Genetic polymorphisms in folate pathway enzymes, DRD4 and GSTM1 are related to temporomandibular disorder.
Temporomandibular disorder (TMD) is a multifactorial syndrome related to a critical period of human life. TMD has been associated with psychological dysfunctions, oxidative state and sexual dimorphism with coincidental occurrence along the pubertal development. In this work we study the association between TMD and genetic polymorphisms of folate metabolism, neurotransmission, oxidative and hormonal metabolism. Folate metabolism, which depends on genes variations and diet, is directly involved in genetic and epigenetic variations that can influence the changes of last growing period of development in human and the appearance of the TMD. A case-control study was designed to evaluate the impact of genetic polymorphisms above described on TMD. A total of 229 individuals (69% women) were included at the study; 86 were patients with TMD and 143 were healthy control subjects. Subjects underwent to a clinical examination following the guidelines by the Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD). Genotyping of 20 Single Nucleotide Polymorphisms (SNPs), divided in two groups, was performed by multiplex minisequencing preceded by multiplex PCR. Other seven genetic polymorphisms different from SNPs (deletions, insertions, tandem repeat, null genotype) were achieved by a multiplex-PCR. A chi-square test was performed to determine the differences in genotype and allelic frequencies between TMD patients and healthy subjects. To estimate TMD risk, in those polymorphisms that shown significant differences, odds ratio (OR) with a 95% of confidence interval were calculated. Six of the polymorphisms showed statistical associations with TMD. Four of them are related to enzymes of folates metabolism: Allele G of Serine Hydoxymethyltransferase 1 (SHMT1) rs1979277 (OR = 3.99; 95%CI 1.72, 9.25; p = 0.002), allele G of SHMT1 rs638416 (OR = 2.80; 95%CI 1.51, 5.21; p = 0.013), allele T of Methylentetrahydrofolate Dehydrogenase (MTHFD) rs2236225 (OR = 3.09; 95%CI 1.27, 7.50; p = 0.016) and allele A of Methionine Synthase Reductase (MTRR) rs1801394 (OR = 2.35; 95CI 1.10, 5.00; p = 0.037). An inflammatory oxidative stress enzyme, Gluthatione S-Tranferase Mu-1(GSTM1), null allele (OR = 2.21; 95%CI 1.24, 4.36; p = 0.030) and a neurotransmission receptor, Dopamine Receptor D4 (DRD4), long allele of 48 bp-repeat (OR = 3.62; 95%CI 0.76, 17.26; p = 0.161). Some genetic polymorphisms related to folates metabolism, inflammatory oxidative stress, and neurotransmission responses to pain, has been significantly associated to TMD syndrome.


Childhood actinic keratosis in an albino transforming into squamous cell carcinoma.
Actinic keratosis is a scaly, cutaneous lesion that is often seen in elderly patients. It is almost never seen in children and young adults. It develops on areas such as the face, ears and dorsa of the hands with chronic sun exposure. Actinic keratosis is a premalignant lesion, since histological changes in the epidermis may progress to squamous cell carcinoma if left untreated. There are roughly 70,000 people with albinism in India. These patients are prone to develop actinic keratosis which may undergo spontaneous remission or develop into invasive squamous cell carcinoma, basal cell carcinoma and malignant melanoma.We present an unusual case of a 35 year old albino who developed actinic keratosis at the age 15 years which progressed to squamous cell carcinoma.


Phorbol ester potentiation of canine pulmonary vasoreactivity to histamine.
The effect of phorbol myristate acetate (PMA) on canine pulmonary vasoreactivity to histamine was determined in the isolated blood-perfused dog lung. Pulmonary vascular resistances and compliances were measured by using vascular occlusion techniques. Histamine (10(-5) M) significantly increased postcapillary resistance by venoconstriction and significantly attenuated total vascular compliance by decreasing large-vessel compliance and middle-compartment compliance. Pretreatment with the phorbol ester PMA (10(-7) M) significantly potentiated the vasoactive response to histamine and elicited an edemagenic effect in the isolated dog lung through modulation of the histaminergic vasoconstrictor effect on precapillary resistance, postcapillary resistance, and pulmonary vascular compliance. Pretreatment with the protein kinase C inhibitors staurosporine (10(-7) M) and calphostin C (10(-6) M) and the dihydropyridine Ca2+ channel blocker nifedipine (10(-5) M) significantly attenuated the effect of PMA on histaminergic-mediated vasoconstriction. The results of this study indicate that phorbol esters may exert their effect on canine pulmonary vasoreactivity predominantly through activation of protein kinase C and influx of Ca2+ through voltage-dependent Ca2+ channels.


Epilepsy, cognitive deficits and neuroanatomy in males with ZDHHC9 mutations.
Systematic investigation of individuals with intellectual disability after genetic diagnosis can illuminate specific phenotypes and mechanisms relevant to common neurodevelopmental disorders. We report the neurological, cognitive and neuroanatomical characteristics of nine males from three families with loss-of-function mutations in ZDHHC9 (OMIM #300799). All known cases of X-linked intellectual disability (XLID) due to ZDHHC9 mutation in the United Kingdom were invited to participate in a study of neurocognitive and neuroimaging phenotypes. Seven out of nine males with ZDHHC9 mutations had been diagnosed with epilepsy, exceeding epilepsy risk in XLID comparison subjects (P = 0.01). Seizure histories and EEG features amongst ZDHHC9 mutation cases shared characteristics with rolandic epilepsy (RE). Specific cognitive deficits differentiated males with ZDHHC9 mutations from XLID comparison subjects and converged with reported linguistic and nonlinguistic deficits in idiopathic RE: impaired oromotor control, reduced verbal fluency, and impaired inhibitory control on visual attention tasks. Consistent neuroanatomical abnormalities included thalamic and striatal volume reductions and hypoplasia of the corpus callosum. Mutations in ZDHHC9 are associated with susceptibility to focal seizures and specific cognitive impairments intersecting with the RE spectrum. Neurocognitive deficits are accompanied by consistent abnormalities of subcortical structures and inter-hemispheric connectivity. The biochemical, cellular and network-level mechanisms responsible for the ZDHHC9-associated neurocognitive phenotype may be relevant to cognitive outcomes in RE.


Intensity-based image registration by minimizing residual complexity.
Accurate definition of the similarity measure is a key component in image registration. Most commonly used intensity-based similarity measures rely on the assumptions of independence and stationarity of the intensities from pixel to pixel. Such measures cannot capture the complex interactions among the pixel intensities, and often result in less satisfactory registration performances, especially in the presence of spatially-varying intensity distortions. We propose a novel similarity measure that accounts for intensity nonstationarities and complex spatially-varying intensity distortions in mono-modal settings. We derive the similarity measure by analytically solving for the intensity correction field and its adaptive regularization. The final measure can be interpreted as one that favors a registration with minimum compression complexity of the residual image between the two registered images. One of the key advantages of the new similarity measure is its simplicity in terms of both computational complexity and implementation. This measure produces accurate registration results on both artificial and real-world problems that we have tested, and outperforms other state-of-the-art similarity measures in these cases.


