0.08 in the Latin American and Eastern Europe regions. This paper concludes that global procurement costs do vary by region and have reduced overall over time. This suggests a mature market is operating when viewed from the global level, but regional variation needs further attention. Such analyses should be done more often to identify and correct market insufficiencies.


Mechanisms of social regulation change across colony development in an ant.
Mutual policing is an important mechanism for reducing conflict in cooperative groups. In societies of ants, bees, and wasps, mutual policing of worker reproduction can evolve when workers are more closely related to the queen's sons than to the sons of workers or when the costs of worker reproduction lower the inclusive fitness of workers. During colony growth, relatedness within the colony remains the same, but the costs of worker reproduction may change. The costs of worker reproduction are predicted to be greatest in incipient colonies. If the costs associated with worker reproduction outweigh the individual direct benefits to workers, policing mechanisms as found in larger colonies may be absent in incipient colonies. We investigated policing behaviour across colony growth in the ant Camponotus floridanus. In large colonies of this species, worker reproduction is policed by the destruction of worker-laid eggs. We found workers from incipient colonies do not exhibit policing behaviour, and instead tolerate all conspecific eggs. The change in policing behaviour is consistent with changes in egg surface hydrocarbons, which provide the informational basis for policing; eggs laid by queens from incipient colonies lack the characteristic hydrocarbons on the surface of eggs laid by queens from large colonies, making them chemically indistinguishable from worker-laid eggs. We also tested the response to fertility information in the context of queen tolerance. Workers from incipient colonies attacked foreign queens from large colonies; whereas workers from large colonies tolerated such queens. Workers from both incipient and large colonies attacked foreign queens from incipient colonies. Our results provide novel insights into the regulation of worker reproduction in social insects at both the proximate and ultimate levels. At the proximate level, our results show that mechanisms of social regulation, such as the response to fertility signals, change dramatically over a colony's life cycle. At the ultimate level, our results emphasize the importance of factors besides relatedness in predicting the level of conflict within a colony. Our results also suggest policing may not be an important regulatory force at every stage of colony development. Changes relating to the life cycle of the colony are sufficient to account for major differences in social regulation in an insect colony. Mechanisms of conflict mediation observed in one phase of a social group's development cannot be generalized to all stages.


Technique for microdissection and measurement in biopsies of human small intestine.
A microdissection and measurement technique has been adapted for biopsy of human small intestine. Specimens fixed in alcohol and acetic acid are Schiff stained in bulk. Villi and crypts are then dissected out under a dissecting microscope, placed under a coverslip, examined, measured, and the number of mitoses in individual crypts counted. With this method specimens of normal small intestine have been found to have villi 500 microns to 1100 microns long and crypts 150 microns to 300 microns. These values were double those obtained when measuring sections of the same specimens stained with haematoxylin and eosin. The mean number of mitoses per crypt in normal duodenum and jejunum ranged from 1 to 12 and most of the cells in mitosis were in prophase or telophase. This rapid, sensitive, and inexpensive technique complements the available methods of measuring small intestinal architecture.


Interaction with DNA polymerase eta is required for nuclear accumulation of REV1 and suppression of spontaneous mutations in human cells.
Defects in the gene encoding human Poleta result in xeroderma pigmentosum variant (XP-V), an inherited cancer-prone syndrome. Poleta catalyzes efficient and accurate translesion DNA synthesis (TLS) past UV-induced lesions. In addition to Poleta, human cells have multiple TLS polymerases such as Poliota, Polkappa, Polzeta and REV1. REV1 physically interacts with other TLS polymerases, but the physiological relevance of the interaction remains unclear. Here we developed an antibody that detects the endogenous REV1 protein and found that human cells contain about 60,000 of REV1 molecules per cell as well as Poleta. In un-irradiated cells, formation of nuclear foci by ectopically expressed REV1 was enhanced by the co-expression of Poleta. Importantly, the endogenous REV1 protein accumulated at the UV-irradiated areas of nuclei in Poleta-expressing cells but not in Poleta-deficient XP-V cells. UV-irradiation induced nuclear foci of REV1 and Poleta proteins in both S-phase and G1 cells, suggesting that these proteins may function both during and outside S phase. We reconstituted XP-V cells with wild-type Poleta or with Poleta mutants harboring substitutions in phenylalanine residues critical for interaction with REV1. The REV1-interaction-deficient Poleta mutant failed to promote REV1 accumulation at sites of UV-irradiation, yet (similar to wild-type Poleta) corrected the UV sensitivity of XP-V cells and suppressed UV-induced mutations. Interestingly however, spontaneous mutations of XP-V cells were only partially suppressed by the REV1-interaction deficient mutant of Poleta. Thus, Poleta-REV1 interactions prevent spontaneous mutations, probably by promoting accurate TLS past endogenous DNA lesions, while the interaction is dispensable for accurate Poleta-mediated TLS of UV-induced lesions.


