Healthcare environments and spatial variability of healthcare associated infection risk: cross-sectional surveys.
Prevalence of healthcare associated infections remains high in patients in intensive care units (ICU), estimated at 23.4% in 2011. It is important to reduce the overall risk while minimizing the cost and disruption to service provision by targeted infection control interventions. The aim of this study was to develop a monitoring tool to analyze the spatial variability of bacteriological contamination within the healthcare environment to assist in the planning of interventions. Within three cross-sectional surveys, in two ICU wards, air and surface samples from different heights and locations were analyzed. Surface sampling was carried out with tryptic Soy Agar contact plates and Total Viable Counts (TVC) were calculated at 48 hrs (incubation at 37 °C). TVCs were analyzed using Poisson Generalized Additive Mixed Model for surface type analysis, and for spatial analysis. Through three cross-sectional survey, 370 samples were collected. Contamination varied from place-to-place, height-to-height, and by surface type. Hard-to-reach surfaces, such as bed wheels and floor area under beds, were generally more contaminated, but the height level at which maximal TVCs were found changed between cross-sectional surveys. Bedside locations and bed occupation were risk factors for contamination. Air sampling identified clusters of contamination around the nursing station and surface sampling identified contamination clusters at numerous bed locations. By investigating dynamic hospital wards, the methodology employed in this study will be useful to monitor contamination variability within the healthcare environment and should help to assist in the planning of interventions.


Discontinuation of L-asparaginase and poor response to prednisolone are associated with poor outcome of ETV6-RUNX1-positive pediatric B-cell precursor acute lymphoblastic leukemia.
ETV6-RUNX1-positive B precursor acute lymphoblastic leukemia (B-ALL) is a common subtype of pediatric B-ALL that has shown excellent outcomes in contemporary clinical trials for pediatric B-ALL. Examinations of the possibility of reducing therapeutic intensity may thus be explored. This prospective study examined outcomes in 205 pediatric patients with ETV6-RUNX1-positive B-ALL uniformly treated following the Japan Association of Childhood Leukemia Study Group (JACLS) ALL-02 protocol. The JACLS ALL-02 protocol does not employ minimal residual disease detected by polymerase chain reaction (PCR-MRD)-based risk stratification; however, 4-year event-free survival (EFS) and overall survival (OS) were 94.4 ± 1.6 and 97.5 ± 1.1%, respectively. In particular, 92 of 205 (44.9%) patients were successfully treated with a less intensive regimen involving only two cycles of high dose methotrexate and one course of re-induction therapy comprising vincristine, L-asparaginase (L-asp), pirarubicin, and prednisolone. Multivariate analysis revealed that discontinuation of L-asp and poor response to prednisolone was, respectively, associated with poor EFS (HR 6.3; 95% CI 1.3-27.0) and OS (HR 17.5; 95% CI 2.3-130), suggesting that the majority of ETV6-RUNX1-positive B-ALL cases may be cured by a less-intensive chemotherapy regimen if the risk stratification system including PCR-MRD monitoring and insufficient use of L-asp is avoided.


Intracellular distribution and stability of a luminescent rhenium(i) tricarbonyl tetrazolato complex using epifluorescence microscopy in conjunction with X-ray fluorescence imaging.
Optical epifluorescence microscopy was used in conjunction with X-ray fluorescence imaging to monitor the stability and intracellular distribution of the luminescent rhenium(i) complex fac-[Re(CO)3(phen)L], where phen = 1,10-phenathroline and L = 5-(4-iodophenyl)tetrazolato, in 22Rv1 cells. The rhenium complex showed no signs of ancillary ligand dissociation, a conclusion based on data obtained via X-ray fluorescence imaging aligning iodine and rhenium distributions. A diffuse reticular localisation was detected for the complex in the nuclear/perinuclear region of cells, by either optical or X-ray fluorescence imaging techniques. X-ray fluorescence also showed that the rhenium complex disrupted the homeostasis of some biologically relevant elements, such as chlorine, potassium and zinc.


BEAST 2: a software platform for Bayesian evolutionary analysis.
We present a new open source, extensible and flexible software platform for Bayesian evolutionary analysis called BEAST 2. This software platform is a re-design of the popular BEAST 1 platform to correct structural deficiencies that became evident as the BEAST 1 software evolved. Key among those deficiencies was the lack of post-deployment extensibility. BEAST 2 now has a fully developed package management system that allows third party developers to write additional functionality that can be directly installed to the BEAST 2 analysis platform via a package manager without requiring a new software release of the platform. This package architecture is showcased with a number of recently published new models encompassing birth-death-sampling tree priors, phylodynamics and model averaging for substitution models and site partitioning. A second major improvement is the ability to read/write the entire state of the MCMC chain to/from disk allowing it to be easily shared between multiple instances of the BEAST software. This facilitates checkpointing and better support for multi-processor and high-end computing extensions. Finally, the functionality in new packages can be easily added to the user interface (BEAUti 2) by a simple XML template-based mechanism because BEAST 2 has been re-designed to provide greater integration between the analysis engine and the user interface so that, for example BEAST and BEAUti use exactly the same XML file format.


Exploring the folding pathways of annexin I, a multidomain protein. I. non-native structures stabilize the partially folded state of the isolated domain 2 of annexin I.
Proteins of the annexin family constitute very attractive models because of their four approximately 70 residue domains, D1 to D4, exhibiting an identical topology comprising five helix segments with only a limited sequence homology of approximately 30%. We focus on the isolated D2 domain, which is only partially folded. A detailed analysis of this equilibrium partially folded state in aqueous solution and micellar solution using 15N-1H multidimensional NMR is presented. Comparison of the residual structure of the entire domain with that of shorter fragments indicates the presence of long-range transient hydrophobic interactions that slightly stabilize the secondary structure elements. The unfolded domain tends to behave as a four-helix, rather than as a five-helix domain. The ensemble of residual structures comprises: (i) a set of native structures consisting of three regions with large helix populations, in rather sharp correspondence with A, B and E helices, and a small helix population in the second part of the C helix; (ii) a set of non-native local structures corresponding to turn-like structures stabilized by several side-chain to side-chain interactions and helix-disruptive side-chains to backbone interactions. Remarkably, residues involved in these local non-native interactions are also involved, in the native structure, in structurally important non-local interactions. During the folding process of annexin I, the local non-native interactions have to switch to native long-range interactions. This structural switch reveals the existence of a sequence-encoded regulation of the folding pathways and kinetics, and emphasizes the key role of the non-native local structures in this regulation.


A current review of cytochrome P450 interactions of psychotropic drugs.
The number of psychotropic drugs has expanded tremendously over the past few decades with a proportional increase in drug-drug interactions. The majority of psychotropic agents are biotransformed by hepatic enzymes, which can lead to significant drug-drug interactions. Most drug-drug interactions of psychotropics occur at metabolic level involving the hepatic cytochrome P450 enzyme system. We searched the National Library of Medicine, PsycINFO, and Cochrane reviews from 1981 to 2012 for original studies including clinical trials, double-blind, placebo-controlled studies, and randomized controlled trials. In addition, case reports, books, review articles, and hand-selected journals were utilized to supplement this review. Based on the clinical intensity of outcome, cytochrome interactions can be classified as severe, moderate, and mild. Severe interactions include effects that might be acutely life threatening. They are mainly inhibitory interactions with cardiovascular drugs. Moderate interactions include efficacy issues. Mild interactions include nonserious side effects, such as somnolence. Psychotropic drugs may interact with other prescribed medications used to treat concomitant medical illnesses. A thorough understanding of the most prescribed medications and patient education will help reduce the likelihood of potentially fatal drug-drug interactions.


Low glomerular filtration rate as an associated risk factor for sarcopenic muscle strength: is creatinine or cystatin C-based estimation more relevant?
We aimed to evaluate the association of a decreased glomerular-filtration-rate (GFR <60 ml/min/1.73 m2), estimated using Modification of Diet in Renal Disease (MDRD), creatinine- and cystatin C-based (CKDEPI-CR and CKDEPI-CC) Chronic Kidney Disease Epidemiology Collaboration equations with handgrip strength (HGS). Community-dwelling males aged ≥60 years admitted to outpatient clinic were included. We used MDRD, CKDEPI-CR, and CKDEPI-CC formulas for GFR estimation and corrected these for body surface area. Muscle strength was assessed by HGS. 209 men (mean age 67.8 ± 6.4) were enrolled. Sixty-two patients (29.7%) had sarcopenic HGS. Subjects with sarcopenic HGS were older, had higher rate of a GFR < 60 ml/min/1.73 m2, had lower mid-upper arm circumference; tended to have lower creatine kinase, albumin, CKDEPI-CC-GFR levels; and higher BUN/creatinine ratio and cystatin C. Multivariate logistic regression analysis revealed a CKDEPI-CC lower than 60 ml/min/1.73 m2 as the only independent factor underlying sarcopenic HGS. Higher age tended to have an independent association. Only higher age was independently associated with low HGS when other estimations were used (p = 0.013 and p = 0.021 when MDRD and CKDEPI-CR were used, respectively). There is a strong association of a GFR level of <60 ml/min/1.73 m2 with sarcopenic HGS, when CKDEPI-CC formula is used.


Prognostic significance of tissue factor in pancreatic ductal adenocarcinoma.
Tissue factor (TF) is a transmembrane glycoprotein that plays roles in the blood coagulation and intracellular signaling pathways, and has also been suggested to modulate the biological behavior of cancer cells. In order to examine the clinicopathologic significance of TF expression in pancreatic ductal adenocarcinoma, TF expression was determined by immunohistochemistry using a newly raised anti-TF monoclonal antibody in 113 patients who had undergone surgical resection of pancreatic ductal adenocarcinoma. According to the incidence of tumor cell immunopositivity, patients were divided into "negative TF" (0%), "weak TF" (<25%), or "high TF" (25% or more) groups, which accounted for 11.6% (n = 13), 44.2% (n = 50), and 44.2% (n = 50) of the total, respectively. Increased TF expression was correlated with the extent of the primary tumor (P = 0.0043), lymph node metastasis (P = 0.0043), lymphatic distant metastasis (P = 0.0039), advanced tumor-node-metastasis stage (P = 0.0002), and high tumor grade (P = 0.0164). Multivariate analysis using the Cox proportional hazards model showed that high TF expression was an independent negative predictor for survival (hazard ratio, 2.014; P = 0.0076). Moreover, patients with TF-negative tumors had a significantly better prognosis even if lymph node metastasis was present (P < 0.0001). We also showed that TF knockdown by RNA interference suppressed the invasiveness of a pancreatic adenocarcinoma cell line in vitro. These results indicate that TF expression may contribute to the aggressiveness of pancreatic ductal adenocarcinoma by stimulating tumor invasiveness, and that evaluation of the primary tumor for TF expression may identify patients with a poor prognosis.