High-throughput manufacturing of size-tuned liposomes by a new microfluidics method using enhanced statistical tools for characterization.
Microfluidics has recently emerged as a new method of manufacturing liposomes, which allows for reproducible mixing in miliseconds on the nanoliter scale. Here we investigate microfluidics-based manufacturing of liposomes. The aim of these studies was to assess the parameters in a microfluidic process by varying the total flow rate (TFR) and the flow rate ratio (FRR) of the solvent and aqueous phases. Design of experiment and multivariate data analysis were used for increased process understanding and development of predictive and correlative models. High FRR lead to the bottom-up synthesis of liposomes, with a strong correlation with vesicle size, demonstrating the ability to in-process control liposomes size; the resulting liposome size correlated with the FRR in the microfluidics process, with liposomes of 50 nm being reproducibly manufactured. Furthermore, we demonstrate the potential of a high throughput manufacturing of liposomes using microfluidics with a four-fold increase in the volumetric flow rate, maintaining liposome characteristics. The efficacy of these liposomes was demonstrated in transfection studies and was modelled using predictive modeling. Mathematical modelling identified FRR as the key variable in the microfluidic process, with the highest impact on liposome size, polydispersity and transfection efficiency. This study demonstrates microfluidics as a robust and high-throughput method for the scalable and highly reproducible manufacture of size-controlled liposomes. Furthermore, the application of statistically based process control increases understanding and allows for the generation of a design-space for controlled particle characteristics.


Subangstrom edge relaxations probed by electron microscopy in hexagonal boron nitride.
Theoretical research on the two-dimensional crystal structure of hexagonal boron nitride (h-BN) has suggested that the physical properties of h-BN can be tailored for a wealth of applications by controlling the atomic structure of the membrane edges. Unexplored for h-BN, however, is the possibility that small additional edge-atom distortions could have electronic structure implications critically important to nanoengineering efforts. Here we demonstrate, using a combination of analytical scanning transmission electron microscopy and density functional theory, that covalent interlayer bonds form spontaneously at the edges of a h-BN bilayer, resulting in subangstrom distortions of the edge atomic structure. Orbital maps calculated in 3D around the closed edge reveal that the out-of-plane bonds retain a strong π(*) character. We show that this closed edge reconstruction, strikingly different from the equivalent case for graphene, helps the material recover its bulklike insulating behavior and thus largely negates the predicted metallic character of open edges.


A resistance exercise set for a total body workout for adults with intellectual disabilities, a pilot study.
Resistance training has beneficial effects on fitness levels, cardiovascular disease risk, risk of sarcopenia and on performing activities of daily living. The focus of this study is to design a total body resistance exercise set for adults with intellectual disabilities (RESID) with minimal equipment required and to test its feasibility. The RESID was selected in an expert meeting, and its feasibility was determined in a cross-sectional pilot study. The feasibility was determined with completion rate, correct execution of exercises and the participant's experience. The expert group (n = 7) selected seven exercises for the RESID. The participants (N = 11) performed the RESID twice during regular sports classes. Completion rate and correctness were excellent for all exercises. The participants did not experience any major problems with the RESID. The RESID is feasible for use in different training settings. A physiotherapist or fitness instructor is required to supervise the training sessions.


Genetic association analysis of the IGFBP7, ADAMTS3, and IL8 genes as the potential osteoarthritis susceptibility that maps to chromosome 4q.
To determine by genetic association analysis whether the 4q functional candidate genes IGFBP7, ADAMTS3, and IL8 might encode for susceptibility to osteoarthritis (OA). Expression of IGFBP7, ADAMTS3, and IL8 in adult OA articular cartilage chondrocytes was demonstrated by reverse transcription-polymerase chain reaction. The genes were screened for common polymorphic DNA variants by direct sequencing of exons, intron-exon boundaries, and the 5' and 3' untranslated regions. The variants were genotyped in the female probands from the 146 families which each contained two or more sisters who had undergone total hip replacement (THR) and in 375 female controls matched for age. Variants showing evidence for association were subsequently genotyped in 244 female-THR patients with OA. Allele frequencies between the probands (or patients) and the controls were compared by chi(2) analysis. Fourteen common variants were identified in the three genes. An ADAMTS3 single nucleotide polymorphism was associated in the probands (p = 0.015) and an ADAMTS3 insertion/deletion approached significance (p = 0.059). However, neither variant was associated in the additional 244 patients with hip OA, with p values of 0.12 and 0.19, respectively. The analysis implies that the chromosome 4q female hip OA susceptibility is not coded for by polymorphism within the functional candidates IGFBP7, ADAMTS3, or IL8.


Report from the American Society of Transplantation on frailty in solid organ transplantation.
A consensus conference on frailty in kidney, liver, heart, and lung transplantation sponsored by the American Society of Transplantation (AST) and endorsed by the American Society of Nephrology (ASN), the American Society of Transplant Surgeons (ASTS), and the Canadian Society of Transplantation (CST) took place on February 11, 2018 in Phoenix, Arizona. Input from the transplant community through scheduled conference calls enabled wide discussion of current concepts in frailty, exploration of best practices for frailty risk assessment of transplant candidates and for management after transplant, and development of ideas for future research. A current understanding of frailty was compiled by each of the solid organ groups and is presented in this paper. Frailty is a common entity in patients with end-stage organ disease who are awaiting organ transplantation, and affects mortality on the waitlist and in the posttransplant period. The optimal methods by which frailty should be measured in each organ group are yet to be determined, but studies are underway. Interventions to reverse frailty vary among organ groups and appear promising. This conference achieved its intent to highlight the importance of frailty in organ transplantation and to plant the seeds for further discussion and research in this field.


End-user involvement to improve predictions and management of populations with complex dynamics and multiple drivers.
Sustainable management of wildlife populations can be aided by building models that both identify current drivers of natural dynamics and provide near-term predictions of future states. We employed a Strategic Foresight Protocol (SFP) involving stakeholders to decide the purpose and structure of a dynamic state-space model for the population dynamics of the Willow Ptarmigan, a popular game species in Norway. Based on local knowledge of stakeholders, it was decided that the model should include food web interactions and climatic drivers to provide explanatory predictions. Modeling confirmed observations from stakeholders that climate change impacts Ptarmigan populations negatively through intensified outbreaks of insect defoliators and later onset of winter. Stakeholders also decided that the model should provide anticipatory predictions. The ability to forecast population density ahead of the harvest season was valued by the stakeholders as it provides the management extra time to consider appropriate harvest regulations and communicate with hunters prior to the hunting season. Overall, exploring potential drivers and predicting short-term future states, facilitate collaborative learning and refined data collection, monitoring designs, and management priorities. Our experience from adapting a SFP to a management target with inherently complex dynamics and drivers of environmental change, is that an open, flexible, and iterative process, rather than a rigid step-wise protocol, facilitates rapid learning, trust, and legitimacy.


Injury severity in relation to seatbelt use in Cape Town, South Africa: a pilot study.
Injuries and deaths from road traffic collisions present an enormous challenge to the South African (SA) healthcare system. The use of restraining devices is an important preventive measure. To determine the relationship between seatbelt use and injury severity in vehicle occupants involved in road traffic collisions in Cape Town, SA. A prospective cohort design was used. Occupants of vehicles involved in road traffic collisions attended to by EMS METRO Rescue were included during the 3-month data collection period. Triage categories of prehospital patients were compared between restrained and unrestrained groups. Patients transferred to hospital were followed up and injury severity scores were calculated. Disposition from the emergency centre and follow-up after 1 week were also documented and compared. A total of 107 patients were included in the prehospital phase. The prevalence of seatbelt use was 25.2%. Unrestrained vehicle occupants were five times more likely to have a high triage score (odds ratio (OR) 5.4; 95% confidence interval (CI) 1.5 - 19.5). Fifty patients were transferred to study hospitals. Although seatbelt non-users were more likely to be admitted to hospital (p=0.002), they did not sustain more serious injuries (OR 0.44; 95% CI 0.02 - 8.8). The prevalence of seatbelt use in vehicle occupants involved in road traffic collisions was very low. The association between seatbelt non-use and injury severity calls for stricter enforcement of current seatbelt laws, together with the development and implementation of road safety interventions specifically focused on high-risk groups.