Young Adult Utilization of a Smoking Cessation Website: An Observational Study Comparing Young and Older Adult Patterns of Use.
There is little research on how young adults or young adult subgroups utilize and engage with Web-based cessation interventions when trying to quit smoking. Addressing this knowledge gap is important to identify opportunities to optimize the effectiveness of online cessation programs across diverse young adult users. This study examines utilization of the BecomeAnEX.org smoking cessation website among young adults and young adult subgroups compared with older adults to identify patterns of use by age, gender, and race/ethnicity. Study participants were 5983 new registered users on a free smoking cessation website who were aged 18 to 70 years. Website utilization was tracked for 6 months; metrics of use included website visits, pages per visit, length of visit, and interaction with specific website features. Differences in website use by age were examined via bivariate analyses and multivariate logistic regression adjusted for age, gender, and race/ethnicity. Interactions were examined to determine differences by gender and race/ethnicity within young (18- to 24-year-olds and 25- to 34-year-olds) and older (35 years and older) adult segments. A greater percentage of young adults aged 18 to 34 years visited the site only once compared with older adults aged 35 years and older (72.05% vs 56.59%, respectively; P<.001). Young adults also spent less time on the site and viewed fewer pages than older adults. In adjusted analyses, young adults were significantly less likely than older adults to visit the site more than once (18-24 years: adjusted odds ratio [AOR] 0.58, 95% CI 0.49-0.68, P<.001; 25-34 years: AOR 0.56, 95% CI 0.50-0.64, P<.001), spend more than 3 minutes on the site (18-24 years: AOR 0.67, 95% CI 0.57-0.79, P<.001; 25-34 years: AOR 0.56, 95% CI 0.49-0.64, P<.001), view 12 or more pages (18-24 years: AOR 0.72, 95% CI 0.61-0.83; P<.001; 25-34 years: AOR 0.67, 95% CI 0.59-0.76, P<.001), utilize the BecomeAnEX.org community (18-24 years: AOR 0.61, 95% CI 0.48-0.79, P<.001; 25-34 years: AOR 0.73, 95% CI 0.60-0.88, P<.001), or utilize Separation Exercises (18-24 years: AOR 0.68, 95% CI 0.51-0.89, P<.01; 25-34 years: AOR 0.77, 95% CI 0.63-0.94, P<.01). Gender differences in utilization were more pronounced among young adults compared with older adults, with lower levels of utilization among young men than young women. For all age groups, utilization was higher among whites and African Americans than among Hispanics and other racial minorities, with one exception-BecomeAnEX.org community utilization was significantly higher among Hispanic young adults compared with white and African American young adults. Results point to important areas of inquiry for future research and development efforts. Research should focus on enhancing demand and increasing engagement among younger adults and men, examining strategies for capitalizing on young adult developmental needs, and increasing utilization of effective site features among diverse young adult users.


Expanding the Biological Application of Fluorescent Benzothiadiazole Derivatives: A Phenotypic Screening Strategy for Anthelmintic Drug Discovery Using Caenorhabditis elegans.
The current methodologies used to identify promising new anthelmintic compounds rely on subjective microscopic examination of worm motility or involve genetic modified organisms. We describe a new methodology to detect worm viability that takes advantage of the differential incorporation of the fluorescent molecular marker propidium iodide and the 2,1,3-benzothiadiazole core, which has been widely applied in light technology. The new assay developed could be validated using the "Pathogen Box" library. By use of this bioassay, it was possible to identify three molecules with activity against Caenorhabditis elegans that were previously described as effective in in vitro assays against other pathogens, such as Schistosoma mansoni, Mycobacterium tuberculosis, and Plasmodium falciparum, accelerating the identification of molecules with anthelmintic potential. The current fluorescence-based bioassay may be used for assessing C. elegans viability. The described methodology replaces the subjectivity of previous assays and provides an enabling technology that is useful for rapid in vitro screens of both natural and synthetic compound libraries. It is expected that the results obtained from these robust in vitro screens would select the most effective compounds for follow-up in vivo experimentation with pathogenic helminths.


Altered mitochondrial functioning induced by preoperative fasting may underlie protection against renal ischemia/reperfusion injury.
We reported previously that the robust protection against renal ischemia/reperfusion (I/R) injury in mice by fasting was largely initiated before the induction of renal I/R. In addition, we found that preoperative fasting downregulated the gene expression levels of complexes I, IV, and V of the mitochondrial oxidative phosphorylation (OXPHOS) system, while it did not change those of complexes II and III. Hence, we now investigated the effect of 3 days of fasting on the functioning of renal mitochondria in order to better understand our previous findings. Fasting did not affect mitochondrial density. Surprisingly, fasting significantly increased the protein expression of complex II of the mitochondrial OXPHOS system by 19%. Complex II-driven state 3 respiratory activity was significantly reduced by fasting (46%), which could be partially attributed to the significant decrease in the enzyme activity of complex II (16%). Fasting significantly inhibited Ca(2+) -dependent mitochondrial permeability transition pore opening that is directly linked to protection against renal I/R injury. The inhibition of the mitochondrial permeability transition pore did not involve the expression of the voltage-dependent anion channel by fasting. In conclusion, 3 days of fasting clearly induces the inhibition of complex II-driven mitochondrial respiration state 3 in part by decreasing the amount of functional complex II, and inhibits mitochondrial permeability transition pore opening. This might be a relevant sequence of events that could contribute to the protection of the kidney against I/R injury.


Injuries and Footwear (Part 1): Athletic Shoe History and Injuries in Relation to Foot Arch Height and Training in Boots.
This article traces the history of the athletic shoe, examines whether selecting running shoes based on foot arch height influences injuries, and examines historical data on injury rates when physical training (PT) is performed in boots versus running shoes. In the 1980s and into the 2000s, running shoe companies were advertising specialized shoes with "motion control," "stability," and "cushioning," designed for individuals with low, normal, and high arches, respectively. Despite marketing claims that these shoes would reduce injury rates, coordinated studies in Army, Air Force, and Marine Corps basic training showed that assigning or selecting shoes on this basis had no effect on injury rates. Consistent with this finding, biomechanical studies have shown that the relationships between arch height, foot joint mobility, and rear-foot motion are complex, variable, and frequently not as strong as often assumed. In 1982, the US Army switched from PT in boots to PT in running shoes because of the belief that boots were causing injuries and that running shoes would reduce injury rates. However, a historical comparison of injury rates before and after the switch to running shoes showed virtually no difference in injury risk between the two periods. It is not clear at this point if the type of footwear effects injury incidence.