Cognitive and noncognitive neurological features of young-onset dementia.
The rarity of young-onset dementia (YOD), the broad differential diagnosis and unusual clinical presentations present unique challenges to correctly recognize the condition and establish an accurate diagnosis. Limited data exist regarding clinical features associated with dementia prior to the age of 45. We retrospectively assessed cognitive and noncognitive neurological characteristics of 235 patients who presented for evaluation of YOD to investigate the clinical characteristics of YOD compared to later-onset dementias and to identify clinical features associated with specific etiologies that may aid in the evaluation of YOD. Multiple cognitive domains were affected in most patients, and no significant differences in affected domains existed between groups. Early psychiatric and behavioral features occurred at very high frequencies. Nearly 80% of this YOD cohort had additional noncognitive symptoms or signs as a feature of their disease. Chorea was strongly associated with Huntington disease. Parkinsonism was not seen in patients having an autoimmune/inflammatory etiology. The rarity of YOD and the high frequency of early psychiatric features led to frequent misdiagnosis early in the clinical course. The high frequency of noncognitive symptoms and signs may aid clinicians in distinguishing patients requiring a more extensive evaluation for YOD.


Spatial Localization of Vitamin D Metabolites in Mouse Kidney by Mass Spectrometry Imaging.
Vitamin D plays a key role in the maintenance of calcium/phosphate homeostasis and elicits biological effects that are relevant to immune function and metabolism. It is predominantly formed through UV exposure in the skin by conversion of 7-dehydrocholsterol (vitamin D3). The clinical biomarker, 25-hydroxyvitamin D (25-(OH)-D), is enzymatically generated in the liver with the active hormone 1,25-dihydroxyvitamin D then formed under classical endocrine control in the kidney. Vitamin D metabolites are measured in biomatrices by liquid chromatography-tandem mass spectrometry (LC-MS/MS). In LC-MS/MS, chemical derivatization (CD) approaches have been employed to achieve the desired limit of quantitation. Recently, matrix-assisted laser desorption/ionization (MALDI) has also been reported as an alternative method. However, these quantitative approaches do not offer any spatial information. Mass spectrometry imaging (MSI) has been proven to be a powerful tool to image the spatial distribution of molecules from the surface of biological tissue sections. On-tissue chemical derivatization (OTCD) enables MSI to image molecules with poor ionization efficiently. In this technical report, several derivatization reagents and OTCD methods were evaluated using different MSI ionization techniques. Here, a method for detection and spatial distribution of vitamin D metabolites in murine kidney tissue sections using an OTCD-MALDI-MSI platform is presented. Moreover, the suitability of using the Bruker ImagePrep for OTCD-based platforms has been demonstrated. Importantly, this method opens the door for expanding the range of other poor ionizable molecules that can be studied by OTCD-MSI by adapting existing CD methods.


PrP antibodies do not trigger mouse hippocampal neuron apoptosis.
Intraperitoneal administration of ICSM18 and 35, monoclonal antibodies against prion protein (PrP), has been shown to significantly delay the onset of prion disease in mice, and humanized versions are candidate therapeutics for prion and Alzheimer's diseases. However, a previous report of severe and widespread apoptosis after intracerebral injection of anti-PrP monoclonal antibodies raised concerns about such therapy and led to an influential model of prion neurotoxicity via cross-linking of cell surface PrP by disease-related PrP aggregates. In extensive studies including ICSM18 and 35, fully humanized ICSM18, and the previously reported proapoptotic antibodies, we found no evidence of apoptosis, thereby questioning this model of prion neurotoxicity.


Spectroscopic investigation of the donor-acceptor interaction between o-phenylenediamine and tetracyanoethylene in dichloromethane.
The interaction between the electron donor o-phenylenediamine (o-phendn) and the pi-acceptor tetracyanoethylene (TCNE) has been investigated spectrophotometrically in dichloromethane at 25 degrees C. The results indicate that the reaction proceeds via two major steps. The formation of the 1:2 charge-transfer complex [(o-phendn)2, (TCNE)4] in which two o-phenylenediamine molecules undergoes slow N-substitution by one TCNE forming the final reaction product 2,2-di-o-aminoaniline-1,1-dicyanoethylene and 2HCN molecules. The reaction was studied using electronic, infrared, photometric titration and cyclic voltametric measurements. A general mechanism for the reactions is proposed.


Appraising the uptake and use of the IDEAL Framework and Recommendations: A review of the literature.
Evaluation of new surgical innovations is complex and variably regulated, and historically the quality of surgical studies has been criticized. The IDEAL (Idea, Development, Exploration, Assessment, Long-term monitoring) Framework was established to provide a pathway for evaluating surgical innovations at each stage of their development in order to produce high quality surgical research. Since the inception of IDEAL in 2009, there has been no assessment of its use. In this review, we look at the uptake and usage of IDEAL by examining the published literature. We conducted a literature search to identify all of the publications that cited IDEAL and included only those papers that intentionally used IDEAL as part of the study methodology. We then characterized these publications by year of publication, specialty, and geographical location. We performed a critical appraisal of Stage 1, 2a, and 2b studies in order to assess the degree to which authors have correctly followed the Framework and Recommendations. We found 790 citations of IDEAL publications, and after abstract and full-text screening, 38 prospective studies for a surgical innovation that used IDEAL remained. We saw an overall increase in the uptake of IDEAL, with a predominance in urology and origin in the United Kingdom. The critical appraisal showed that although authors identified their project as using IDEAL, they often failed to include key IDEAL characteristics; this was especially true for the features unique to IDEAL Stages 2a and 2b. It is evident from the large number of studies citing IDEAL that the importance and challenges of reporting surgical research is well recognized among researchers. There is growing enthusiasm for using IDEAL but the current level of understanding of the Recommendations is low. Clearer and more comprehensive explanation of the application of the IDEAL Framework and Recommendations is needed to guide surgical researchers undertaking IDEAL based studies of surgical innovations.


Transmission of white spot syndrome virus (WSSV) to Litopenaeus vannamei from infected cephalothorax, abdomen, or whole shrimp cadaver.
Shrimp viruses can remain infectious in frozen shrimp tissue and have been found in frozen commodity shrimp. Therefore, the threat of viral outbreaks in wild and cultured shrimp via frozen commodity shrimp exists. Because frozen shrimp are imported with and without the cephalothorax, more knowledge is needed concerning the infectivity of a cephalothorax relative to that of an abdomen. We compared the mortality rates from shrimp exposed to a WSSV-infected cephalothorax, abdomen, or whole shrimp cadaver. Estimates of transmission coefficients from the exposures to the infected cephalothorax, abdomen, or whole shrimp were also calculated because the transmission coefficients account for differences in the initial doses. In addition, we compared the variability in infectivity of pieces of shrimp by feeding 24 equal-sized pieces of cephalothorax and abdomen to 24 individually isolated shrimp. In Expt 1, susceptible shrimp did not completely consume the infected abdomen, and a significant difference was detected among shrimp exposed to the abdomen (mortality rate = 0.40), cephalothorax (mortality rate = 0.75), and whole shrimp cadaver (mortality rate = 0.67). The calculated transmission coefficients were 0.95 from an infected cephalothorax, 0.59 from an infected abdomen, and 0.69 from an infected whole shrimp cadaver. In Expt 2, susceptible shrimp were starved to ensure complete ingestion of each dose. No significant difference was observed in the estimated mortality rates from an infected cephalothorax (0.58), abdomen (0.63), or whole shrimp (0.67). The calculated transmission coefficients were 0.84 from an infected cephalothorax, 0.83 from an infected abdomen, and 0.60 from an infected whole shrimp cadaver. In Expt 3, no difference was observed in the mortality rates resulting from exposures to pieces of infected cephalothorax (0.57) or abdomen (0.58). Our results suggested that there was no difference in the viral loads of a WSSV-infected cephalothorax or abdomen, but that the cephalothorax was more infectious, probably because it was more palatable. In addition, our results are inconsistent with some assumptions of pathogen transmission used in epidemiological models. Some shrimp may be less aggressive feeders; therefore, susceptible shrimp are differentially contacting the dead infected shrimp in the exposure tanks, violating the random mixing assumption. Moreover, virus is probably not homogeneously distributed throughout an infected shrimp, suggesting that contacts between susceptible and infected shrimp are not equally likely to result in transmission.


A descriptive study of potential participant preferences for the design of an incentivised weight loss programme for people with type 2 diabetes mellitus attending a public hospital in Lima, Peru.
Background: Weight loss is important for the control of type 2 diabetes mellitus but is difficult to achieve and sustain. Programmes employing financial incentives have been successful in areas such as smoking cessation. However, the optimum design for an incentivised programme for weight loss is undetermined, and may depend on social, cultural and demographic factors. Methods: An original questionnaire was designed whose items addressed respondent personal and health characteristics, and preferences for a hypothetical incentivised weight loss programme. One hundred people with type 2 diabetes mellitus were recruited to complete the questionnaire from the endocrinology clinic of a public hospital in Lima, Peru. A descriptive analysis of responses was performed. Results: Ninety-five percent of subjects who had previously attempted to lose weight had found this either 'difficult' or 'very difficult'. Eighty-five percent of subjects would participate in an incentivised weight loss programme. Median suggested incentive for 1 kg weight loss every 2 weeks over 9 months was PEN 100 (~USD $30). Cash was preferred by 70% as payment method. Only 56% of subjects would participate in a deposit-contract scheme, and the median suggested deposit amount was PEN 20 (~USD $6). Eighty percent of subjects would share the incentive with a helper, and family members were the most common choice of helper. Conclusions: The challenge of achieving and sustaining weight loss is confirmed in this setting. Direct cash payments of PEN 100 were generally preferred, with substantial scope for involving a co-participant with whom the incentive could be shared. Employing direct financial incentives in future weight loss programmes appears to be widely acceptable among people with type 2 diabetes mellitus.