Effect of geometric lattice design on optical/electrical properties of transparent silver grid for organic solar cells.
Silver (Ag) grid transparent electrode is one of the most promising transparent conducting electrodes (TCEs) to replace conventional indium tin oxide (ITO). We systematically investigate an effect of geometric lattice modifications on optical and electrical properties of Ag grid electrode. The reference Ag grid with 5 μm width and 100 μm pitch (duty of 0.05) prepared by conventional photo-lithography and lift-off processes shows the sheet resistance of 13.27 Ω/sq, transmittance of 81.1%, and resultant figure of merit (FOM) of 129.05. Three different modified Ag grid electrodes with stripe added-mesh (SAM), triangle-added mesh (TAM), and diagonal-added mesh (DAM) are suggested to improve optical and electrical properties. Although all three of SAM, TAM, and DAM Ag grid electrodes exhibit the lower transmittance values of about 72 - 77%, they showed much decreased sheet resistance of 6 - 8 Ω/sq. As a result, all of the lattice-modified Ag grid electrodes display significant improvement of FOM and the highest value of 171.14 is obtained from DAM Ag grid, which is comparable to that of conventional ITO electrode (175.46). Also, the feasibility of DAM Ag gird electrode for use in organic solar cell is confirmed by finite difference time domain (FDTD) simulations. Unlike a conventional ITO electrode, DAM Ag grid electrode can induce light scattering and trapping due to the diffuse transmission that compensates for the loss in optical transparency, resulting in comparable light absorption in the photo active layer of poly(3-hexylthiophene) (P3HT): [6,6]-phenyl-C61-butyric acid methyl ester (PC₆₀BM). P3HT:PC₆₀BM based OSCs with the DAM Ag grid electrode were fabricated, which also showed the potential for ITO-free transparent electrode.


Health care costs and personal bankruptcy.
In response to published but unconfirmed reports that health care costs were a leading cause of personal bankruptcy in the U.S., court records of all bankruptcy petitioners in one judicial district were examined. The records were analyzed by income, employment, debt categories and amounts. Within the limitations of the study, health care costs seem not to have played a significant role in the financial lives of this population.


Replication-biased genome organisation in the crenarchaeon Sulfolobus.
Species of the crenarchaeon Sulfolobus harbour three replication origins in their single circular chromosome that are synchronously initiated during replication. We demonstrate that global gene expression in two Sulfolobus species is highly biased, such that early replicating genome regions are more highly expressed at all three origins. The bias by far exceeds what would be anticipated by gene dosage effects alone. In addition, early replicating regions are denser in archaeal core genes (enriched in essential functions), display lower intergenic distances, and are devoid of mobile genetic elements. The strong replication-biased structuring of the Sulfolobus chromosome implies that the multiple replication origins serve purposes other than simply shortening the time required for replication. The higher-level chromosomal organisation could be of importance for minimizing the impact of DNA damage, and may also be linked to transcriptional regulation.


Atrophin proteins interact with the Fat1 cadherin and regulate migration and orientation in vascular smooth muscle cells.
Fat1, an atypical cadherin induced robustly after arterial injury, has significant effects on mammalian vascular smooth muscle cell (VSMC) growth and migration. The related Drosophila protein Fat interacts genetically and physically with Atrophin, a protein essential for development and control of cell polarity. We hypothesized that interactions between Fat1 and mammalian Atrophin (Atr) proteins might contribute to Fat1 effects on VSMCs. Like Fat1, mammalian Atr expression increased after arterial injury and in VSMCs stimulated with growth and chemotactic factors including angiotensin II, basic fibroblast growth factor, and platelet-derived growth factor BB. Two distinct Atr2 transcripts, atr2L and atr2S, were identified by Northern analysis; in VSMCs, atr2S mRNA expression was more responsive to stimuli. By immunocytochemistry, Fat1 and Atrs colocalized at cell-cell junctions, in the perinuclear area, and in the nucleus. In coimmunoprecipitation studies, Fat1 interacted with both Atr1 and Atr2; these interactions required Fat1 amino acids 4300-4400 and an intact Atro-box in the Atrs. Knock-down of Atrs by small interfering RNA did not affect VSMC growth but had complex effects on migration, which was impaired by Atr1 knockdown, enhanced by Atr2L knockdown, and unchanged when both Atr2S and Atr2L were depleted. Enhanced migration caused by Atr2L knockdown required Fat1 expression. Similarly, orientation of cells after monolayer denudation was impaired in cells with Atr1 knockdown but enhanced in cells selectively depleted of Atr2L. Together these findings suggest that Fat1 and Atrs act in concert after vascular injury but show further that distinct Atr isoforms have disparate effects on VSMC directional migration.


Influenza Illness and Hospitalizations Averted by Influenza Vaccination in the United States, 2005-2011.
The goal of influenza vaccination programs is to reduce influenza-associated disease outcomes. Therefore, estimating the reduced burden of influenza as a result of vaccination over time and by age group would allow for a clear understanding of the value of influenza vaccines in the US, and of areas where improvements could lead to greatest benefits. To estimate the direct effect of influenza vaccination in the US in terms of averted number of cases, medically-attended cases, and hospitalizations over six recent influenza seasons. Using existing surveillance data, we present a method for assessing the impact of influenza vaccination where impact is defined as either the number of averted outcomes or as the prevented disease fraction (the number of cases estimated to have been averted relative to the number of cases that would have occurred in the absence of vaccination). We estimated that during our 6-year study period, the number of influenza illnesses averted by vaccination ranged from a low of approximately 1.1 million (95% confidence interval (CI) 0.6-1.7 million) during the 2006-2007 season to a high of 5 million (CI 2.9-8.6 million) during the 2010-2011 season while the number of averted hospitalizations ranged from a low of 7,700 (CI 3,700-14,100) in 2009-2010 to a high of 40,400 (CI 20,800-73,000) in 2010-2011. Prevented fractions varied across age groups and over time. The highest prevented fraction in the study period was observed in 2010-2011, reflecting the post-pandemic expansion of vaccination coverage. Influenza vaccination programs in the US produce a substantial health benefit in terms of averted cases, clinic visits and hospitalizations. Our results underscore the potential for additional disease prevention through increased vaccination coverage, particularly among nonelderly adults, and increased vaccine effectiveness, particularly among the elderly.


Identification of shared genetic variants between schizophrenia and lung cancer.
Epidemiology studies suggest associations between schizophrenia and cancer. However, the underlying genetic mechanisms are not well understood, and difficult to identify from epidemiological data. We investigated if there is a shared genetic architecture between schizophrenia and cancer, with the aim to identify specific overlapping genetic loci. First, we performed genome-wide enrichment analysis and second, we analyzed specific loci jointly associated with schizophrenia and cancer by the conjunction false discovery rate. We analyzed the largest genome-wide association studies of schizophrenia and lung, breast, prostate, ovary, and colon-rectum cancer including more than 220,000 subjects, and included genetic association with smoking behavior. Polygenic enrichment of associations with lung cancer was observed in schizophrenia, and weak enrichment for the remaining cancer sites. After excluding the major histocompatibility complex region, we identified three independent loci jointly associated with schizophrenia and lung cancer. The strongest association included nicotinic acetylcholine receptors and is an established pleiotropic locus shared between lung cancer and smoking. The two other loci were independent of genetic association with smoking. Functional analysis identified downstream pleiotropic effects on epigenetics and gene-expression in lung and brain tissue. These findings suggest that genetic factors may explain partly the observed epidemiological association of lung cancer and schizophrenia.