Predicting amphibian intraspecific diversity with machine learning: Challenges and prospects for integrating traits, geography, and genetic data.
The growing availability of genetic data sets, in combination with machine learning frameworks, offers great potential to answer long-standing questions in ecology and evolution. One such question has intrigued population geneticists, biogeographers, and conservation biologists: What factors determine intraspecific genetic diversity? This question is challenging to answer because many factors may influence genetic variation, including life history traits, historical influences, and geography, and the relative importance of these factors varies across taxonomic and geographic scales. Furthermore, interpreting the influence of numerous, potentially correlated variables is difficult with traditional statistical approaches. To address these challenges, we analysed repurposed data using machine learning and investigated predictors of genetic diversity, focusing on Nearctic amphibians as a case study. We aggregated species traits, range characteristics, and >42,000 genetic sequences for 299 species using open-access scripts and various databases. After identifying important predictors of nucleotide diversity with random forest regression, we conducted follow-up analyses to examine the roles of phylogenetic history, geography, and demographic processes on intraspecific diversity. Although life history traits were not important predictors for this data set, we found significant phylogenetic signal in genetic diversity within amphibians. We also found that salamander species at northern latitudes contained low genetic diversity. Data repurposing and machine learning provide valuable tools for detecting patterns with relevance for conservation, but concerted efforts are needed to compile meaningful data sets with greater utility for understanding global biodiversity.


Phosphate tablets or polyethylene glycol for preparation to colonoscopy? A multicentre non-inferiority randomized controlled trial.
Adequate bowel preparation is a crucial step in colonoscopy procedure and has been identified as the cornerstone of a quality colonoscopy. Polyethylene glycol (PEG) for bowel cleansing still had up to 10 % unprepared colon. We herein compare efficacy, acceptability, tolerance and safety of sodium phosphate (NaP) tablets and split-dose PEG for bowel cleansing. A prospective non-inferiority randomized trial was performed and registered on www.clinicaltrials.gov (NCT01840553). Patients were randomized to either 32 NaP tablets or 4 L of PEG. Blind readers assessed the efficacy of colon cleansing using the Boston Bowel Preparation Scale (BBPS). A total of 461 patients were randomized in groups (NaP group: n = 231; PEG group: n = 230). Median age was 54 and 52 in NaP group and PEG group, respectively (p < 0.01). Patients experienced an overall compliance to the treatment in 99.6 and 94.1 % in the NaP group and in the PEG group, respectively (p < 0.001). The mean time of withdrawal was 15.1 ± 8.9 and 15.4 ± 9.5 min in the NaP group and in the PEG group, respectively (p = 0.95). The good quality of bowel preparation, defined as BBPS score ≥7, was obtained in 86.4 and 89.0 % of cases in the NaP group and in the PEG group, respectively (p = 0.42). In all segment (right colon, transverse colon and left colon and rectum), the NaP group was non-inferior to the PEG group. Bowel prep regimen was more frequently considered as "easy" by patients from the NaP group (54.8 % of patients) than patients from the PEG group (29.0 % of patients; p < 0.001). No serious adverse events were reported. No statistical differences were found between the NaP group and the PEG group concerning the incidence of an adverse event (338 vs. 322, respectively). While NaP tablets appeared as efficient as PEG in terms of colon cleansing prior to a colonoscopy, they significantly improved the overall compliance and eased product administration. At an era where bowel cleansing appears to be the cornerstone of a quality colonoscopy, NaP tablets in patients without contraindication might be considered as an option.


Why Dom34 stimulates growth of cells with defects of 40S ribosomal subunit biosynthesis.
A set of genome-wide screens for proteins whose absence exacerbates growth defects due to pseudo-haploinsufficiency of ribosomal proteins in Saccharomyces cerevisiae identified Dom34 as being particularly important for cell growth when there is a deficit of 40S ribosomal subunits. In contrast, strains with a deficit of 60S ribosomal proteins were largely insensitive to the loss of Dom34. The slow growth of cells lacking Dom34 and haploinsufficient for a protein of the 40S subunit is caused by a severe shortage of 40S subunits available for translation initiation due to a combination of three effects: (i) the natural deficiency of 40S subunits due to defective synthesis, (ii) the sequestration of 40S subunits due to the large accumulation of free 60S subunits, and (iii) the accumulation of ribosomes "stuck" in a distinct 80S form, insensitive to the Mg(2+) concentration, and at least temporarily unavailable for further translation. Our data suggest that these stuck ribosomes have neither mRNA nor tRNA. We postulate, based on our results and on previously published work, that the stuck ribosomes arise because of the lack of Dom34, which normally resolves a ribosome stalled due to insufficient tRNAs, to structural problems with its mRNA, or to a defect in the ribosome itself.


Molecular constituents of maxi KCa channels in human coronary smooth muscle: predominant alpha + beta subunit complexes.
1. Human large-conductance voltage- and calcium-sensitive K+ (maxi KCa) channels are composed of at least two subunits: the pore-forming subunit, alpha, and a modulatory subunit, beta. Expression of the beta subunit induces dramatic changes in alpha subunit function. It increases the apparent Ca2+ sensitivity and it allows dehydrosoyasaponin I (DHS-I) to upregulate the channel. 2. The functional coupling of maxi KCa channel alpha and beta subunits in freshly dissociated human coronary smooth muscle cells was assessed. To distinguish maxi KCa currents modulated by the beta subunit, we examined (a) their apparent Ca2+ sensitivity, as judged from the voltage necessary to half-activate the channel (V1/2), and (b) their activation by DHS-I. 3. In patches with unitary currents, the majority of channels were half-activated near -85 mV at 18 microM Ca2+, a value similar to that obtained when the human KCa channel alpha (HSLO) and beta (HKV,Ca beta) subunits are co-expressed. A small number of channels half-activated around 0 mV, suggesting the activity of the alpha subunit alone. 4. The properties of macroscopic currents were consistent with the view that most pore-forming alpha subunits were coupled to beta subunits, since the majority of currents had values for V1/2 near to -90 mV, and currents were potentiated by DHS-I. 5. We conclude that in human coronary artery smooth muscle cells, most maxi KCa channels are composed of alpha and beta subunits. The higher Ca2+ sensitivity of maxi KCa channels, resulting from their coupling to beta subunits, suggests an important role of this channel in regulating coronary tone. Their massive activation by micromolar Ca2+ concentrations may lead to a large hyperpolarization causing profound changes in coronary blood flow and cardiac function.