Realignment and extended fusion with use of a medial column screw for midfoot deformities secondary to diabetic neuropathy. Surgical technique.
The failure of nonsurgical treatment of patients with midfoot and hindfoot deformity secondary to diabetic Charcot arthropathy may lead to a rocker-bottom foot deformity with recurrent or persistent plantar ulceration. We report our experience with realignment and extended fusion with primary use of a medial column screw for this midfoot deformity. From July 2001 through July 2005, we performed reconstructive surgery on fifteen adults with diabetes mellitus who had a severe neuropathic midfoot deformity consisting of a collapsed plantar arch with a rocker-bottom foot deformity. Thirteen had a nonhealing midfoot plantar ulcer. All underwent realignment and arthrodesis with a medial column screw; some required additional fixation techniques depending on the extent of the deformity. Outcome measures included ulcer and surgical wound-healing, radiographic results, complications, and the need for amputation. The mean duration of clinical follow-up was forty-two months. Fourteen patients were able to walk, and there were no recurrent plantar ulcers. Thirteen patients were able to wear custom-made extra-depth, wide-toed shoes with molded inserts. One patient without prior ulceration had development of a deep infection that necessitated an amputation. Four feet had a nonunion, one of which was symptomatic requiring a revision to obtain union. Surgical reconstruction of a collapsed neuropathic foot deformity is technically demanding, but a successful outcome can result in a plantigrade foot that is free of ulceration and abnormal pressure points and a patient who is able to walk. The procedure described has an acceptable degree of complications although it has a high rate of nonunion.


Disruption of Germination and Seedling Development in Brassica napus by Mutations Causing Severe Seed Hormonal Imbalance.
The Brassica napus (oilseed rape) accession 1012-98 shows a disturbed germination phenotype that was thought to be associated with its lack of testa pigmentation and thin seed coat. Here, we demonstrate that the disturbed germination and seedling development are actually due to independent mutations that disrupt the balance of hormone metabolites and their regulators in the seeds. High-throughput UPLC-MS/MS hormone profiling of seeds and seedlings before and after germination revealed that 1012-98 has a severely disturbed hormone balance with extremely atypical, excessive quantities of auxin and ABA metabolites. The resulting hypersensitivity to abscisic acid (ABA) and a corresponding increase in dormancy often results in death of the embryo after imbibition or high frequencies of disturbed, often lethal developmental phenotypes, resembling Arabidopsis mutants for the auxin regulatory factor gene ARF10 or the auxin-overproducing transgenic line iaaM-OX. Molecular cloning of Brassica ARF10 orthologs revealed four loci in normal B. napus, two derived from the Brassica A genome and two from the C genome. On the other hand, the phenotypic mutant 1012-98 exhibited amplification of C-genome BnaC.ARF10 copy number along with a chimeric allele originating from recombination between homeologous A and C genome loci which lead to minor increase of Bna.ARF10 transcription on the critical timepoint for seed germination, the indirect regulator of ABI3, the germinative inhibitor. Bna.GH3.5 expression was upregulated to conjugate free auxin to IAA-asp between 2 and 6 DAS. Functional amino acid changes were also found in important DNA binding domains of one BnaC.ARF10 locus, suggesting that regulatory changes in Bna.ARF10 are collectively responsible for the observed phenotpyes in 1012-98. To our knowledge, this study is the first to report disruption of germination and seedling development in Brassica napus caused by the crosstalk of auxin-ABA and the corresponding regulators Bna.ARF10 and Bna.GH3.5.


Quantitative digital imaging of banana growth suppression by plant parasitic nematodes.
A digital camera fitted with a hemispherical lens was used to generate canopy leaf area index (LAI) values for a banana (Musa spp.) field trial with the aim of establishing a method for monitoring stresses on tall crop plants. The trial in Uganda consisted of two cultivars susceptible to nematodes, a plantain, Gonja manjaya and an East African Highland banana, Mbwazirume, plus a nematode resistant dessert banana, Yangambi km5. A comparative approach included adding a mixed population of Radopholus similis, Helicotylenchus multicinctus and Meloidogyne spp. to the soil around half the plants of each cultivar prior to field planting. Measurements of LAI were made fortnightly from 106 days post-planting over two successive cropping cycles. The highest mean LAI during the first cycle for Gonja manjaya was suppressed to 74.8±3.5% by the addition of nematodes, while for Mbwazirume the values were reduced to 71.1±1.9%. During the second cycle these values were 69.2±2.2% and 72.2±2.7%, respectively. Reductions in LAI values were validated as due to the biotic stress by assessing nematode numbers in roots and the necrosis they caused at each of two harvests and the relationship is described. Yield losses, including a component due to toppled plants, were 35.3% and 55.3% for Gonja manjaya and 31.4% and 55.8% for Mbwazirume, at first and second harvests respectively. Yangambi km5 showed no decrease in LAI and yield in the presence of nematodes at both harvests. LAI estimated by hemispherical photography provided a rapid basis for detecting biotic growth checks by nematodes on bananas, and demonstrated the potential of the approach for studies of growth checks to other tall crop plants caused by biotic or abiotic stresses.


Human methylome variation across Infinium 450K data on the Gene Expression Omnibus.
While DNA methylation (DNAm) is the most-studied epigenetic mark, few recent studies probe the breadth of publicly available DNAm array samples. We collectively analyzed 35 360 Illumina Infinium HumanMethylation450K DNAm array samples published on the Gene Expression Omnibus. We learned a controlled vocabulary of sample labels by applying regular expressions to metadata and used existing models to predict various sample properties including epigenetic age. We found approximately two-thirds of samples were from blood, one-quarter were from brain and one-third were from cancer patients. About 19% of samples failed at least one of Illumina's 17 prescribed quality assessments; signal distributions across samples suggest modifying manufacturer-recommended thresholds for failure would make these assessments more informative. We further analyzed DNAm variances in seven tissues (adipose, nasal, blood, brain, buccal, sperm and liver) and characterized specific probes distinguishing them. Finally, we compiled DNAm array data and metadata, including our learned and predicted sample labels, into database files accessible via the recountmethylation R/Bioconductor companion package. Its vignettes walk the user through some analyses contained in this paper.


Update in glaucoma medicinal chemistry: emerging evidence for the importance of melatonin analogues.
Glaucoma is a chronic progressive optic neuropathy, which can result in visual impairment and blindness. Elevated intraocular pressure (IOP) is currently the only modifiable risk factor. Several recent studies have shown the benefits of IOP reduction in open-angle glaucoma. Therefore, current glaucoma drugs are IOP-lowering substances such as α(2)-adrenergic agonists, β(2)-adrenergic antagonists, carbonic anhydrase inhibitors and hypotensive lipids, which are used separately or in combination. In spite of the wide variety of antiglaucoma medicines, all therapies have several undesirable side effects. As a consequence, there are constant research attempts on the discovery of novel ocular hypotensive drugs. In the current paper, we review the latest available patents and literature for the pharmacological treatment of glaucoma, focusing on their molecular targets and/or their chemical characteristics and especially directed to melatoninergic drugs. Melatonin is a hormone secreted into the blood mainly from the pineal gland allowing the entrainment of the circadian rhythms of several biological functions. Melatonin and its analogues potently reduce IOP in rabbits, monkeys and humans. In addition, there are indications of long-term hypotensive effects and a proven neuroprotective role of melatoninergic substances. Furthermore, antidepressant and normalizing circadian rhythm actions of melatonin analogues might be beneficial for glaucoma patients. All the above mentioned facts suggest these agents as proper candidates for the glaucoma treatment. Consequently, the scientific research has given new and significant progress on the development of new, potent and selective melatonin ligands.


Quantitative calcaneal ultrasonometry: normative data and age-related changes for stiffness index in the Turkish population.
The aim of this cross-sectional study was to define the normative data for stiffness index in a large sample of Turkish population and to clarify sex differences as well as age-related changes. A total of 10,435 subjects (aged 18-89 yr) were screened with calcaneal ultrasound and were requested to complete a detailed questionnaire listing all important risk factors, diseases, and treatments affecting bone metabolism. To be included in the study, subjects had to be free of any disease and any medical treatment known to affect bone metabolism. A total of 8,156 subjects (1,389 males and 6,767 females) were included in the study. Normative data was expressed using two statistical models including mean and 95th percentile, and regression analysis. The mean value of stiffness index in females peaked in the third decade, whereas in males it peaked in the age group of 18-29 yr. The stiffness index of females decreased by 24.26%. The total age-related decrease was 17.8% for stiffness index in the males. Stiffness index in males was a function of age (negatively) and body mass index (positively). Stiffness index in females was a function of age (negatively) and weight (positively). The results of this study could be useful as a guide for comparing the data of individual studies and may serve as reference normative data for the Turkish population.


Classification of diabetes-related retinal diseases using a deep learning approach in optical coherence tomography.
Spectral Domain Optical Coherence Tomography (SD-OCT) is a volumetric imaging technique that allows measuring patterns between layers such as small amounts of fluid. Since 2012, automatic medical image analysis performance has steadily increased through the use of deep learning models that automatically learn relevant features for specific tasks, instead of designing visual features manually. Nevertheless, providing insights and interpretation of the predictions made by the model is still a challenge. This paper describes a deep learning model able to detect medically interpretable information in relevant images from a volume to classify diabetes-related retinal diseases. This article presents a new deep learning model, OCT-NET, which is a customized convolutional neural network for processing scans extracted from optical coherence tomography volumes. OCT-NET is applied to the classification of three conditions seen in SD-OCT volumes. Additionally, the proposed model includes a feedback stage that highlights the areas of the scans to support the interpretation of the results. This information is potentially useful for a medical specialist while assessing the prediction produced by the model. The proposed model was tested on the public SERI-CUHK and A2A SD-OCT data sets containing healthy, diabetic retinopathy, diabetic macular edema and age-related macular degeneration. The experimental evaluation shows that the proposed method outperforms conventional convolutional deep learning models from the state of the art reported on the SERI+CUHK and A2A SD-OCT data sets with a precision of 93% and an area under the ROC curve (AUC) of 0.99 respectively. The proposed method is able to classify the three studied retinal diseases with high accuracy. One advantage of the method is its ability to produce interpretable clinical information in the form of highlighting the regions of the image that most contribute to the classifier decision.