Development and Characterization of a Chest CT Atlas.
A major goal of lung cancer screening is to identify individuals with particular phenotypes that are associated with high risk of cancer. Identifying relevant phenotypes is complicated by the variation in body position and body composition. In the brain, standardized coordinate systems (e.g., atlases) have enabled separate consideration of local features from gross/global structure. To date, no analogous standard atlas has been presented to enable spatial mapping and harmonization in chest computational tomography (CT). In this paper, we propose a thoracic atlas built upon a large low dose CT (LDCT) database of lung cancer screening program. The study cohort includes 466 male and 387 female subjects with no screening detected malignancy (age 46-79 years, mean 64.9 years). To provide spatial mapping, we optimize a multi-stage inter-subject non-rigid registration pipeline for the entire thoracic space. Briefly, with 50 scans of 50 randomly selected female subjects as fine tuning dataset, we search for the optimal configuration of the non-rigid registration module in a range of adjustable parameters including: registration searching radius, degree of keypoint dispersion, regularization coefficient and similarity patch size, to minimize the registration failure rate approximated by the number of samples with low Dice similarity score (DSC) for lung and body segmentation. We evaluate the optimized pipeline on a separate cohort (100 scans of 50 female and 50 male subjects) relative to two baselines with alternative non-rigid registration module: the same software with default parameters and an alternative software. We achieve a significant improvement in terms of registration success rate based on manual QA. For the entire study cohort, the optimized pipeline achieves a registration success rate of 91.7%. The application validity of the developed atlas is evaluated in terms of discriminative capability for different anatomic phenotypes, including body mass index (BMI), chronic obstructive pulmonary disease (COPD), and coronary artery calcification (CAC).


Systemic inflammation is associated with pulmonary hypertension in patients undergoing haemodialysis.
Pulmonary hypertension (PH) is an overlooked cardiovascular morbidity in patients undergoing haemodialysis. Inflammation has been demonstrated to play a significant role with certain types of PH in non-uraemic patients, but studies analysing the mechanisms in dialyzed patients with PH are rare. Hence, we investigated systemic and local inflammation biomarkers associated with PH in uraemia patients to elucidate the potential mechanism. A cross-sectional study was conducted in which 97 haemodialysis patients were initially evaluated in our hospital. Twelve inflammatory cytokines were measured using a cytometric beads assay in patients with and without PH. FE(NO) (fractional exhaled nitric oxide) was checked by a chemiluminescence analyser in patients with and without PH as well as by normal controls. Thirty-nine eligible patients were enrolled. Compared to patients without PH (group A), patients with PH (group B) had significantly higher serum levels of hs-CRP, IL-1beta, TNF-alpha and IL-6. FE(NO) was also measured. Though the pre-dialysis FE(NO) levels were elevated in both groups; group B patients had significantly higher pre-dialysis FE(NO) levels than group A patients (39.9 +/- 16.7 versus 31.8 +/- 10.3, P = 0.045). The post-dialysis FE(NO) levels returned to normal in group A while the remaining were significantly higher in group B (30.3 +/- 10.3 versus 20.1 +/- 10.9, P = 0.003). Our study revealed that dialyzed patients with PH had a significantly higher level of airway FE(NO) as well as serum levels of acute phase reactive protein and cytokines, including IL-1beta, TNF-alpha and IL-6. A chronic inflammation might play an important role in the pathogenesis of PH in patients undergoing haemodialysis.


Ancient teeth, phenetic affinities, and African hominins: Another look at where Homo naledi fits in.
A new species of Homo, Homo naledi, was described in 2015 based on the hominin skeletal remains from the Dinaledi Chamber of the Rising Star cave system, South Africa. Subsequent craniodental comparative analyses, both phenetic and cladistic, served to support its taxonomic distinctiveness. Here we provide a new quantitative analysis, where up to 78 nonmetric crown and root traits of the permanent dentition were compared among samples of H. naledi (including remains from the recently discovered Lesedi Chamber) and eight other species from Africa: Australopithecus afarensis, Australopithecus africanus, Paranthropus boisei, Paranthropus robustus, Homo habilis, Homo erectus, Middle Pleistocene Homo sp., and Pleistocene and Holocene Homo sapiens. By using the mean measure of divergence distance statistic, phenetic affinities were calculated among samples to evaluate interspecific relatedness. The objective was to compare the results with those previously obtained, to assess further the taxonomic validity of the Rising Star hominin species. In accordance with earlier findings, H. naledi appears most similar dentally to the other African Homo samples. However, the former species is characterized by its retention and full expression of features relating to the main cusps, as well as the root numbers, with a near absence of accessory traits-including many that, based on various cladistic studies, are plesiomorphic in both extinct and extant African hominins. As such, the present findings provide additional support for the taxonomic validity of H. naledi as a distinct species of Homo.


Experimental tests of different solutions to the diffusion equation for optical characterization of scattering media by time-resolved transmittance.
A detailed investigation of the use of time-resolved trasmittance for the optical characterization of scattering media by use of different analytical solutions to the diffusion equation has been performed. A femtosecond Ti:sapphire laser working at 800 nm and a streak camera with a time resolution of a few picoseconds were employed. Different latex and Intralipid solutions as well as biological samples were investigated. Reduced scattering coefficients were evaluated, and good agreement with the Mie predictions was found. An estimation of the order of magnitude of the absorption coefficient was obtained for the low-absorbance samples examined. These studies confirm experimentally that time-resolved trasmittance can be employed usefully for evaluating s values of thick scattering samples when a proper theoretical description that takes into account realistic boundary conditions is used.


The inflammatory response triggered by Influenza virus: a two edged sword.
Influenza A virus (IAV) is a relevant respiratory tract pathogen leading to a great number of deaths and hospitalizations worldwide. Secondary bacterial infections are a very common cause of IAV associated morbidity and mortality. The robust inflammatory response that follows infection is important for the control of virus proliferation but is also associated with lung damage, morbidity and death. The role of the different components of immune response underlying protection or disease during IAV infection is not completely elucidated. Overall, in the context of IAV infection, inflammation is a 'double edge sword' necessary to control infection but causing disease. Therefore, a growing number of studies suggest that immunomodulatory strategies may improve disease outcome without affecting the ability of the host to deal with infection. This review summarizes recent aspects of the inflammatory responses triggered by IAV that are preferentially involved in causing severe pulmonary disease and the anti-inflammatory strategies that have been suggested to treat influenza induced immunopathology.


Sources and determinants of vitamin D intake in Danish pregnant women.
Vitamin D deficiency during pregnancy has been associated with the development of several adverse health outcomes, e.g., pre-eclampsia, gestational diabetes mellitus, preterm delivery, low birth weight, birth length, and bone mineral content. The aims of the present study were to estimate the intake and sources of vitamin D in Danish pregnant women and to examine potential determinants of vitamin D intake of the recommended level (10 µg per day). In 68,447 Danish pregnant women the mean ± SD for vitamin D intake was 9.23 ± 5.60 µg per day (diet: 3.56 ± 2.05 µg per day, supplements: 5.67 ± 5.20 µg per day). 67.6% of the women reported use of vitamin D supplements but only 36.9% reported use of vitamin D supplements of at least 10 µg. Supplements were the primary source of vitamin D for the two higher quartiles of total vitamin D intake, with diet being the primary source for the two lower quartiles. Determinants of sufficient total vitamin D intake were: high maternal age, nulliparity, non-smoking, and filling out of the Food Frequency Questionnaire (FFQ) during summer or fall. We propose that clinicians encourage vitamin D supplementation among pregnant women, with special focus on vulnerable groups such as the young, smokers and multiparous women, in order to improve maternal and fetal health both during and after pregnancy.