On the ASR and ASR thermal residues characterization of full scale treatment plant.
In order to obtain 85% recycling, several procedures on Automotive Shredder Residue (ASR) could be implemented, such as advanced metal and polymer recovery, mechanical recycling, pyrolysis, the direct use of ASR in the cement industry, and/or the direct use of ASR as a secondary raw material. However, many of these recovery options appear to be limited, due to the possible low acceptability of ASR based products on the market. The recovery of bottom ash and slag after an ASR thermal treatment is an option that is not usually considered in most countries (e.g. Italy) due to the excessive amount of contaminants, especially metals. The purpose of this paper is to provide information on the characteristics of ASR and its full-scale incineration residues. Experiments have been carried out, in two different experimental campaigns, in a full-scale tyre incineration plant specifically modified to treat ASR waste. Detailed analysis of ASR samples and combustion residues were carried out and compared with literature data. On the basis of the analytical results, the slag and bottom ash from the combustion process have been classified as non-hazardous wastes, according to the EU waste acceptance criteria (WAC), and therefore after further tests could be used in future in the construction industry. It has also been concluded that ASR bottom ash (EWC - European Waste Catalogue - code 19 01 12) could be landfilled in SNRHW (stabilized non-reactive hazardous waste) cells or used as raw material for road construction, with or without further treatment for the removal of heavy metals. In the case of fly ash from boiler or Air Pollution Control (APC) residues, it has been found that the Cd, Pb and Zn concentrations exceeded regulatory leaching test limits therefore their removal, or a stabilization process, would be essential prior to landfilling the use of these residues as construction material.


On the Effectiveness of Sampling for Evolutionary Optimization in Noisy Environments.
In real-world optimization tasks, the objective (i.e., fitness) function evaluation is often disturbed by noise due to a wide range of uncertainties. Evolutionary algorithms are often employed in noisy optimization, where reducing the negative effect of noise is a crucial issue. Sampling is a popular strategy for dealing with noise: to estimate the fitness of a solution, it evaluates the fitness multiple ([Formula: see text]) times independently and then uses the sample average to approximate the true fitness. Obviously, sampling can make the fitness estimation closer to the true value, but also increases the estimation cost. Previous studies mainly focused on empirical analysis and design of efficient sampling strategies, while the impact of sampling is unclear from a theoretical viewpoint. In this article, we show that sampling can speed up noisy evolutionary optimization exponentially via rigorous running time analysis. For the (1[Formula: see text]1)-EA solving the OneMax and the LeadingOnes problems under prior (e.g., one-bit) or posterior (e.g., additive Gaussian) noise, we prove that, under a high noise level, the running time can be reduced from exponential to polynomial by sampling. The analysis also shows that a gap of one on the value of [Formula: see text] for sampling can lead to an exponential difference on the expected running time, cautioning for a careful selection of [Formula: see text]. We further prove by using two illustrative examples that sampling can be more effective for noise handling than parent populations and threshold selection, two strategies that have shown to be robust to noise. Finally, we also show that sampling can be ineffective when noise does not bring a negative impact.


Habitat, food availability and group territoriality in the European badger, Meles meles.
Since European badgers (Meles meles L.) form non-cooperative groups in parts of their geographic range, but are solitary elsewhere, their social systems have been at the centre of a debate about the evolution of group living in the Carnivora. In a recent review of models of non-cooperative sociality, Woodroffe and Macdonald (1993) presented evidence in favour of two hypotheses, which suggested that badger groups might form because either the distribution of blocks of foodrich habitat, or the economics of excavating new setts, prevented the division of group territories into individual territories. We present data upon the response of badger spatial organisation to a reduction in food-patch dispersion, brought about by the conversion of carthwormpoor arable land to earthworm-rich pasture over a 15-year period. This change in the distribution of earthworm-rich habitats was accompanied by territory fission, facilitated by the excavation of new setts. This indicates that the availability of sett sites had not constrained territory size at the start of the study. However, sett distribution did define the size and configuration of the daughter territories. We also show that variation among territories in the availability of food-rich habitats was reflected in the reproductive rates and body weights of the groups that inhabited them, although there was no detectable effect upon group size.


Visualization of microtubule growth in living platelets reveals a dynamic marginal band with multiple microtubules.
The marginal band of microtubules maintains the discoid shape of resting blood platelets. Although studies of platelet microtubule coil structure conclude that it is composed of a single microtubule, no investigations of its dynamics exist. In contrast to previous studies, permeabilized platelets incubated with GTP-rhodamine-tubulin revealed tubulin incorporation at 7.9 (+/- 1.9) points throughout the coil, and anti-EB1 antibodies stained 8.7 (+/- 2.0) sites, indicative of multiple free microtubules. To pursue this result, we expressed the microtubule plus-end marker EB3-GFP in megakaryocytes and examined its behavior in living platelets released from these cells. Time-lapse microscopy of EB3-GFP in resting platelets revealed multiple assembly sites within the coil and a bidirectional pattern of assembly. Consistent with these findings, tyrosinated tubulin, a marker of newly assembled microtubules, localized to resting platelet microtubule coils. These results suggest that the resting platelet marginal band contains multiple highly dynamic microtubules of mixed polarity. Analysis of microtubule coil diameters in newly formed resting platelets indicates that microtubule coil shrinkage occurs with aging. In addition, activated EB3-GFP-expressing platelets exhibited a dramatic increase in polymerizing microtubules, which travel outward and into filopodia. Thus, the dynamic microtubules associated with the marginal band likely function during both resting and activated platelet states.