Repetitive N-WASP-binding elements of the enterohemorrhagic Escherichia coli effector EspF(U) synergistically activate actin assembly.
Enterohemorrhagic Escherichia coli (EHEC) generate F-actin-rich adhesion pedestals by delivering effector proteins into mammalian cells. These effectors include the translocated receptor Tir, along with EspF(U), a protein that associates indirectly with Tir and contains multiple peptide repeats that stimulate actin polymerization. In vitro, the EspF(U) repeat region is capable of binding and activating recombinant derivatives of N-WASP, a host actin nucleation-promoting factor. In spite of the identification of these important bacterial and host factors, the underlying mechanisms of how EHEC so potently exploits the native actin assembly machinery have not been clearly defined. Here we show that Tir and EspF(U) are sufficient for actin pedestal formation in cultured cells. Experimental clustering of Tir-EspF(U) fusion proteins indicates that the central role of the cytoplasmic portion of Tir is to promote clustering of the repeat region of EspF(U). Whereas clustering of a single EspF(U) repeat is sufficient to bind N-WASP and generate pedestals on cultured cells, multi-repeat EspF(U) derivatives promote actin assembly more efficiently. Moreover, the EspF(U) repeats activate a protein complex containing N-WASP and the actin-binding protein WIP in a synergistic fashion in vitro, further suggesting that the repeats cooperate to stimulate actin polymerization in vivo. One explanation for repeat synergy is that simultaneous engagement of multiple N-WASP molecules can enhance its ability to interact with the actin nucleating Arp2/3 complex. These findings define the minimal set of bacterial effectors required for pedestal formation and the elements within those effectors that contribute to actin assembly via N-WASP-Arp2/3-mediated signaling pathways.


Childhood Circumstances and Health Inequality in Old Age: Comparative Evidence from China and the USA.
This paper estimates the extent to which childhood circumstances contribute to health inequality in old age and evaluates the importance of major domains of childhood circumstances to health inequalities in the USA and China. We link two waves of the China Health and Retirement Longitudinal Study in 2013 and 2015 with the newly released 2014 Life History Survey, and two waves of the Health and Retirement Study in 2014 and 2016 with the newly released 2015 Life History Mail Survey in the USA, to quantify health inequality due to childhood circumstances for which they have little control. Using the Shapley value decomposition approach, we show that childhood circumstances may explain 7-16 and 14-30% of health inequality in old age in China and the USA, respectively. Specifically, the contribution of childhood circumstances to health inequality is larger in the USA than in China for self-rated health, mental health, and physical health. Examining domains of childhood circumstance, regional and rural/urban status contribute more to health inequality in China, while family socioeconomic status contributes more to health inequality in the USA. Our findings support the value of a life course approach in identifying the key determinants of health in old age. Distinguishing sources of health inequality and rectifying inequality due to early childhood circumstances should be the basis of policy promoting health equity.


Vacuolar H(+)-ATPase, but not mitochondrial F(1)F(0)-ATPase, is required for NaCl tolerance in Saccharomyces cerevisiae.
Salt tolerance in Saccharomyces cerevisiae is a complex trait, involving regulation of membrane polarization, Na(+) efflux and sequestration of Na(+) in the vacuole. Since transmembrane transport energized by H(+)-adenosine triphosphatases (ATPases) is common to all of these tolerance mechanisms, the objective of this study was to characterize the responses of the plasma membrane H(+)-ATPase, vacuolar H(+)-ATPase and mitochondrial F(1)F(0)-ATPase to NaCl stress. We hypothesized that since the vacuolar ATPase is responsible for generating the proton motive force required for import of cations (such as Na(+)) into the vacuole, strains lacking this activity should be hypersensitive to NaCl. We found that strains lacking vacuolar ATPase activity were in fact hypersensitive to NaCl, while strains lacking ATP synthase were not. This effect was specific to the ionic component of NaCl stress, since the mutant strains were indistinguishable from wild-type and complemented strains in the presence of sorbitol.


Asymptotic approaches to marginally stable resonators.
We present analytical solutions valid for large Fresnel number of the Fresnel-Kirchhoff integral equation for marginally stable resonators, for the specific case of flat circular mirrors. The asymptotic approaches used for curved mirrors have been extended to the waveguide region given by m < 1 + 1/ radicalN. The resonator modes are expressed in terms of a slowly varying core term similar in form to the electromagnetic fields of a closed resonator and a small, rapidly oscillating term arising from diffraction around the mirror edge.


[Optimization of the reduction of arterial blood pressure in essential hypertensives patients].
A blood pressure below or equal to 140/90 mmHg, the aim of antihypertensive treatment, is rarely achieved. Only 16% of patients controlled by our group reach this goal. To analyze the causes of suboptimal treatment and to assess the effects of an optimization of antihypertensive therapy. A random sample of 160 patients was analyzed and followed during one year. Sixty six patients (41%) had a normal blood pressure, maintained during the first three months of follow up. The main causes of suboptimal reduction of blood pressure in the remaining 94 patients were an incorrect prescription or dosage of medications in 37.5%, lack of compliance in 34%, insufficient delivery of medications by the health service in 24% and secondary effects of drugs in 5%. When these factors were corrected, blood pressure normalized in 41 of them. In other 37, a reduction of 5 mmHg or more in blood pressure, was obtained. The most frequent changes introduced were modifications in dosage and addition of a new medication. Therefore, in 90% of these patients, blood pressure was reduced or normalized. A correct identification of the cause of antihypertensive treatment failure is imperative. The correction of this cause leads to a further reduction in blood pressure in 90% of those subjects with suboptimal treatment.


High intensity focused ultrasound (HIFU).
Curative treatments for localized prostate cancer, from least invasive to most invasive, include brachytherapy, cryosurgery, three-dimensional conformal radiation therapy, external beam radiation therapy, and radical prostatectomy. A patient with localized, low risk or intermediate risk prostate cancer who is diagnosed at an early age and receives one of these treatments has only an approximately 50% chance of maintaining an undetectable prostate-specific antigen (PSA) level, good spontaneous erections, and total continence by 5 years after treatment. This article discusses transrectal high intensity focused ultrasound (HIFU) treatment of localized prostate cancer using the Sonablate 500 (Focus Surgery, Indianapolis, IN, USA) device, which the author has adopted in favor of the Ablatherm (EDAP, TMS S. A., Lyons, France) device, the other HIFU device approved for use in Canada. Characteristics of the ideal prostate cancer include stage T1-T2b, less than 40 cc in size, and with an anterior-posterior dimension of up to 35 mm high. The anterior zone of the prostate is treated before the posterior zone. The procedure involves 2 to 3 second bursts of ultrasound energy, followed by 3 second cooling cycles. In each treatment lesion, the physician achieves a temperature of 100 C at the focal point. The device allows for real-time visualization of tissue response following the delivery of ultrasound energy. HIFU is a minimally invasive, outpatient treatment for localized prostate cancer that provides similar short term and medium term cure rates and considerably less morbidity and side effects than other treatments. Although the effectiveness of HIFU has not yet been demonstrated in large, long term studies, this treatment option should be discussed with patients who have just been diagnosed with low risk or intermediate risk prostate cancer and desire aggressive, noninvasive, curative therapy, with potentially a lower incidence of side effects compared to conventional therapy.


Appropriate evidence sources for populating decision analytic models within health technology assessment (HTA): a systematic review of HTA manuals and health economic guidelines.
An increasing number of evidence sources are relevant for populating decision analytic models. What is needed is detailed methodological advice on which type of data is to be used for what type of model parameter. We aim to identify standards in health technology assessment manuals and economic (modeling) guidelines on appropriate evidence sources and on the role different types of data play within a model. Documents were identified via a call among members of the International Network of Agencies for Health Technology Assessment and by hand search. We included documents from Europe, the United States, Canada, Australia, and New Zealand as well as transnational guidelines written in English or German. We systematically summarized in a narrative manner information on appropriate evidence sources for model parameters, their advantages and limitations, data identification methods, and data quality issues. A large variety of evidence sources for populating models are mentioned in the 28 documents included. They comprise research- and non-research-based sources. Valid and less appropriate sources are identified for informing different types of model parameters, such as clinical effect size, natural history of disease, resource use, unit costs, and health state utility values. Guidelines do not provide structured and detailed advice on this issue. The article does not include information from guidelines in languages other than English or German, and the information is not tailored to specific modeling techniques. The usability of guidelines and manuals for modeling could be improved by addressing the issue of evidence sources in a more structured and comprehensive format.


Increased C4d in post-reperfusion biopsies and increased donor specific antibodies at one-week post transplant are risk factors for acute rejection in mild to moderately sensitized kidney transplant recipients.
In order to define the intensity of immunosuppression, we examined risk factors for acute rejection in desensitization protocols that use baseline donor-specific antibody levels measured as mean fluorescence intensity (MFImax). The study included 146 patients transplanted with a negative flow crossmatch and a mean follow-up of 18 months with the majority (83%) followed for at least 1 year. At the time of transplant, mean-calculated panel-reactive antibody and MFImax ranged from 10.3-57.2% and 262-1691, respectively, between low- and high-risk protocols. Mean MFImax increased significantly from transplant to 1 week and 1 year. The incidence of acute rejection (mean 1.65 months) as a combination of clinical and subclinical rejection was 32%, including 14% cellular, 12% antibody-mediated, and 6% mixed rejection. In regression analyses, only C4d staining in post-reperfusion biopsies (hazard ratio 3.3, confidence interval 1.71-6.45) and increased specific antibodies at 1-week post transplant were significant predictors of rejection. A rise in MFImax by 500 was associated with a 2.8-fold risk of rejection. Thus, C4d staining in post-reperfusion biopsies and an early rise in donor specific antibodies after transplantation are risk factors for rejection in moderately sensitized patients.


Functional effects of TrkA inhibition on system xC--mediated glutamate release and cancer-induced bone pain.
Breast cancer cells release the signalling molecule glutamate via the system xC- antiporter, which is upregulated to exchange extracellular cystine for intracellular glutamate to protect against oxidative stress. Here, we demonstrate that this antiporter is functionally influenced by the actions of the neurotrophin nerve growth factor on its cognate receptor tyrosine kinase, TrkA, and that inhibiting this complex may reduce cancer-induced bone pain via its downstream actions on xCT, the functional subunit of system xC-. We have characterized the effects of the selective TrkA inhibitor AG879 on system xC- activity in murine 4T1 and human MDA-MB-231 mammary carcinoma cells, as well as its effects on nociception in our validated immunocompetent mouse model of cancer-induced bone pain, in which BALB/c mice are intrafemorally inoculated with 4T1 murine carcinoma cells. AG879 decreased functional system xC- activity, as measured by cystine uptake and glutamate release, and inhibited nociceptive and physiologically relevant responses in tumour-bearing animals. Cumulatively, these data suggest that the activation of TrkA by nerve growth factor may have functional implications on system xC--mediated cancer pain. System xC--mediated TrkA activation therefore presents a promising target for therapeutic intervention in cancer pain treatment.