Chirality transfer and stereoselectivity of imprinted cholesteric networks.
Imprinting of cholesteric textures in a polymer network is a method of preserving a macroscopically chiral phase in a system with no molecular chirality. By modifying the elastic properties of the network, the resulting stored helical twist can be manipulated within a wide range since the imprinting efficiency depends on the balance between the elastic constants and twisting power at network formation. One spectacular property of phase chirality imprinting is the created ability of the network to adsorb preferentially one stereo component from a racemic mixture. In this paper we explore this property of chirality transfer from a macroscopic to a molecular scale. In particular, we focus on the competition between the phase chirality and the local nematic order. We demonstrate that it is possible to control the subsequent release of a chiral solvent component from the imprinting network and the reversibility of the stereo-selective swelling by racemic solvents.


GP96 interacts with HHV-6 during viral entry and directs it for cellular degradation.
CD46 and CD134 mediate attachment of Human Herpesvirus 6A (HHV-6A) and HHV-6B to host cell, respectively. But many cell types interfere with viral infection through rapid degradation of viral DNA. Hence, not all cells expressing these receptors are permissive to HHV-6 DNA replication and production of infective virions suggesting the involvement of additional factors that influence HHV-6 propagation. Here, we used a proteomics approach to identify other host cell proteins necessary for HHV-6 binding and entry. We found host cell chaperone protein GP96 to interact with HHV-6A and HHV-6B and to interfere with virus propagation within the host cell. In human peripheral blood mononuclear cells (PBMCs), GP96 is transported to the cell surface upon infection with HHV-6 and interacts with HHV-6A and -6B through its C-terminal end. Suppression of GP96 expression decreased initial viral binding but increased viral DNA replication. Transient expression of human GP96 allowed HHV-6 entry into CHO-K1 cells even in the absence of CD46. Thus, our results suggest an important role for GP96 during HHV-6 infection, which possibly supports the cellular degradation of the virus.


Binge drinking and total alcohol consumption from 16 to 43 years of age are associated with elevated fasting plasma glucose in women: results from the northern Swedish cohort study.
Studies have indicated that moderate alcohol consumption is associated with lower incidence of diabetes in women. However, not only the amount but also the drinking pattern could be of importance when assessing the longitudinal relation between alcohol and glucose. Also, there is a lack of studies on alcohol use beginning in adolescence on adult glucose levels. The aim was to examine the association between total alcohol consumption and binge drinking between ages 16 and 43 and fasting plasma glucose at age 43. Data were retrieved from a 27-year prospective cohort study, the Northern Swedish Cohort. In 1981, all 9th grade students (n = 1083) within a municipality in Sweden were invited to participate. There were re-assessments at ages 18, 21, 30 and 43. This particular study sample consisted of 897 participants (82.8%). Fasting plasma glucose (mmol/L) was measured at a health examination at age 43. Total alcohol consumption (in grams) and binge drinking were calculated from alcohol consumption data obtained from questionnaires. Descriptive analyses showed that men had higher levels of fasting plasma glucose as compared to women. Men also reported higher levels of alcohol consumption and binge drinking behavior. Linear regressions showed that total alcohol consumption in combination with binge drinking between ages 16 and 43 was associated with elevated fasting plasma glucose at age 43 in women (beta = 0.14, p = 0.003) but not in men after adjustment for BMI, hypertension and smoking at age 43. Our findings indicate that reducing binge drinking and alcohol consumption among young and middle-aged women with the highest consumption might be metabolically favorable for their future glucose metabolism.


Complete Genome Sequences of Two Interactive Moderate Thermophiles, Paenibacillus napthalenovorans 32O-Y and Paenibacillus sp. 32O-W.
Microorganisms with the capability to desulfurize petroleum are in high demand with escalating restrictions currently placed on fuel purity. Thermophilic desulfurizers are particularly valuable in high-temperature industrial applications. We report the whole-genome sequences of Paenibacillus napthalenovorans 32O-Y and Paenibacillus sp. 32O-W, which can and cannot, respectively, metabolize dibenzothiophene.


Cognitive and Clinical Characteristics of Sexual and Religious Obsessions.
Sexual and religious obsessions are often grouped together as unacceptable thoughts, symptoms of obsessive-compulsive disorder hypothesized to be maintained by maladaptive beliefs about the importance and control of thoughts. Although there is empirical justification for this typology, there are several reasons to suspect that sexual and religious obsessions may differ with respect to associated obsessional beliefs and personality traits. In this study, we examined the associations between sexual and religious obsessions (separately) and (a) putatively obsessional cognitive styles, especially beliefs about the importance and control of thoughts, and responsibility, (b) obsessive-compulsive personality traits, and (c) schizotypal personality traits. Whereas sexual obsessions were predicted only by increased beliefs about the importance and control of thoughts, and contamination obsessions were predicted only by inflated responsibility appraisals and threat estimation, religious obsessions were independently predicted by both of these constructs. In addition, only religious obsessions were related to self-reported obsessive-compulsive personality traits. Researchers and clinicians should be cognizant of potentially important distinctions between sexual and religious obsessions, and the possibility that scrupulous OCD shares processes with both autogenous and reactive presentations.


Dexamethasone-induced Krüppel-like factor 9 expression promotes hepatic gluconeogenesis and hyperglycemia.
Chronic glucocorticoid therapy has serious side effects, including diabetes and fatty liver. However, the molecular mechanisms responsible for steroid-induced diabetes remain largely enigmatic. Here, we show that hepatic Krüppel-like factor 9 (Klf9) gene expression is induced by dexamethasone and fasting. The overexpression of Klf9 in primary hepatocytes strongly stimulated Pgc1a gene expression through direct binding to its promoter, thereby activating the gluconeogenic program. However, Klf9 mutation abolished the stimulatory effect of dexamethasone on cellular glucose output. Adenovirus-mediated overexpression of KLF9 in the mouse liver markedly increased blood glucose levels and impaired glucose tolerance. Conversely, both global Klf9-mutant mice and liver-specific Klf9-deleted mice displayed fasting hypoglycemia. Moreover, the knockdown of Klf9 in the liver in diabetic mouse models, including ob/ob and db/db mice, markedly lowered fasting blood glucose levels. Notably, hepatic Klf9 deficiency in mice alleviated hyperglycemia induced by chronic dexamethasone treatment. These results suggest a critical role for KLF9 in the regulation of hepatic glucose metabolism and identify hepatic induction of KLF9 as a mechanism underlying glucocorticoid therapy-induced diabetes.


A column test for leaching of organochlorines from soil by amphiphilic nonionic nanopolymers.
Amphiphilic nonionic cross-linked nanopolymers (NPs) were synthesized to examine removal of five organochlorines (OCs), namely lindane, heptachlor, aldrin, dieldrin, endrin, and DDT, from a range of Thai agricultural soils. The synthesized NP particles had polarity characteristics similar to those of nonionic surfactant micelles and were largely in the size range of 55-155 nm. This work aimed to determine the optimal conditions for leaching of OC contaminated soil with NPs and also to investigate the role and influence of soil properties on this leaching. An investigation of the concentrations of aqueous dispersions of these particles found that a concentration of 10 g L(-1). was found most effective in leaching the OCs from a column of spiked soil. The optimal contact time that allowed a NP dispersion and spiked soil to reach equilibrium was 48 h. The results indicated influencing factors for OC removal and soil remediation were properties both of the soil and the compounds themselves. Soil organic carbon (SOC) content and soil texture played an important role on the sorption as well as compound hydrophobicity expressed as log K(OW) values. The removal efficiency was found to be in the range of 85.2-92.8 % for all soil samples and in the order of DDT < aldrin < heptachlor < dieldrin < endrin < lindane regardless of soil type. This order is inversely related to the log K(OC) values of these compounds. For OC compounds with a similar molecular structure, removal efficiency was related to molecular weight (MW).