Isolation of Murine Adipose Tissue-derived Microvascular Fragments as Vascularization Units for Tissue Engineering.
A functional microvascular network is of pivotal importance for the survival and integration of engineered tissue constructs. For this purpose, several angiogenic and prevascularization strategies have been established. However, most cell-based approaches include time-consuming in vitro steps for the formation of a microvascular network. Hence, they are not suitable for intraoperative one-step procedures. Adipose tissue-derived microvascular fragments (ad-MVF) represent promising vascularization units. They can be easily isolated from fat tissue and exhibit a functional microvessel morphology. Moreover, they rapidly reassemble into new microvascular networks after in vivo implantation. In addition, ad-MVF have been shown to induce lymphangiogenesis. Finally, they are a rich source of mesenchymal stem cells, which may further contribute to their high vascularization potential. In previous studies we have demonstrated the remarkable vascularization capacity of ad-MVF in engineered bone and skin substitutes. In the present study, we report on a standardized protocol for the enzymatic isolation of ad-MVF from murine fat tissue.


Biochemical Recurrence in Prostate Cancer and Temporal Association to Bone Metastasis.
BACKGROUND Prostate cancer is a common cancer in men. Radical prostatectomy, i.e., the surgical removal of the entire prostate, is a frequently used option. Biochemical recurrence (BCR), i.e., detectable prostate specific antigen (PSA), is common in some men following such treatment. The timing of BCR to metastatic spread of disease in bones is usually a few years. If the biochemical failure occurs after a longer duration from the time of curative intent, it is generally believed to lead to local recurrence. CASE REPORT We report on two cases. A 78-year-old male was diagnosed with Gleason 7, prostate cancer in 2001. He subsequently underwent an open radical prostatectomy. Serial post-operative PSA's were undetectable (<0.01 ng/mL) up to 2016. He was diagnosed with a detectable PSA for the first time with a value of 0.3 ng/mL, that year. The PSA continued to rise to a level of 1.1 ng/mL. This rise in the PSA was within a 12-month interval. Subsequent bone scan and bone biopsy detected prostate cancer metastasis in multiple bones. Our second case was a 65-year-old male who underwent a laparoscopic radical prostatectomy in the year 2006 for a biopsy proven prostate cancer with Gleason 3+4=7. Serial post-operative PSA's were undetectable up to 2017. Within a span of 8 months, the PSA rose from 0.3 ng/mL to 1.52 ng/mL. A positron emission tomography scan demonstrated pubic bone lesion indicative of prostate cancer metastasis. CONCLUSIONS BCR can occur a decade after curative intent treatment of prostate cancer. The duration from BCR to detectable metastasis can be shorter. We demonstrated here that the site of recurrence, in such scenarios, can be distant metastasis and not local recurrence alone. Better imaging modalities are needed to identify the spread of prostate cancer at low levels of PSA.


A non-linear model of hydrogen production by Caldicellulosiruptor saccharolyticus for diauxic-like consumption of lignocellulosic sugar mixtures.
Caldicellulosiruptor saccharolyticus is an attractive hydrogen producer suitable for growth on various lignocellulosic substrates. The aim of this study was to quantify uptake of pentose and hexose monosaccharides in an industrial substrate and to present a kinetic growth model of C. saccharolyticus that includes sugar uptake on defined and industrial media. The model is based on Monod and Hill kinetics extended with gas-to-liquid mass transfer and a cybernetic approach to describe diauxic-like growth. Mathematical expressions were developed to describe hydrogen production by C. saccharolyticus consuming glucose, xylose, and arabinose. The model parameters were calibrated against batch fermentation data. The experimental data included four different cases: glucose, xylose, sugar mixture, and wheat straw hydrolysate (WSH) fermentations. The fermentations were performed without yeast extract. The substrate uptake rate of C. saccharolyticus on single sugar-defined media was higher on glucose compared to xylose. In contrast, in the defined sugar mixture and WSH, the pentoses were consumed faster than glucose. Subsequently, the cultures entered a lag phase when all pentoses were consumed after which glucose uptake rate increased. This phenomenon suggested a diauxic-like behavior as was deduced from the successive appearance of two peaks in the hydrogen and carbon dioxide productivity. The observation could be described with a modified diauxic model including a second enzyme system with a higher affinity for glucose being expressed when pentose saccharides are consumed. This behavior was more pronounced when WSH was used as substrate. The previously observed co-consumption of glucose and pentoses with a preference for the latter was herein confirmed. However, once all pentoses were consumed, C. saccharolyticus most probably expressed another uptake system to account for the observed increased glucose uptake rate. This phenomenon could be quantitatively captured in a kinetic model of the entire diauxic-like growth process. Moreover, the observation indicates a regulation system that has fundamental research relevance, since pentose and glucose uptake in C. saccharolyticus has only been described with ABC transporters, whereas previously reported diauxic growth phenomena have been correlated mainly to PTS systems for sugar uptake.


How do hoverflies use their righting reflex?
When taking off from a sloping surface, flies have to reorient themselves dorsoventrally and stabilize their body by actively controlling their flapping wings. We have observed that righting is achieved solely by performing a rolling manoeuvre. How flies manage to do this has not yet been elucidated. It was observed here for the first time that hoverfly reorientation is entirely achieved within 6 wingbeats (48.8 ms) at angular roll velocities of up to 10×103 deg s-1 and that the onset of their head rotation consistently follows that of their body rotation after a time lag of 16 ms. The insects' body roll was found to be triggered by the asymmetric wing stroke amplitude, as expected. The righting process starts immediately with the first wingbeat and seems unlikely to depend on visual feedback. A dynamic model for the fly's righting reflex is presented, which accounts for the head/body movements and the time lag recorded in these experiments. This model consists of a closed-loop control of the body roll, combined with a feedforward control of the head/body angle. During the righting manoeuvre, a strong coupling seems to exist between the activation of the halteres (which measure the body's angular speed) and the gaze stabilization reflex. These findings again confirm the fundamental role played by the halteres in both body and head stabilization processes.