The peripheral neuropathy in Machado-Joseph disease.
Peripheral nerve biopsies were taken from 11 patients with Machado-Joseph disease (MJD), a heredo-degenerative disease within the group of autosomal dominant ataxias. On the basis of the clinical symptoms, 2 patients were found to suffer from type I, 4 from type II and 5 from type III. All cases shared the same pathological features, which consisted of a reduction in density of myelinated and unmyelinated fibres and an increase in endoneurial collagen. It was also observed that some Schwann cells were not related to axons, whilst others showed numerous budding processes. The intensity of the changes varied considerably: it was mild in type I and II and severe in type III. Peripheral nerve changes in MJD are compared with those previously described in other forms of heredo-ataxias. It is concluded that involvement of peripheral nerves is a significant feature in this group of diseases and that peripheral nerve biopsy could be useful in the identification of the subtypes of MJD.


Post-lockdown SARS-CoV-2 nucleic acid screening in nearly ten million residents of Wuhan, China.
Stringent COVID-19 control measures were imposed in Wuhan between January 23 and April 8, 2020. Estimates of the prevalence of infection following the release of restrictions could inform post-lockdown pandemic management. Here, we describe a city-wide SARS-CoV-2 nucleic acid screening programme between May 14 and June 1, 2020 in Wuhan. All city residents aged six years or older were eligible and 9,899,828 (92.9%) participated. No new symptomatic cases and 300 asymptomatic cases (detection rate 0.303/10,000, 95% CI 0.270-0.339/10,000) were identified. There were no positive tests amongst 1,174 close contacts of asymptomatic cases. 107 of 34,424 previously recovered COVID-19 patients tested positive again (re-positive rate 0.31%, 95% CI 0.423-0.574%). The prevalence of SARS-CoV-2 infection in Wuhan was therefore very low five to eight weeks after the end of lockdown.


Oophorectomy after menopause and the risk of breast cancer in BRCA1 and BRCA2 mutation carriers.
To evaluate the effect of the cumulative number of ovulatory cycles and its contributing components on the risk of breast cancer among BRCA mutation carriers. We conducted a matched case-control study on 2,854 pairs of women with a BRCA1 or BRCA2 mutation. Conditional logistic regression was used to estimate the association between the number of ovulatory cycles and various exposures and the risk of breast cancer. Information from a subset of these women enrolled in a prospective cohort study was used to calculate age-specific breast cancer rates. The annual risk of breast cancer decreased with the number of ovulatory cycles experienced (ρ = -0.69; P = 0.03). Age at menarche and duration of breastfeeding were inversely related with risk of breast cancer among BRCA1 (P(trend) < 0.0001) but not among BRCA2 (P(trend) ≥ 0.28) mutation carriers. The reduction in breast cancer risk associated with surgical menopause [OR, 0.52; 95% confidence interval (CI), 0.40-0.66; P(trend) < 0.0001] was greater than that associated with natural menopause (OR, 0.81; 95% CI, 0.62-1.07; P(trend) = 0.14). There was a highly significant reduction in breast cancer risk among women who had an oophorectomy after natural menopause (OR, 0.13; 95% CI, 0.02-0.54; P = 0.006). These data challenge the hypothesis that breast cancer risk can be predicted by the lifetime number of ovulatory cycles in women with a BRCA mutation. Both pre- and postmenopausal oophorectomy protect against breast cancer. Understanding the basis for the protective effect of oophorectomy has important implications for chemoprevention.


Rats exhibit similar biases in foraging and intertemporal choice tasks.
Animals, including humans, consistently exhibit myopia in two different contexts: foraging, in which they harvest locally beyond what is predicted by optimal foraging theory, and intertemporal choice, in which they exhibit a preference for immediate vs. delayed rewards beyond what is predicted by rational (exponential) discounting. Despite the similarity in behavior between these two contexts, previous efforts to reconcile these observations in terms of a consistent pattern of time preferences have failed. Here, via extensive behavioral testing and quantitative modeling, we show that rats exhibit similar time preferences in both contexts: they prefer immediate vs. delayed rewards and they are sensitive to opportunity costs of delays to future decisions. Further, a quasi-hyperbolic discounting model, a form of hyperbolic discounting with separate components for short- and long-term rewards, explains individual rats' time preferences across both contexts, providing evidence for a common mechanism for myopic behavior in foraging and intertemporal choice.


Observing the cell in its native state: Imaging subcellular dynamics in multicellular organisms.
True physiological imaging of subcellular dynamics requires studying cells within their parent organisms, where all the environmental cues that drive gene expression, and hence the phenotypes that we actually observe, are present. A complete understanding also requires volumetric imaging of the cell and its surroundings at high spatiotemporal resolution, without inducing undue stress on either. We combined lattice light-sheet microscopy with adaptive optics to achieve, across large multicellular volumes, noninvasive aberration-free imaging of subcellular processes, including endocytosis, organelle remodeling during mitosis, and the migration of axons, immune cells, and metastatic cancer cells in vivo. The technology reveals the phenotypic diversity within cells across different organisms and developmental stages and may offer insights into how cells harness their intrinsic variability to adapt to different physiological environments.


The prevalence of X-linked hypohidrotic ectodermal dysplasia (XLHED) in Denmark, 1995-2010.
X-linked hypohidrotic ectodermal dysplasia (XLHED) is characterised by hypohidrosis, sparse hair, and teeth abnormalities. Infants with XLHED have an increased risk of death by hyperpyrexia. XLHED is the most common form of hypohidrotic ectodermal dysplasia (HED); however, no population-based prevalence estimates are available. We aimed to: 1) estimate the prevalence of XLHED in the Danish population per January 1, 2011; 2) identify the most frequent age at time of diagnosis; and 3) quantify the most frequent clinical feature associated with XLHED. We conducted a nationwide cross-sectional study (1995-2010). We leveraged national medical registries and data from clinical departments to categorise XLHED cases into three groups: 1) Molecularly-confirmed XLHED; 2) Clinically-diagnosed HED (registered with ICD-10 Q 82.4); and 3) Possible HED (registered with sufficient clinical features based on a clinical algorithm that we designed). We identified 90 molecularly-confirmed XLHED, 146 clinically-diagnosed HED, and 988 possible HED cases between 1995 and 2010 (total n = 1224). The prevalence was 21.9 per 100,000 overall and 1.6 per 100,000 when restricting to molecularly-confirmed XLHED cases. The most frequent age at time of XLHED diagnosis occurred between the ages of 11 and 18 years. Teeth abnormalities occurred in 79% of all cases and 52% of molecularly-confirmed cases as a primary clinical marker. We present the first ever population-based prevalence estimates of XLHED and suggest that the prevalence of XLHED may be higher than previously estimated. Diagnosis occurs most frequently during adolescence and teeth abnormalities were the most frequent clinical marker of XLHED.


Single-aliquot EPR dosimetry of wallboard (drywall).
Electron paramagnetic resonance spectra and dose-response curves are presented for a variety of wallboard samples obtained from different manufacturing facilities, as well as for source gypsum and anhydrite. The intensity of the CO(3)(-) paramagnetic centre (G2) is enhanced with gamma radiation. Isothermal decay curves are used to propose annealing methods for the removal of the radiosensitive CO(3)(-) radical without affecting the unirradiated baseline. Post-irradiation annealing of wallboard prevents recuperation of the radiosensitive CO(3)(-) radical with additional irradiation. A single-aliquot additive dose procedure is developed that successfully measures test doses as low as 0.76 Gy.


A National Descriptive Portrait of Adolescent Relationship Abuse: Results From the National Survey on Teen Relationships and Intimate Violence.
This article reports results from the National Survey on Teen Relationships and Intimate Violence (STRiV) for 12- to 18-year-old youth (n = 1,804). STRiV provides the first nationally representative household survey focused on adolescent relationship abuse (ARA), covering perpetration and victimization. Among respondents (37%) reporting current- or past-year dating, 69% reported lifetime ARA victimization (63% lifetime ARA perpetration). Although psychological abuse was most common for these youth (more than 60%), the rates of sexual abuse (18%) and physical abuse victimization (18%), as well as 12% reporting perpetrating physical abuse and/or sexual abuse (12%) were substantial as well. Other than differences by age and gender, ARA rates were consistent by race/ethnicity, geographic region, urbanicity, and household characteristics, highlighting the importance of universal prevention programs. Compared with youth aged 15 to 18, those 12 to 14 years old reported lower rates of psychological and sexual ARA victimization. Similarly, we found lower ARA perpetration rates for those 12 to 14. We found no gender differences for ARA victimization but found that girls perpetrated more physical ARA than boys. Girls aged 15 to 18 reported perpetrating moderate threats/physical violence at more than twice the rate of younger girls and 3 times the rate compared with boys aged 15 to 18; girls aged 15 to 18 reported perpetrating more than 4 times the rate of serious psychological abuse than boys 15 to 18. Finally, these data document the significant positive correlation between ARA victimization and perpetration. Findings suggest that when working with youth in prevention services, interventions should not be designed for monolithic groups of "victims" or "perpetrators."


Transcription in the yeast rRNA gene locus: distribution of the active gene copies and chromatin structure of their flanking regulatory sequences.
In growing yeast cells, about half of the 150 tandemly repeated rRNA genes are transcriptionally active and devoid of nucleosomes. By using the intercalating drug psoralen as a tool to mark accessible sites along chromatin DNA in vivo, we found that the active rRNA gene copies are rather randomly distributed along the ribosomal rRNA gene locus. Moreover, results from the analysis of a single, tagged transcription unit in the tandem array are not consistent with the presence of a specific subset of active genes that is stably maintained throughout cell divisions. In the rRNA intergenic spacers of yeast cells, an enhancer is located at the 3' end of each transcription unit, 2 kb upstream of the next promoter. Analysis of the chromatin structure along the tandem array revealed a structural link between transcription units and adjacent, 3' flanking enhancer sequences: each transcriptionally active gene is flanked by a nonnucleosomal enhancer, whereas inactive, nucleosome-packed gene copies are followed by enhancers regularly packaged in nucleosomes. From the fact that nucleosome-free enhancers were also detected in an RNA polymerase I mutant strain, we interpret these open chromatin structures as being the result of specific protein-DNA interactions that can occur before the onset of transcription. In contrast, in this mutant strain, all of the rRNA coding sequences are packaged in nucleosomal arrays. This finding indicates that the establishment of the open chromatin conformation on the activated gene copies requires elongating RNA polymerase I molecules advancing through the template.