An intervention to decrease catheter-related bloodstream infections in the ICU.
Catheter-related bloodstream infections occurring in the intensive care unit (ICU) are common, costly, and potentially lethal. We conducted a collaborative cohort study predominantly in ICUs in Michigan. An evidence-based intervention was used to reduce the incidence of catheter-related bloodstream infections. Multilevel Poisson regression modeling was used to compare infection rates before, during, and up to 18 months after implementation of the study intervention. Rates of infection per 1000 catheter-days were measured at 3-month intervals, according to the guidelines of the National Nosocomial Infections Surveillance System. A total of 108 ICUs agreed to participate in the study, and 103 reported data. The analysis included 1981 ICU-months of data and 375,757 catheter-days. The median rate of catheter-related bloodstream infection per 1000 catheter-days decreased from 2.7 infections at baseline to 0 at 3 months after implementation of the study intervention (P< or =0.002), and the mean rate per 1000 catheter-days decreased from 7.7 at baseline to 1.4 at 16 to 18 months of follow-up (P<0.002). The regression model showed a significant decrease in infection rates from baseline, with incidence-rate ratios continuously decreasing from 0.62 (95% confidence interval [CI], 0.47 to 0.81) at 0 to 3 months after implementation of the intervention to 0.34 (95% CI, 0.23 to 0.50) at 16 to 18 months. An evidence-based intervention resulted in a large and sustained reduction (up to 66%) in rates of catheter-related bloodstream infection that was maintained throughout the 18-month study period.


A novel glycoprotein obtained from Chlorella vulgaris strain CK22 shows antimetastatic immunopotentiation.
A glycoprotein extract (CVS), derived from the unicellular green alga Chlorella vulgaris, strain CK22, exhibited a pronounced antitumor effect against both spontaneous and experimentally induced metastasis in mice. Inhibition of tumor metastasis was enhanced when intratumor administration of CVS was followed by s.c. injection of CVS. Anti-metastatic immunopotentiation was observed in euthymic mice, but not in athymic nude mice. The antitumor activity of CVS was reflected in antigen-specific, T-cell-mediated immunity. Both CD4 and CD8 T cells contributed to the antimetastatic effects, as shown by in vivo depletion experiments with anti-T-cell subset antibodies. Furthermore, CVS caused the recruitment of T cells to the regional lymph nodes and their proliferation in these organs. The CD4-positive population, following CVS injection at the time of tumor rechallenge, displayed a pronounced increase in the proportion of T cells that were CD18 bright, CD44 bright, CD25+, CD54+, CD69+ or CD71+ in the lymph nodes. Thus, CVS induces T cell activation in peripheral lymph nodes in tumor-bearing mice. We conclude that CVS augments antimetastatic immunity through T cell activation in lymphoid organs and enhances recruitment of these cells to the tumor sites. Presurgical treatment with CVS might prevent metastasis or tumor progression.


Obsessive-compulsive disorder and acquired toxoplasmosis in two children.
Two children presenting symptoms of obsessive-compulsive disorder (OCD) and with acquired toxoplasmosis are described and the possibility of a previously rarely reported association between OCD and acquired toxoplasmosis is discussed. Case 1 is a 14-year-old boy with Tourette syndrome (TS), attention deficit hyperactivity disorder (ADHD) in partial remission and a three-year history of OCD referred to our department due to an acute deterioration of obsessive-compulsive (OC) symptoms. Case 2 is an 11-year-old boy referred to our department because of a two-year history of OCD. The OC symptoms were observed immediately following an infection. In both cases laboratory tests confirmed the diagnosis of acquired toxoplasmosis. The pharmacological therapy of T.gondi infection without any psychopharmacological treatment caused remission or significant improvement regarding OC symptoms.


Branching patterns determine the size of single subcortical infarctions.
The size variation of single subcortical infarcts (SSIs) may be because of differences in stroke mechanisms or branching patterns of perforators. We aim to investigate this issue using high-resolution MRI. Patients with high-resolution MRI-identified SSI without significant (≥50%) middle cerebral artery stenosis were enrolled. Perforator stems were defined as perforators originating from the middle cerebral artery and perforator branches as linear structures inside the infarcted area, traceable from >2 adjacent slices. The branching index was calculated as the number of perforator branches divided by the number of perforator stems. Clinical and imaging characteristics were compared between large (≥20 mm in diameter) and small SSI groups. Forty-one patients (10 large and 31 small SSIs) were enrolled. Larger SSIs were more closely associated with diabetes mellitus and severe neurological dysfunction but not with the presence of middle cerebral artery plaque. Although there was no difference in the number of perforator stems, the number of perforator branches (4.8±2.2 versus 2.3±1.4; P=0.005) and branching index (2.9±1.0 versus 1.2±0.8; P<0.001) was higher in the large SSI group. SSI diameter showed a significant correlation with the number of perforator branches (r=0.630; P<0.001) and branching index (r=0.750; P<0.001). SSI diameter seems to be associated with anatomic branching variation rather than the mechanism of stroke. Definition of small vessel disease with lesion diameter criteria may not be appropriate.


Aggression-inhibiting influence of sexual humor.
Forty-eight undergraduate males participated in an experiment designed to investigate the hypothesis that prior exposure to sexual humor would reduce the level of aggression directed by angry individuals against the person who had previously provoked them. In order to examine this suggestion, subjects were first angered or not angered by a male confederate; next, exposed to either neutral, nonhumorous pictures or to one of two types of sexual humor (nonexploitative, exploitative); and finally, provided with an opportunity to aggress against this individual by means of electric shock. Results indicated that exposure to exploitative sexual humor, but not exposure to nonexploitative sexual humor, significantly reduced the strength of subjects' later attacks against the victim. These findings are discussed in terms of the results of a follow-up study suggesting that individuals are more likely to think or fantasize about exploitative than nonexploitative sexual humor following the removal of such stimuli.


Prognostic implications of mutations in NOTCH1 and FBXW7 in childhood T-ALL treated according to the NOPHO ALL-1992 and ALL-2000 protocols.
In children, T-cell acute lymphoblastic leukemia (T-ALL) has inferior prognosis compared with B-cell precursor ALL. In order to improve survival, individualized treatment strategies and thus risk stratification algorithms are warranted, ideally already at the time of diagnosis. We analyzed the frequency and prognostic implication of mutations in NOTCH1 and FBXW7 in 79 cases of Swedish childhood T-ALL treated according to the Nordic Society of Pediatric Hematology and Oncology (NOPHO) ALL-1992 and ALL-2000 protocols. In a subgroup of patients, we also investigated the functional relevance of NOTCH1 mutations measured as expression of the HES1, MYB, and MYC genes. Forty-seven of the cases (59%) displayed mutations in NOTCH1 and/or FBXW7. There was no difference in overall (P = 0.14) or event-free survival (EFS) (P = 0.10) in patients with T-ALL with mutation(s) in NOTCH1/FBXW7 compared with patients with T-ALL without mutations in any of these genes. T-ALL carrying NOTCH1 mutations had increased HES1 and MYB mRNA expression (HES1 9.2 ± 1.9 (mean ± SEM), MYB 8.7 ± 0.8 (mean ± SEM)) compared to T-ALL with wild-type NOTCH1 (HES1 1.8 ± 0.7, MYB 5.1 ± 1.2, P = 0.02 and 0.008, respectively). In cases of T-ALL with high HES1 expression, improved overall (P = 0.02) and EFS (P = 0.028) was seen. Increased NOTCH activity, reflected by increased HES1 expression, is associated with improved outcome in pediatric T-ALL, but its role as a diagnostic tool or a therapeutic target in future clinical treatment protocols remains to be elucidated.