HIV seroprevalence among military blood donors in Manica Province, Mozambique.
HIV seroprevalence data show an alarming HIV situation in central Mozambique, but little is known about the situation of HIV in Mozambican military personnel. This study is a retrospective analysis of laboratory records for voluntary blood donors at a rural hospital from January 1997 through December 1999. The hospital screened blood samples with HIV SPOT rapid test for HIV and rapid plasma reagin (RPR) serological test for syphilis. Of the 797 blood donors during this period, 110 (13.8%) were military personnel of whom 39.1% were HIV positive (35.0% in 1997, 33.3% in 1998 and 48.7% in 1999). Among the 687 nonmilitary donors 15.3% were HIV positive (P<0.0001 vs military). 74.4% of HIV-positive military personnel were also RPR positive. Conversely, only 3.0% of HIV-negative military donors were RPR positive. In light of the high rates of HIV and syphilis in military personnel, aggressive intervention measures must be taken to prevent and treat HIV and STDs in this population.


Gene expression microarray profiles of cumulus cells in lean and overweight-obese polycystic ovary syndrome patients.
The aim of this work was to study gene expression patterns of cultured cumulus cells from lean and overweight-obese polycystic ovary syndrome (PCOS) patients using genome-wide oligonucleotide microarray. The study included 25 patients undergoing in vitro fertilization and intra-cytoplasmic sperm injection: 12 diagnosed with PCOS and 13 matching controls. Each of the groups was subdivided into lean (body mass index (BMI) < 24) and overweight (BMI > 27) subgroups. The following comparisons of gene expression data were made: lean PCOS versus lean controls, lean PCOS versus overweight PCOS, all PCOS versus all controls, overweight PCOS versus overweight controls, overweight controls versus lean controls and all overweight versus all lean. The largest number of differentially expressed genes (DEGs), with fold change (FC) |FC| >or= 1.5 and P-value < 0.01, was found in the lean PCOS versus lean controls comparison (487) with most of these genes being down-regulated in PCOS. The second largest group of DEGs originated from the comparison of lean PCOS versus overweight PCOS (305). The other comparisons resulted in a much smaller number of DEGs (174, 109, 125 and 12, respectively). In the comparison of lean PCOS with lean controls, most DEGs were transcription factors and components of the extracellular matrix and two pathways, Wnt/beta-catenin and mitogen-activated protein kinase. When comparing overweight PCOS with overweight controls, most DEGs were of pathways related to insulin signaling, metabolism and energy production. The finding of unique gene expression patterns in cumulus cells from the two PCOS subtypes is in agreement with other studies that have found the two to be separate entities with potentially different pathophysiologies.


One CNV Discordance in NRXN1 Observed Upon Genome-wide Screening in 38 Pairs of Adult Healthy Monozygotic Twins.
Monozygotic (MZ) twins stem from the same single fertilized egg and therefore share all their inherited genetic variation. This is one of the unequivocal facts on which genetic epidemiology and twin studies are based. To what extent this also implies that MZ twins share genotypes in adult tissues is not precisely established, but a common pragmatic assumption is that MZ twins are 100% genetically identical also in adult tissues. During the past decade, this view has been challenged by several reports, with observations of differences in post-zygotic copy number variations (CNVs) between members of the same MZ pair. In this study, we performed a systematic search for differences of CNVs within 38 adult MZ pairs who had been misclassified as dizygotic (DZ) twins by questionnaire-based assessment. Initial scoring by PennCNV suggested a total of 967 CNV discordances. The within-pair correlation in number of CNVs detected was strongly dependent on confidence score filtering and reached a plateau of r = 0.8 when restricting to CNVs detected with confidence score larger than 50. The top-ranked discordances were subsequently selected for validation by quantitative polymerase chain reaction (qPCR), from which one single ~120kb deletion in NRXN1 on chromosome 2 (bp 51017111-51136802) was validated. Despite involving an exon, no sign of cognitive/mental consequences was apparent in the affected twin pair, potentially reflecting limited or lack of expression of the transcripts containing this exon in nerve/brain.


Are two interviews better than one? eyewitness memory across repeated cognitive interviews.
Eyewitnesses to a filmed event were interviewed twice using a Cognitive Interview to examine the effects of variations in delay between the repeated interviews (immediately & 2 days; immediately & 7 days; 7 & 9 days) and the identity of the interviewers (same or different across the two repeated interviews). Hypermnesia (an increase in total amount of information recalled in the repeated interview) occurred without any decrease in the overall accuracy. Reminiscence (the recall of new information in the repeated interview) was also found in all conditions but was least apparent in the longest delay condition, and came with little cost to the overall accuracy of information gathered. The number of errors, increased across the interviews, but the relative accuracy of participants' responses was unaffected. However, when accuracy was calculated based on all unique details provided across both interviews and compared to the accuracy of recall in just the first interview it was found to be slightly lower. The identity of the interviewer (whether the same or different across interviews) had no effects on the number of correct details. There was an increase in recall of new details with little cost to the overall accuracy of information gathered. Importantly, these results suggest that witnesses are unlikely to report everything they remember during a single Cognitive Interview, however exhaustive, and a second opportunity to recall information about the events in question may provide investigators with additional information.


Occupational therapy in a Medicare-approved home health agency.
The clinical and professional considerations of the occupational therapist in a Medicare-approved home health agency are discussed. These considerations include the effect of Medicare regulations on occupational therapy screening, evaluation, treatment, and discharge. An occupational therapy chart review was conducted to determine the diagnoses of patients, the duration of treatment, and the outcome of interventions. The results show that the majority of patients referred to an occupational therapist have more than one treatable diagnosis. The average duration of treatment is 7.25 visits per patient. The outcome of intervention shows that 79% of patients treated by occupational therapy were able to remain safely at home either independently or with assistance.