Urbanisation and its effect on risk factors associated with childhood diarrhoea in Mbour, Senegal: A visualisation.
Rapid urbanisation, particularly in secondary cities in Africa, brings along specific challenges for global health, including the prevention and control of infectious diseases such as diarrhoea. Our purpose was to visualise urbanisation trends and its effect on risk factors associated with childhood diarrhoea, e.g. water supply, sanitation, wastewater and solid waste management in Mbour, a secondary city in south-western Senegal. Our visualisation is facilitated by epidemiological and geographical surveys carried out in 2016. A deeper spatial and visual understanding of the urbanisation trends and the disparities of diarrhoea-associated risk factors might lead to the implementation of suitable health interventions and preventive measures. Our visualisation is aimed to serve as a basis for discussion and as a decision support tool for policymakers, municipal officials and local communities to prioritise interventions related to water, sanitation and waste management with a view to reduce the environmental and health risks in the rapidly growing city of Mbour, which is set as an example for other similar secondary cities across low- and middle-income countries in Africa.


To Consent or Decline HPV Vaccination: A Pilot Study at the Start of the National School-Based Vaccination Program in Sweden.
Parents' beliefs about human papillomavirus (HPV) vaccination influence whether they allow their daughters to be vaccinated. We examined the association between parents' refusal and sociodemographic background, knowledge and beliefs about HPV, and the HPV vaccination in relation to the Health Belief Model. The sample consisted of 200 (55%) parents of children aged 11-12 years in the Swedish national vaccination program. Data were collected using a self-reported questionnaire. Most parents (N = 186) agreed to the vaccination. Pearson's chi-square, Fisher's exact test, and the Mann-Whitney U test were used to analyze data. Declining parents saw more risks and fewer benefits of HPV vaccination but no differences in beliefs regarding the severity or young girls' susceptibility to HPV were found. There was an association between refusing the HPV vaccine and lower acceptance of previous childhood vaccinations, and their main source of information was the Internet. Parents who declined the vaccine believed it could adversely affect condom use, the age of their daughter's sexual debut, and the number of sexual partners. Parents should have the possibility to discuss HPV and HPV vaccine with a school nurse or other health care professionals, and should have access to evidence-based information on the Internet.


A portable battery powered microfluidic impedance cytometer with smartphone readout: towards personal health monitoring.
We present a portable system for personalized blood cell counting consisting of a microfluidic impedance cytometer and portable analog readout electronics, feeding into an analog-to-digital converter (ADC), and being transmitted via Bluetooth to a user-accessible mobile application. We fabricated a microfluidic impedance cytometer with a novel portable analog readout. The novel design of the analog readout, which consists of a lock-in-amplifier followed by a high-pass filter stage for subtraction of drift and DC offset, and a post-subtraction high gain stage, enables detection of particles and cells as small as 1 μm in diameter, despite using a low-end 8-bit ADC. The lock-in-amplifier and the ADC were set up to receive and transmit data from a Bluetooth module. In order to initiate the system, as well as to transmit all of the data, a user friendly mobile application was developed, and a proof-of-concept trial was run on a blood sample. Applications such as personalized health monitoring require robust device operation and resilience to clogging. It is desirable to avoid using channels comparable in size to the particles being detected thus requiring high levels of sensitivity. Despite using low-end off-the-shelf hardware, our sensing platform was capable of detecting changes in impedance as small as 0.032%, allowing detection of 3 μm diameter particles in a 300 μm wide channel. The sensitivity of our system is comparable to that of a high-end bench-top impedance spectrometer when tested using the same sensors. The novel analog design allowed for an instrument with a footprint of less than 80 cm2. The aim of this work is to demonstrate the potential of using microfluidic impedance spectroscopy for low cost health monitoring. We demonstrated the utility of the platform technology towards cell counting, however, our platform is broadly applicable to assaying wide panels of biomarkers including proteins, nucleic acids, and various cell types.


Six Years of Sick Leave Spells in a Group of University Civil Workers. Can Modern Work Bring Them a New Health Problem?
The objective of this study is to analyse sick leave episodes of a university's collective of statutory workers in the State of São Paulo, between January 2010 and December 2015. For this, a descriptive study analysed 5776 registered spells of sick leave of four university units: agricultural sciences; human health, health and animal reproduction, and biological sciences; an administrative unit; and a university hospital. The medical expert assessment was carried out by general practitioners and psychiatrists who managed sick leave and return to work cases. Around 52% had up to three sick leave episodes, and 10% of the workers had 20 or more episodes. Each spell of sickness absence lasted a median of 30 days (IQR 8⁻60 days). Among all of sick leaves, 35% had as a primary cause mental or behavioural diseases, of which 30% were depressive disorders, followed by around 18% related to the musculoskeletal system and the connective tissues. In the medical reports, 80% of the workers reported pain and 30% reported psychological symptoms. The collective, seen as privileged by many for their job stability, has a high percentage of sick leave due to mental illness, with extended periods which affect the levels of disability and reduce possibilities of return.


First Report of Penicillium crustosum Causing Blue Mold on Stored Apple Fruit in Serbia.
Penicillium crustosum Thom (1930) causes blue mold on pome fruits and is also regularly found on cheese, nuts, and soil (1,3). The fungus produces a wide range of mycotoxins such as penitrem A, roquefortine C, terrestric acid, and cyclopenol, which impact human health (1). In January and February 2013, 20 decayed apples, 'Golden Delicious' and 'Jonagold' (Malus × domestica Borkh.) with blue mold symptoms were collected from cold storages in Svilajnac and Bela Crkva, Serbia. Decayed areas were light to medium brown with blue green sporulation on the surface of the lesion. Decayed tissue was soft and watery with a sharp margin between the diseased and healthy areas. One isolate from each cultivar was designated JP2 ('Golden Delicious') and JBC7 ('Jonagold') and further characterized. Conidiophores of both isolates were terverticillate, stipes were septate with rough walls, and phialides were ampulliform. Conidia were smooth, borne in columns, and were spherical to subglobose. Conidial dimensions for JP2 were 3.2 to 4.56 (3.73) × 2.64 to 4.3 (3.32) μm and for JBC7 were 3.1 to 4.46 (3.65) × 2.81 to 4.27 (3.31) μm (n = 50). The isolates were cultured on Czapek yeast autolysate agar (CYA), malt extract agar (MEA), and yeast extract sucrose agar (YES) media and incubated at 25°C for 7 days. Mycelia were white with heavy sporulation yielding grayish green colonies on all media. Colonies were radially sulcate and velutinous, with clear exudate, and produced a yellow to orange reverse on CYA and YES. On MEA, colonies were plane, low, and mycelia subsurface with conidia having a dry powdery appearance. Crusts of conidial masses formed after 10 or more days. No growth was observed on CYA when these isolates were incubated at 37°C. Both isolates were identified as P. crustosum Thom using morphological characters according to (2) and (1). Species level identification was confirmed by isolating genomic DNA followed by amplification of the β-tubulin locus using gene specific primers via conventional PCR (4). MegaBLAST analysis of the 2X consensus nucleotide sequences revealed that JP2 and JBC7 (GenBank KJ433984 and 85) were 99% identical to P. crustosum culture collection isolate IBT 21518 (JN112030.1). Koch's postulates were examined using two apple cvs. Idared and Kolacara. Ten fruit per cultivar per isolate were inoculated on two sides of each fruit; 20 fruit were used as water-only inoculated controls. Fruit were washed with soap and water, surface sanitized with 70% ethanol, and placed into polyethylene boxes. Using a finishing nail, 4-mm wounds were created and inoculated with 50 μl of a 3 × 105/ml conidial suspension or Tween-treated sterile distilled water. Boxes with inoculated and control fruit were stored at 25°C for 10 days. The inoculated fruit developed small, soft, watery lesions, which enlarged into decayed areas with defined edges and abundant sporulation on the surface. Symptoms were identical to the original ones, while the control fruit remained symptomless. The fungus was re-isolated from infected tissue and showed the same morphological characteristics as the original isolates, thus completing Koch's postulates. Blue mold occurs during long term storage of apples and is predominantly caused by P. expansum. This is the first report of P. crustosum causing postharvest blue mold decay on apple fruit obtained from storage in Serbia and indicates that P. crustosum is an emerging pathogen for the Serbian pome fruit growing and packing industry. References: (1) J. C. Frisvad and R. A. Samson. Stud. Mycol. 49:1, 2004. (2) J. I. Pitt and A. D. Hocking. Fungi and Food Spoilage, 239. Springer, 2009. (3) P. G. Sanderson and R. A. Spotts. Phytopathology 85:103. 1995. (4) P. L. Sholberg et al. Postharvest Biol. Technol. 36:41, 2005.


CMF-regimen preferred as first-course chemotherapy for older and sicker women with breast cancer: Findings from a SEER-Medicare-based population study.
The objective of this study was to determine the sociodemographic and clinical characteristics associated with Cyclophosphamide, Methotrexate, and 5-Fluorouracil (CMF) utilization as a first-course chemotherapy regimen among female Medicare patients with early-stage breast cancer. A longitudinal study was conducted with women 66 years and older, diagnosed with stage I to III breast cancer from 1993 to 2004, and receiving chemotherapy using the Surveillance, Epidemiology, and End Result-Medicare data. First-course CMF chemotherapy was defined as chemotherapy initiation within 6 months of breast cancer diagnosis, with at least 1 claim of CMF each within 1 year of diagnosis. Logistic regression was used to perform the analysis. Older and sicker women, living in census tracts with lower average education, and diagnosed with advanced stage, hormone receptor-negative tumors have a higher probability of CMF administration. Receipt of lymph node dissection and nonreceipt of radiation therapy were also associated with CMF administration. CMF administration has declined over the years and has significant regional variation. Reduction in CMF use overtime indicates the increased use of newer and more effective systemic therapies among breast cancer patients. In spite of the reduction in CMF use over time, CMF is more frequently administered to older and sicker women, possibly because of higher risk of anthracycline-induced toxicities in these patients. Clinical guidelines have no recommendations for CMF administration in breast cancer patients with certain clinical characteristics. Hence, it is important to understand if the associations observed in this study can be clinically justified in order to reduce unjustified use of less-effective regimens.