Providers and women's perspectives on person-centered maternity care: a mixed methods study in Kenya.
Globally, there has been increasing attention to women's experiences of care and calls for a person-centered care approach. At the heart of this approach is the patient-provider relationship. It is necessary to examine the extent to which providers and women agree on the care that is provided and received. Studies have found that incongruence between women's and providers' perceptions may negatively impact women's compliance, satisfaction, and future use of health facilities. However, there are no studies that examine patient and provider perspectives on person-centered care. To fill this gap in the literature, we use cross-sectional data of 531 women and 33 providers in seven government health facilities in Kenya to assess concordance and discordance in person-centered care measures. Additionally, we analyze 41 in-depth interviews with providers from three of these facilities to examine why differences in reporting may occur. Descriptive statistical methods were used to measure the magnitude of differences between reports of women and reports of providers. Thematic analyses were conducted for provider surveys. Our findings suggest high discordance between women and providers' perspectives in regard to person-centered care experiences. On average, women reported lower levels of person-centered care compared to providers, including low respectful and dignified care, communication and autonomy, and supportive care. Providers were more likely to report higher rates of poor health facility environment such as having sufficient staff. We summarize the overarching reasons for the divergence in women and provider reports as: 1) different understanding or interpretation of person-centered care behaviors, and 2) different expectations, norms or values of provider behaviors. Providers rationalized abuse towards women, did not allow a companion of choice, and blamed women for poor patient-provider communication. Women lacked assurance in privacy and confidentiality, and faced challenges related to the health facility environment. Providers attributed poor person-centered care to both individual and facility/systemic factors. Implications of this study suggests that providers should be trained on person-centered care approaches and women should be counseled on understanding patient rights and how to communicate with health professionals.


Trends in anemia management in US hemodialysis patients 2004-2010.
There have been major changes in the management of anemia in US hemodialysis patients in recent years. We sought to determine the influence of clinical trial results, safety regulations, and changes in reimbursement policy on practice. We examined indicators of anemia management among incident and prevalent hemodialysis patients from a medium-sized dialysis provider over three time periods: (1) 2004 to 2006 (2) 2007 to 2009, and (3) 2010. Trends across the three time periods were compared using generalized estimating equations. Prior to 2007, the median proportion of patients with monthly hemoglobin >12 g/dL for patients on dialysis 0 to 3, 4 to 6 and 7 to 18 months, respectively, was 42%, 55% and 46% declined to 41%, 54%, and 40% after 2007, and declined more sharply in 2010 to 34%, 41%, and 30%. Median weekly Epoeitin alpha doses over the same periods were 18,000, 12,400, and 9,100 units before 2007; remained relatively unchanged from 2007 to 2009; and decreased sharply in the patients 3-6 and 6-18 months on dialysis to 10,200 and 7,800 units, respectively in 2010. Iron doses, serum ferritin, and transferrin saturation levels increased over time with more pronounced increases in 2010. Modest changes in anemia management occurred between 2007 and 2009, followed by more dramatic changes in 2010. Studies are needed to examine the effects of declining erythropoietin use and hemoglobin levels and increasing intravenous iron use on quality of life, transplantation rates, infection rates and survival.


Loss of chromosomes 2R and 5RS in octoploid triticale selected for agronomic traits.
The advanced lines of octoploid triticale which have been bred for nearly a half century in China show significant improvements in agronomic traits such as plant height, fertility, threshability, maturity and seed plumpness, although no intentional cytological selection had been performed. In this study, eight primary and six advanced lines were analyzed by fluorescence and genomic in situ hybridization to elucidate their chromosome constitutions. In the advanced lines, about 70% of the plants examined had 2n = 56 chromosomes (range: 50 to 58). Almost all advanced lines, however, had lost rye chromosome 2R and the short arm of 5R (5RS). The exceptions were lines Y1005 and Y4683: The former had lost only the 2R chromosome and the latter only 5RS. The reduction of rye chromosomes was compensated by an extra pair of 2D or A-genome (possibly 2A) chromosomes in plants with 2n = 56. This suggests that the loss of 2R and 5RS chromosomes contributes to the improvement of octoploid triticale. Since the plants with chromosome 2R are non-free threshing and chromosome 2D of synthetic wheat is known to carry the Tg (tenacious glumes) gene, it is possible that chromosome 2R carries a gene affecting the threshability, and we carried out selection to remove it. We also discuss the possible relationshipbetween 5RS and the genetic stability of octoploid triticale.


Melatonin for the prevention of postoperative delirium in older adults: a systematic review and meta-analysis.
Older surgical patients are at high risk of developing postoperative delirium. Non-pharmacological strategies are recommended for delirium prevention, but no pharmacological agents have compelling evidence to decrease the incidence of delirium. The purpose of this study was to assess whether perioperative melatonin decreases the incidence of delirium in older adults undergoing surgical procedures. A systematic search using PubMed/Medline, Embase, PsycINFO, CINAHL, and references of identified articles published in English between January 1990 and October 2017 was performed. Two independent reviewers screened titles and abstracts, and then extracted data following a full-text review of included articles with consensus generation and bias assessment. Studies reporting outcomes for melatonin or ramelteon use to prevent delirium in postoperative hospitalized patients (mean age ≥ 50 years) were eligible for inclusion. Data were pooled using a fixed-effects model to generate a forest plot and obtain a summary odds ratio for the outcome of interest (delirium incidence). Cochran's Q and I2 values were used to investigate heterogeneity. Of 335 records screened, 6 studies were selected for the qualitative analysis and 6 were included in the meta-analysis (n = 1155). The mean age of patients in included studies ranged from 59 to 84 years. Patients in intervention groups typically received melatonin or ramelteon at daily doses of two to eight milligrams around cardiothoracic, orthopedic, or hepatic surgeries for one to nine days, starting on the evening before or the day of surgery. The incidence of delirium ranged from 0 to 30% in the intervention groups versus 4-33% in the comparator groups, and was significantly reduced in the melatonin group, with a summary effect of the meta-analysis yielding an odds ratio of 0.63 (95% CI 0.46 to 0.87; 0.006; I2 = 72.1%). A one study removed analysis reduced overall odds ratio to 0.310 (95% CI 0.19 to 0.50), while reducing heterogeneity (Cochran's Q = 0.798, I2 = 0.000). Perioperative melatonin reduced the incidence of delirium in older adults in the included studies. While optimal dosing remains an unanswered question, the potential benefit of melatonin and melatonin receptor agonists may make them a reasonable option to use for delirium prevention in older adults undergoing surgical procedures.