Induction of labour versus expectant monitoring for gestational hypertension or mild pre-eclampsia between 34 and 37 weeks' gestation (HYPITAT-II): a multicentre, open-label randomised controlled trial.
Gestational hypertension (GH) and pre-eclampsia (PE) can result in severe complications such as eclampsia, placental abruption, syndrome of Hemolysis, Elevated Liver enzymes and Low Platelets (HELLP) and ultimately even neonatal or maternal death. We recently showed that in women with GH or mild PE at term induction of labour reduces both high risk situations for mothers as well as the caesarean section rate. In view of this knowledge, one can raise the question whether women with severe hypertension, pre-eclampsia or deterioration chronic hypertension between 34 and 37 weeks of gestation should be delivered or monitored expectantly. Induction of labour might prevent maternal complications. However, induction of labour in late pre-term pregnancy might increase neonatal morbidity and mortality compared with delivery at term. Pregnant women with severe gestational hypertension, mild pre-eclampsia or deteriorating chronic hypertension at a gestational age between 34+0 and 36+6 weeks will be asked to participate in a multi-centre randomised controlled trial. Women will be randomised to either induction of labour or expectant monitoring. In the expectant monitoring arm, women will be induced only when the maternal or fetal condition detoriates or at 37+0 weeks of gestation. The primary outcome measure is a composite endpoint of maternal mortality, severe maternal complications (eclampsia, HELLP syndrome, pulmonary oedema and thromboembolic disease) and progression to severe pre-eclampsia. Secondary outcomes measures are respiratory distress syndrome (RDS), neonatal morbidity and mortality, caesarean section and vaginal instrumental delivery rates, maternal quality of life and costs. Analysis will be intention to treat. The power calculation is based on an expectant reduction of the maternal composite endpoint from 5% to 1% for an expected increase in neonatal RDS from 1% at 37 weeks to 10% at 34 weeks. This implies that 680 women have to be randomised. This trial will provide insight as to whether in women with hypertensive disorders late pre-term, induction of labour is an effective treatment to prevent severe maternal complications without compromising the neonatal morbidity. NTR1792 CLINICAL TRIAL REGISTRATION: http://www.trialregister.nl.


Adiponectin and future coronary heart disease events among men with type 2 diabetes.
Adiponectin, predominantly synthesized in the adipose tissue, seems to have substantial anti-inflammatory properties and to be a major modulator of insulin resistance and dyslipidemia, mechanisms that are associated with an increased atherosclerotic risk in diabetic patients. However, it is unknown whether higher levels of adiponectin are associated with a reduced risk for coronary heart disease (CHD) among diabetic individuals. We investigated the association between plasma adiponectin levels and incidence of CHD among 745 men with confirmed type 2 diabetes in the Health Professionals Follow-up Study. Participants were aged 46-81 years and were free of diagnosed cardiovascular disease at the time of blood draw in 1993/1994. During an average of 5 years of follow-up (3,980 person-years), we identified 89 incident cases of CHD (19 myocardial infarction and 70 coronary artery bypass surgery), confirmed by medical records. Levels of adiponectin were inversely associated with BMI and directly associated with age, alcohol intake, and duration of diabetes (P < 0.05). After adjustment for age, BMI, smoking, alcohol consumption, duration of diabetes, and other lifestyle factors, adiponectin was associated with a decreased risk for CHD events. The multivariate relative risk for CHD for a doubling of adiponectin was 0.71 (95% CI 0.53-0.95). Further adjustment for HDL cholesterol attenuated this association (0.78 [0.57-1.06]). The inverse association between adiponectin and CHD was consistent across strata of aspirin use, family history of myocardial infarction, alcohol consumption, insulin use, duration of diabetes, and levels of HbA(1c), triglycerides, C-reactive protein, and HDL cholesterol. Our study suggests that increased adiponectin levels are associated with a moderately decreased CHD risk in diabetic men. This association seems to be mediated in part by effects of adiponectin on HDL cholesterol levels.


Impact of Decreased Transmural Conduction Velocity on the Function of the Human Left Ventricle: A Simulation Study.
This study investigates the impact of reduced transmural conduction velocity (TCV) on output parameters of the human heart. In a healthy heart, the TCV contributes to synchronization of the onset of contraction in individual layers of the left ventricle (LV). However, it is unclear whether the clinically observed decrease of TCV contributes significantly to a reduction of LV contractility. The applied three-dimensional finite element model of isovolumic contraction of the human LV incorporates transmural gradients in electromechanical delay and myocyte shortening velocity and evaluates the impact of TCV reduction on pressure rise (namely, (dP/dt)max) and on isovolumic contraction duration (IVCD) in a healthy LV. The model outputs are further exploited in the lumped "Windkessel" model of the human cardiovascular system (based on electrohydrodynamic analogy of respective differential equations) to simulate the impact of changes of (dP/dt)max and IVCD on chosen systemic parameters (ejection fraction, LV power, cardiac output, and blood pressure). The simulations have shown that a 50% decrease in TCV prolongs substantially the isovolumic contraction, decelerates slightly the LV pressure rise, increases the LV energy consumption, and reduces the LV power. These negative effects increase progressively with further reduction of TCV. In conclusion, these results suggest that the pumping efficacy of the human LV decreases with lower TCV due to a higher energy consumption and lower LV power. Although the changes induced by the clinically relevant reduction of TCV are not critical for a healthy heart, they may represent an important factor limiting the heart function under disease conditions.