Comparison of methods for handling censored records in beef fertility data: field data.
The purpose of this study was to compare methods for handling censored days to calving records in beef cattle data, and verify results of an earlier simulation study. Data were records from natural service matings of 33,176 first-calf females in Australian Angus herds. Three methods for handling censored records were evaluated. Censored records (records on noncalving females) were assigned penalty values on a within-contemporary group basis under the first method (DCPEN). Under the second method (DCSIM), censored records were drawn from their respective predictive truncated normal distributions, whereas censored records were deleted under the third method (DCMISS). Data were analyzed using a mixed linear model that included the fixed effects of contemporary group and sex of calf, linear and quadratic covariates for age at mating, and random effects of animal and residual error. A Bayesian approach via Gibbs sampling was used to estimate variance components and predict breeding values. Posterior means (PM) (SD) of additive genetic variance for DCPEN, DCSIM, and DCMISS were 22.6d2 (4.2d2), 26.1d2 (3.6d2), and 13.5d2 (2.9d2), respectively. The PM (SD) of residual variance for DCPEN, DCSIM, and DCMISS were 431.4d2 (5.0d2), 371.4d2 (4.5d2), and 262.2d2 (3.4d2), respectively. The PM (SD) of heritability for DCPEN, DCSIM, and DCMISS were 0.05 (0.01), 0.07 (0.01), and 0.05 (0.01), respectively. Simulating trait records for noncalving females resulted in similar heritability to the penalty method but lower residual variance. Pearson correlations between posterior means of animal effects for sires with more than 20 daughters with records were 0.99 between DCPEN and DCSIM, 0.77 between DCPEN and DCMISS, and 0.81 between DCSIM and DCMISS. Of the 424 sires ranked in the top 10% and bottom 10% of sires in DCPEN, 91% and 89%, respectively, were also ranked in the top 10% and bottom 10% in DCSIM. Little difference was observed between DCPEN and DCSIM for correlations between posterior means of animal effects for sires, indicating that no major reranking of sires would be expected. This finding suggests little difference between these two censored data handling techniques for use in genetic evaluation of days to calving.


Stroke chameleons.
Many conditions called "stroke mimics" may resemble acute stroke. The converse of the "stroke mimic" is a presentation suggestive of another condition, which actually represents stroke. These would be "stroke chameleons." The recognition of a chameleon as stroke has implications for therapy and quality of care. We performed a retrospective chart review, including all cases for 1 year in which patients had a stroke missed on hospital presentation. Initial erroneous diagnoses were compared for all patients correctly admitted with those diagnoses to determine positive predictive value (PPV) for each chameleon. Ninety-four cases were identified as chameleons where brain imaging revealed acute stroke. The common chameleons were initially diagnosed as altered mental status (AMS) (29, 31%), syncope (15, 16%), hypertensive emergency (12, 13%), systemic infection (10, 11%), and suspected acute coronary syndrome (ACS) (9, 10%). The total number of patients who were diagnosed with these conditions over the same year were AMS (393), syncope (326), hypertensive emergency (144), systemic infection (753), and suspected ACS (817) (total N = 2528). For each chameleon diagnosis, the PPV of each presentation for acute stroke was AMS (7%), syncope (4%), hypertensive emergency (8%), systemic infection (1%), and suspected ACS (1%). Stroke chameleons may result in patients not receiving appropriate care. The largest proportions of chameleons were AMS, syncope, hypertensive emergency, systemic infection, and suspected ACS. Patients diagnosed with hypertensive emergency or AMS had an 8% and 7% chance of having an acute stroke. Physicians should consider stroke in patients with these diagnoses with a lower threshold to obtain neuroimaging with subsequent appropriate management.


Quantitative measurement of thin phase objects: comparison of speckle deflectometry and defocus-variant lateral shear interferometry.
The two techniques of lateral shear interferometry and speckle deflectometry are analyzed in a common optical system for their ability to measure phase gradient fields of a thin phase object. The optical system is designed to introduce a shear in the frequency domain of a telecentric imaging system that gives a sensitivity of both techniques in proportion to the defocus introduced. In this implementation, both techniques successfully measure the horizontal component of the phase gradient field. The response of both techniques scales linearly with the defocus distance, and the precision is comparative, with a random error in the order of a few rad/mm. It is further concluded that the precision of the two techniques relates to the transverse speckle size in opposite ways. While a large spatial coherence width, and correspondingly a large lateral speckle size, makes lateral shear interferometry less susceptible to defocus, a large lateral speckle size is detrimental for speckle correlation. The susceptibility for the magnitude of the defocus is larger for the lateral shear interferometry technique as compared to the speckle deflectometry technique. The two techniques provide the same type of information; however, there are a few fundamental differences. Lateral shear interferometry relies on a special hardware configuration in which the shear angle is intrinsically integrated into the system. The design of a system sensitive to both in-plane phase gradient components requires a more complex configuration and is not considered in this paper. Speckle deflectometry, on the other hand, requires no special hardware, and both components of the phase gradient field are given directly from the measured speckle deformation field.


Antiviral adhesion molecular mechanisms for influenza: W. G. Laver's lifetime obsession.
Infection by the influenza virus depends firstly on cell adhesion via the sialic-acid-binding viral surface protein, haemagglutinin, and secondly on the successful escape of progeny viruses from the host cell to enable the virus to spread to other cells. To achieve the latter, influenza uses another glycoprotein, the enzyme neuraminidase (NA), to cleave the sialic acid receptors from the surface of the original host cell. This paper traces the development of anti-influenza drugs, from the initial suggestion by MacFarlane Burnet in 1948 that an effective 'competitive poison' of the virus' NA might be useful in controlling infection by the virus, through to the determination of the structure of NA by X-ray crystallography and the realization of Burnet's idea with the design of NA inhibitors. A focus is the contribution of the late William Graeme Laver, FRS, to this research.


Investigating Focal Adhesion Substructures by Localization Microscopy.
Cells rely on focal adhesions (FAs) to carry out a variety of important tasks, including motion, environmental sensing, and adhesion to the extracellular matrix. Although attaining a fundamental characterization of FAs is a compelling goal, their extensive complexity and small size, which can be below the diffraction limit, have hindered a full understanding. In this study we have used single-molecule localization microscopy (SMLM) to investigate integrin β3 and paxillin in rat embryonic fibroblasts growing on two different extracellular matrix-representing substrates (i.e., fibronectin-coated substrates and specifically biofunctionalized nanopatterned substrates). To quantify the substructure of FAs, we developed a clustering method based on expectation maximization of a Gaussian mixture that accounts for localization uncertainty and background. Analysis of our SMLM data indicates that the structures within FAs, characterized as a Gaussian mixture, typically have areas between 0.01 and 1 μm2, contain 10-100 localizations, and can exhibit substantial eccentricity. Our approach based on SMLM opens new avenues for studying structural and functional biology of molecular assemblies that display substantial varieties in size, shape, and density.


Global plant trait relationships extend to the climatic extremes of the tundra biome.
The majority of variation in six traits critical to the growth, survival and reproduction of plant species is thought to be organised along just two dimensions, corresponding to strategies of plant size and resource acquisition. However, it is unknown whether global plant trait relationships extend to climatic extremes, and if these interspecific relationships are confounded by trait variation within species. We test whether trait relationships extend to the cold extremes of life on Earth using the largest database of tundra plant traits yet compiled. We show that tundra plants demonstrate remarkably similar resource economic traits, but not size traits, compared to global distributions, and exhibit the same two dimensions of trait variation. Three quarters of trait variation occurs among species, mirroring global estimates of interspecific trait variation. Plant trait relationships are thus generalizable to the edge of global trait-space, informing prediction of plant community change in a warming world.


Acid deposition induced base cation loss and different responses of soils and sediments in Taihu Lake watershed, China.
Acid deposition and algae blooms have resulted in great changes in the water chemistry of Taihu Lake; however, there have been few calculated results to describe these processes. Here we used a mass balance model to estimate base cation losses and evaluate the model applicability in this intensively human-impacted watershed based on a long-term database (1985-2015). The results showed that carbonate weathering induced Ca2+ and Mg2+ losses in the watershed were responsible for the increased ion net reaction (INR) of Ca2+and Mg2+ in the lake. While the increase of K+ and Na+ were not appropriate to provide independents check on the mass balance model because they generally entered the lake as human discharges, not reflecting change of the geochemical process in the watershed as the watershed dominant bedrock is carbonate but not silicate. Acid deposition in Taihu region caused decrease in pH, lime potential, and different Ca, Mg species of surface soils. Our field measurements of sediments in the two lake parts showed that the sediment lime potential was significantly higher in the algae dominated lake area than in the hydrophyte-dominated area due to the in-lake alkalinization by algae blooms, indicating that algae blooms played a significant role in the acidification resistance. Meanwhile, the measured lime potential of the watershed soils was lower than that of the sediment, implying a potential risk of acidification in the watershed. This research helps understand the accelerated interactions between human activities and natural geochemical processes and accelerated water chemistry change at the watershed level.


Overexpression of GTP cyclohydrolase 1 feedback regulatory protein is protective in a murine model of septic shock.
Overproduction of nitric oxide (NO) by inducible NO synthase contributes toward refractory hypotension, impaired microvascular perfusion, and end-organ damage in septic shock patients. Tetrahydrobiopterin (BH4) is an essential NOS cofactor. GTP cyclohydrolase 1 (GCH1) is the rate-limiting enzyme for BH4 biosynthesis. Under inflammatory conditions, GCH1 activity and hence BH4 levels are increased, supporting pathological NOS activity. GCH1 activity can be controlled through allosteric interactions with GCH1 feedback regulatory protein (GFRP). We investigated whether overexpression of GFRP can regulate BH4 and NO production and attenuate cardiovascular dysfunction in sepsis. Sepsis was induced in mice conditionally overexpressing GFRP and wild-type littermates by cecal ligation and puncture. Blood pressure was monitored by radiotelemetry, and mesenteric blood flow was quantified by laser speckle contrast imaging. Blood biochemistry data were obtained using an iSTAT analyzer, and BH4 levels were measured in plasma and tissues by high-performance liquid chromatography. Increased BH4 and NO production and hypotension were observed in all mice, but the extents of these pathophysiological changes were attenuated in GFRP OE mice. Perturbations in blood biochemistry were similarly attenuated in GFRP OE compared with wild-type controls. These results suggest that GFRP overexpression regulates GCH1 activity during septic shock, which in turn limits BH4 bioavailability for iNOS. We conclude that the GCH1-GFRP axis is a critical regulator of BH4 and NO production and the cardiovascular derangements that occur in septic shock.