Chiral and achiral imidazole-linked tetrahedral zinc phosphonate frameworks with photoluminescent properties.
Presented here are three imidazole-linked tetrahedral zinc phosphonate frameworks based on a special ligand 2-(1-imidazole)-1-hydroxyl-1,1'-ethylidenediphosphonic acid (= ImhedpH4) with both an organic imidazole linker and inorganic phosphonate groups. Three new compounds, namely, [Zn2(ImhedpH2)2(ox)](H2ppz) (1), Zn3(ImhedpH)2(H2O)4 (2) and [Zn3(Imhedp)2](H2ppz) (3) (ox = oxalate and ppz = piperazine), were obtained by hydrothermal synthesis and structurally characterized by single-crystal X-ray diffraction. Compound 1 shows a chain structure with the ox ligands linking the [Zn2(ImhedpH2)2] units, and the resulting chains are further connected to form a 3D structure through the strong N-H···O and O-H···O hydrogen bonds between the neighboring chains. Compound 2 displays an inorganic layer structure with dangling imidazole units, where these protonated imidazoles also act as pillars between adjacent inorganic layers. Compound 3 features an unusual chiral three-dimensional (3D) Zn-Imhedp framework with guest H2ppz(2+) cations. It can be topologically represented as a 4-connected qtz network. Furthermore, the luminescent properties of the three compounds were investigated in the solid state.


Diabetic retinopathy and the effect of pregnancy.
Pregnancy is associated with increased risk of development and progression of diabetic retinopathy (DR). Although pregnancy does not have any long term effect on DR, progression of retinopathy changes occur in 50%-70% of cases. The greatest risk of worsening occurs during the second trimester and persists as long as 12 months postpartum. The other factors found to be associated with its progression include duration of the diabetes, severity of retinopathy at conception, hyperglycaemic control, anaemia and progression of coexisting hypertension. Because of the increased risk of progression of the disease in pregnancy, conception should be delayed till the ocular disease is treated and stabilized and laser photocoagulation should be promptly instituted in all cases of severe non-proliferative retinopathy and should not be delayed till the patient develops early proliferative changes. Good diabetic control before and during pregnancy can help prevent this increase in the progression and serious vision loss.


Performing bimanual activities: the experiences of young persons with hemiplegic cerebral palsy.
This qualitative research study was designed to explore and describe the process of planning and performing bimanual activities in young persons with hemiplegic cerebral palsy. Interviews with 10 persons individually and four persons in a focus group provided rich information about their reasoning when confronting problems as well as insight into how they view their situations. The data were analyzed using a comparative method. The findings show that the participants had to make conscious choices about what would be the most effective strategies to use for carrying out activities. The choices involved weighing different options to find the least negative alternative. Even when able to find alternative strategies for performing the activity, the participants were often dissatisfied with negative consequences related to the strategy. Examples of such negative consequences could be, for example, that they would have to accept a need for extra time, planning, or concentration, to perform desired activities. When selecting a strategy it was thus favorable to have a repertoire of strategies from which to choose. In conclusion, the planning and performing of bimanual activities turned out to be a complex process influenced by a range of factors both internal and external to the person.


Deep Learning for Assessing the Corneal Endothelium from Specular Microscopy Images up to 1 Year after Ultrathin-DSAEK Surgery.
To present a fully automatic method to estimate the corneal endothelium parameters from specular microscopy images and to use it to study a one-year follow-up after ultrathin Descemet stripping automated endothelial keratoplasty. We analyzed 383 post ultrathin Descemet stripping automated endothelial keratoplasty images from 41 eyes acquired with a Topcon SP-1P specular microscope at 1, 3, 6, and 12 months after surgery. The estimated parameters were endothelial cell density (ECD), coefficient of variation (CV), and hexagonality (HEX). Manual segmentation was performed in all images. Our method provided an estimate for ECD, CV, and HEX in 98.4% of the images, whereas Topcon's software had a success rate of 71.5% for ECD/CV and 30.5% for HEX. For the images with estimates, the percentage error in our method was 2.5% for ECD, 5.7% for CV, and 5.7% for HEX, whereas Topcon's software provided an error of 7.5% for ECD, 17.5% for CV, and 18.3% for HEX. Our method was significantly better than Topcon's (P < 0.0001) and was not statistically significantly different from the manual assessments (P > 0.05). At month 12, the subjects presented an average ECD = 1377 ± 483 [cells/mm2], CV = 26.1 ± 5.7 [%], and HEX = 58.1 ± 7.1 [%]. The proposed method obtains reliable and accurate estimations even in challenging specular images of pathologic corneas. CV and HEX, not currently used in the clinic owing to a lack of reliability in automatic methods, are useful biomarkers to analyze the postoperative healing process. Our accurate estimations allow now for their clinical use.


The Interobserver and Intraobserver Reliability of the Sanders Classification Versus the Risser Stage.
Estimation of skeletal maturity, classically performed using Risser sign, plays a crucial role in the treatment of AIS. Recent data, however, has shown the simplified Tanner-Whitehouse (Sanders) classification, based on an anteriorposterior (AP) hand radiographs, to correlate more closely to the rapid growth phase and thus curve progression. This study evaluated the interobserver and intraobserver reliability of the Sanders and Risser classifications among clinicians at different levels of training. Twenty AP scoliosis radiographs and 20 AP hand radiographs were randomized and distributed to 11 graders. The graders consisted of 3 orthopaedic residents, 3 spine fellows, 3 spine surgeons, and 1 radiologist. The graders were then asked to classify the radiographs according to the Sanders and Risser classifications. There were 3 rounds of grading, each done 3 weeks apart. The overall κ coefficient was then calculated for each system to evaluate the interobserver and intraobserver reliability. For all graders the average κ coefficient for the interobserver and intraobserver reliability of the Sanders classification was 0.54 and 0.62, respectively, and 0.46 and 0.49 for the Risser classification. With respect to spine attendings alone, the average κ coefficient for the interobserver and intraobserver reliability of Sanders classification was 0.72 and 0.77, respectively, and 0.46 and 0.67 for the Risser classification. Our study demonstrated that the Sanders classification had moderate reliability with respect to physicians at various levels of training and had good reliability with respect to attending spine surgeons. Interestingly, the Risser staging was found to have less interobserver and intraobserver reliability overall. The Sanders classification is a reliable and reproducible system and should be in the armamentarium of surgeons who treat adolescent idiopathic scoliosis. Level III.