Workload of Swedish Special Forces Operators Experienced During Stressful Simulation Training: A Pilot Study.
Stress week was included during training of Special Forces (SF) Operators in Sweden to test their ability and limits for handling stress in different unknown situations and environments at a military training facility in Sweden. The aim of the study was to examine the effects of stress and workload experienced in various tasks during firefighting and military medicine simulation training. This pilot study was performed during the second day of stress week. The National Aeronautics and Space Administration Task Load Index (NASA-TLX) is a validated, subjective, and multidimensional assessment tool for rating perceived workload with six subscales: mental demand, physical demand, temporal demand, performance, effort, and frustration. These subscales were used as an indicator of stress experienced. The different tasks were assessed by the SF Operators by rating the NASA-TLX subscales for each task, which were then analyzed and compared using ANOVA. There was a significant difference between the two simulation exercises assessed by the participants and instructors, and both groups considered firefighting to be more demanding than medical. The participants perceived the mental and physical demands as more demanding in the firefighting exercises, as well as for the level of frustration and effort. However, no differences regarding performance or temporal demands between the simulation exercises were found. The principle "train as you fight" implies difficult and demanding situations. When exposing Swedish SF Operators to challenging situations, assessment of perceived stress and performance are possible.


Does Treatment Adherence Therapy reduce expense of healthcare use in patients with psychotic disorders? Cost-minimization analysis in a randomized controlled trial.
Adherence interventions in psychotic disorders have produced mixed results. Even when an intervention improved adherence, benefits to patients were unclear. Treatment Adherence Therapy (TAT) also improved adherence relative to Treatment As Usual (TAU), but it had no effects on symptoms or quality of life. TAT may or may not reduce healthcare costs. To determine whether TAT reduces the use of healthcare resources, and thus healthcare costs. Randomized controlled trial of TAT versus TAU with 98 patients. Interviews were conducted at baseline (T0), six months later, when TAT had been completed (T1) and at six-month follow-up (T2). We have used admission data and part of the Trimbos/iMTA questionnaire for Costs associated with Psychiatric Illness (TiC-P). We compared total costs in the TAT group with those in the control group with the help of multivariate analysis of covariance. TAT did not significantly minimize total costs. In the TAT group, the mean one-year health-treatment cost per patient (including TAT sessions) was € 23 003.64 (SD=19 317.95), whereas in the TAU group it was € 22 489.88 (SD=25 224.57) (F(1)=.652, p=.42). However, there were two significant differences at item-level, both with higher costs for the TAU group: psychiatric nurse contacts and legal proceedings for court-ordered admissions. Because TAT did not reduce total healthcare costs, it did not contribute to cost-minimization. Its benefits are therefore questionable. No other adherence intervention has included analysis of cost-effectiveness or cost-minimization.


The significance of the cerebrospinal fluid examination in the management of chlorpropamide-induced hypoglycemia.
Chlorpropamide-induced hypoglycemia is often overlooked, misdiagnosed, and mistreated, because of the atypical, insidious, and intermittent clinical picture and because of the normal serum glucose level in some of the patients when arriving at the hospital. These facts are demonstrated in three case reports. Since the correction of low glucose levels in the cerebrospinal fluid occurs hours after its correction in the serum, examining and at times following the cerebrospinal fluid glucose levels in patients with chlorpropamide-induced neuroglycopenia will enable physicians to diagnose and cure more patients. A high index of suspicion should exist in the presence of any atypical encephalopathy, mainly in the elderly diabetic patient treated with chlorpropamide and suffering from impaired cerebral, hepatic, or renal function. By suspecting and identifying neuroglycopenia, disabling residual deficits and even death could eventually be prevented.


An amphioxus Gli gene reveals conservation of midline patterning and the evolution of hedgehog signalling diversity in chordates.
Hedgehog signalling, interpreted in receiving cells by Gli transcription factors, plays a central role in the development of vertebrate and Drosophila embryos. Many aspects of the signalling pathway are conserved between these lineages, however vertebrates have diverged in at least one key aspect: they have evolved multiple Gli genes encoding functionally-distinct proteins, increasing the complexity of the hedgehog-dependent transcriptional response. Amphioxus is one of the closest living relatives of the vertebrates, having split from the vertebrate lineage prior to the widespread gene duplication prominent in early vertebrate evolution. We show that amphioxus has a single Gli gene, which is deployed in tissues adjacent to sources of hedgehog signalling derived from the midline and anterior endoderm. This shows the duplication and divergence of the Gli gene family, and hence the origin of vertebrate Gli functional diversity, was specific to the vertebrate lineage. However we also show that the single amphioxus Gli gene produces two distinct transcripts encoding different proteins. We utilise three tests of Gli function to examine the transcription regulatory capacities of these different proteins, demonstrating one has activating activity similar to Gli2, while the other acts as a weak repressor, similar to Gli3. These data show that vertebrates and amphioxus have evolved functionally-similar repertoires of Gli proteins using parallel molecular routes; vertebrates via gene duplication and divergence, and amphioxus via alternate splicing of a single gene. Our results demonstrate that similar functional complexity of intercellular signalling can be achieved via different evolutionary pathways.


Selective use of contemporary drug-eluting stents in primary angioplasty for ST-elevation myocardial infarction: pooled analysis of COMFORTABLE AMI and EXAMINATION.
Selective use of DES only in patients at higher risk of MACE is common practice, particularly in healthcare systems with a large premium payable for DES. We aimed to identify subgroups of patients in which the use of BMS in primary percutaneous coronary intervention (PPCI) for STEMI can still be justified. We performed a patient-level pooled analysis of COMFORTABLE AMI and EXAMINATION comparing contemporary DES with BMS in PPCI. A risk score was applied using three parameters: lesion length >15 mm, vessel size <3 mm, and diabetes mellitus. Individual data were available for 2,655 patients. The incidence of MACE at one year was incrementally higher in patients with risk scores of 1 or 2/3. MACE rates were lower in patients with a risk score 0 or 1 who were treated with DES (p=0.0073 and p=0.008). No difference in death or reinfarction was seen between DES and BMS in any group. There was a significant reduction in TLR with DES in all three groups. A score comprising vessel size, lesion length, and diabetes did not identify patients at low risk with equivalent or better results from BMS use. The results suggest that the practice of only selective use of DES in primary PCI should be discouraged.


Multifunctional Alloys Obtained via a Dislocation-Free Plastic Deformation Mechanism.
We describe a group of alloys that exhibit "super" properties, such as ultralow elastic modulus, ultrahigh strength, super elasticity, and super plasticity, at room temperature and that show Elinvar and Invar behavior. These "super" properties are attributable to a dislocation-free plastic deformation mechanism. In cold-worked alloys, this mechanism forms elastic strain fields of hierarchical structure that range in size from the nanometer scale to several tens of micrometers. The resultant elastic strain energy leads to a number of enhanced material properties.


Type 2 inflammation suppression by T-regulatory cells attenuates the eosinophil recruitment in mucosa of chronic sinusitis.
Type 2 inflammation and eosinophilic infiltration are prominent pathologic features of chronic rhinosinusitis with nasal polyps (CRSwNP). The purpose of the present study was to determine the roles of Tregs in controlling type 2 inflammation and inhibiting eosinophilic infiltration in CRSwNP. A total of 134 nasal polyps, 67 ostiomeatal complex from chronic rhinosinusitis (CRS) and 62 normal nasal tissues from controls were collected to study the enumeration and function of Tregs cells and the expressions of cytokine profiles via immunofluorescence staining, flow cytometry, qRT-PCR, ELISA, and/or H&E staining. The effects of Tregs on type2 and type3 inflammations were determined in an eosinophilic chronic sinusitis (ECRS) mice model. It was confirmed that the CRSwNP displayed the features of Th2 and Th17 cells-mediated inflammation, accompanying by an increased level of eosinophilic infiltration and the eosinophil cationic protein (ECP), with a decreased frequency of Treg cells. Furthermore, the percentages of CD4+CD25+CD127lowTreg and CD4+CD25+Foxp3+Treg were only decreased in the polyps of CRSwNP but not in the paired peripheral blood. The CRSwNP possessed the decreased Nrp1+Tregs, Helios+Treg, and low TGF-β and interleukin (IL)-10 expressions in Tregs. The ECRS mice showed similar inflammatory characteristics to CRSwNP patients. The adoptive transfer of CD4+CD25+Foxp3+ Treg cells significantly decreased the inflammatory cytokines, eosinophilic chemotactic factors in the mucosa of the ECRS mice without alteration of the immune balance in the peripheral blood and spleen. In conclusion, CRSwNP showed high type 2 and type3 inflammation and defective Tregs. The induced regulatory T cell (iTreg) may correct the imbalance between immune tolerance and effect via limiting the eosinophil recruitment of mucosa in CRSwNP.


Muscle-Bone Crosstalk in Chronic Kidney Disease: The Potential Modulatory Effects of Exercise.
Chronic kidney disease (CKD) is a prevalent worldwide public burden that increasingly compromises overall health as the disease progresses. Two of the most negatively affected tissues are bone and skeletal muscle, with CKD negatively impacting their structure, function and activity, impairing the quality of life of these patients and contributing to morbidity and mortality. Whereas skeletal health in this population has conventionally been associated with bone and mineral disorders, sarcopenia has been observed to impact skeletal muscle health in CKD. Indeed, bone and muscle tissues are linked anatomically and physiologically, and together regulate functional and metabolic mechanisms. With the initial crosstalk between the skeleton and muscle proposed to explain bone formation through muscle contraction, it is now understood that this communication occurs through the interaction of myokines and osteokines, with the skeletal muscle secretome playing a pivotal role in the regulation of bone activity. Regular exercise has been reported to be beneficial to overall health. Also, the positive regulatory effect that exercise has been proposed to have on bone and muscle anatomical, functional, and metabolic activity has led to the proposal of regular physical exercise as a therapeutic strategy for muscle and bone-related disorders. The detection of bone- and muscle-derived cytokine secretion following physical exercise has strengthened the idea of a cross communication between these organs. Hence, this review presents an overview of the impact of CKD in bone and skeletal muscle, and narrates how these tissues intrinsically communicate with each other, with focus on the potential effect of exercise in the modulation of this intercommunication.