Acid stress response and protein induction in Campylobacter jejuni isolates with different acid tolerance.
During the transmission route from poultry to the human host, the major foodborne pathogen C. jejuni may experience many types of stresses, including low pH caused by different acids. However, not all strains are equally sensitive to the stresses. The aim of this study was to investigate the response to acid stress of three sequenced C. jejuni strains with different acid tolerances using HCl and acetic acid. Two-dimensional gel electrophoresis was used for proteomic analysis and proteins were radioactively labelled with methionine to identify proteins only related to acid exposure. To allow added radioactive methionine to be incorporated into induced proteins, a modified chemically defined broth was developed with the minimal amount of methionine necessary for satisfactory growth of all strains. Protein spots were analyzed using image software and identification was done with MALDI-TOF-TOF. The most acid-sensitive isolate was C. jejuni 327, followed by NCTC 11168 and isolate 305 as the most tolerant. Overall, induction of five proteins was observed within the pI range investigated: 19 kDa periplasmic protein (p19), thioredoxin-disulfide (TrxB), a hypothetical protein Cj0706 (Cj0706), molybdenum cofactor biosynthesis protein (MogA), and bacterioferritin (Dps). Strain and acid type dependent differences in the level of response were observed. For strain NCTC 11168, the induced proteins and the regulator fur were analysed at the transcriptomic level using qRT-PCR. In this transcriptomic analysis, only up-regulation of trxB and p19 was observed. A defined medium that supports the growth of a range of Campylobacter strains and suitable for proteomic analysis was developed. Mainly proteins normally involved in iron control and oxidative stress defence were induced during acid stress of C. jejuni. Both strain and acid type affected sensitivity and response.


pH-Controlled two-step uncoating of influenza virus.
Upon endocytosis in its cellular host, influenza A virus transits via early to late endosomes. To efficiently release its genome, the composite viral shell must undergo significant structural rearrangement, but the exact sequence of events leading to viral uncoating remains largely speculative. In addition, no change in viral structure has ever been identified at the level of early endosomes, raising a question about their role. We performed AFM indentation on single viruses in conjunction with cellular assays under conditions that mimicked gradual acidification from early to late endosomes. We found that the release of the influenza genome requires sequential exposure to the pH of both early and late endosomes, with each step corresponding to changes in the virus mechanical response. Step 1 (pH 7.5-6) involves a modification of both hemagglutinin and the viral lumen and is reversible, whereas Step 2 (pH <6.0) involves M1 dissociation and major hemagglutinin conformational changes and is irreversible. Bypassing the early-endosomal pH step or blocking the envelope proton channel M2 precludes proper genome release and efficient infection, illustrating the importance of viral lumen acidification during the early endosomal residence for influenza virus infection.


Quantitative analysis of visible surface defect risk in tablets during film coating using terahertz pulsed imaging.
Tablets are the most common form of solid oral dosage produced by pharmaceutical industries. There are several challenges to successful and consistent tablet manufacturing. One well-known quality issue is visible surface defects, which generally occur due to insufficient physical strength, causing breakage or abrasion during processing, packaging, or shipping. Techniques that allow quantitative evaluation of surface strength and the risk of surface defect would greatly aid in quality control. Here terahertz pulsed imaging (TPI) was employed to evaluate the surface properties of core tablets with visible surface defects of varying severity after film coating. Other analytical methods, such as tensile strength measurements, friability testing, and scanning electron microscopy (SEM), were used to validate TPI results. Tensile strength and friability provided no information on visible surface defect risk, whereas the TPI-derived unique parameter terahertz electric field peak strength (TEFPS) provided spatial distribution of surface density/roughness information on core tablets, which helped in estimating tablet abrasion risk prior to film coating and predicting the location of the defects. TPI also revealed the relationship between surface strength and blending condition and is a nondestructive, quantitative approach to aid formulation development and quality control that can reduce visible surface defect risk in tablets.


The Martian chronicles: remotely guided diagnosis and treatment in the Arctic Circle.
Despite rigorous health screening in astronaut crews, there are a number of conditions that may occur during long duration, exploration class spaceflight. The risk of abdominal conditions requiring surgical intervention is not clear, yet submarine and polar base experiences suggest contingency planning is warranted. While radio communication time delay is only 2 s to the international space station (ISS), a potential Mars mission would necessitate time delays of about 15 min. We sought to demonstrate the feasibility of remote expert guidance of diagnostic ultrasound followed by laparoscopic appendectomy in a simulated Mars environment. Research was deemed exempt by the institutional review board. A simulated Mars research environment was utilized on Devon Island in the Canadian Arctic. Electronic communications including audio and video were established between the Arctic base and Henry Ford Hospital serving as Mission Control and incorporated the 15-min communications lag into all communication. Ultrasound and laparoscopic capabilities were integrated into communications for remote guidance. Remote guidance methods and technology utilized has been previously published in communication with the ISS. A simulated scenario involving a young female astronaut developing right lower quadrant pain was developed and utilized for this demonstration. An anatomical appendectomy model was utilized for the ultrasound and laparoscopic portions. Reference aids describing background technical aspects were developed. A set of confirmation milestones was used to generate a hard stop and mandated remote review. The simulated appendectomy was successfully pursued on the first attempt with no delays or untoward events. Reference aids were appropriate for non-surgical personnel and hard stops for milestones with remote approval and go ahead were shown to be feasible. The appendicitis was appropriately diagnosed utilizing remote guidance of ultrasonography and the appendix removed laparoscopically using stapled technique with remote guidance as well. We report a successful remote guidance demonstration from a simulated mars environment with clinical control from a terrestrial base utilizing appropriate delay and consistent bandwidth and technology.


Does a biomedical research centre affect patient care in local hospitals?
Biomedical research can have impacts on patient care at research-active hospitals. We qualitatively evaluated the impact of the Oxford Biomedical Research Centre (Oxford BRC), a university-hospital partnership, on the effectiveness and efficiency of healthcare in local hospitals. Effectiveness and efficiency are conceptualised in terms of impacts perceived by clinicians on the quality, quantity and costs of patient care they deliver. First, we reviewed documentation from Oxford BRC and literature on the impact of research activity on patient care. Second, we interviewed leaders of the Oxford BRC's research to identify the direct and indirect impacts they expected their activity would have on local hospitals. Third, this information was used to inform interviews with senior clinicians responsible for patient care at Oxford's acute hospitals to discover what impacts they observed from research generally and from Oxford BRC's research work specifically. We compared and contrasted the results from the two sets of interviews using a qualitative approach. Finally, we identified themes emerging from the senior clinicians' responses, and compared them with an existing taxonomy of mechanisms through which quality of healthcare may be affected in research-active settings. We were able to interview 17 research leaders at the Oxford BRC and 19 senior clinicians at Oxford's acute hospitals. The research leaders identified a wide range of beneficial impacts that they expected might be felt at local hospitals as a result of their research activity. They expected the impact of their research activity on patient care to be generally positive. The senior clinicians responsible for patient care at those hospitals presented a more mixed picture, identifying many positive impacts, but also a smaller number of negative impacts, from research activity, including that of the Oxford BRC. We found the existing taxonomy of benefit types to be helpful in organising the findings, and propose modifications to further improve its usefulness. Impacts from research activity on the effectiveness and efficiency of patient care at the local acute hospitals, as perceived by senior clinicians, were more often beneficial than harmful. The Oxford BRC contributed to those impacts.


Pneumococcal conjugate vaccine--a health priority.
Pneumonia is a major cause of childhood mortality and morbidity. Streptococcus pneumoniae is the most important bacterial pathogen causing pneumonia in children. The HIV epidemic has increased the burden and severity of childhood pneumococcal pneumonia and invasive disease fortyfold. Pneumococcal conjugate vaccine (PCV) is a highly effective intervention to reduce invasive pneumococcal disease and pneumonia. Studies evaluating a 9-valent PCV in South Africa and The Gambia reported a 72 - 77% reduction in vaccine-serotype-specific invasive disease in vaccinated children. As many of the pneumococcal serotypes associated with antibiotic resistance are included in PCV, vaccination has also been associated with a reduction in antimicrobial-resistant invasive disease. PCV may also reduce childhood mortality, especially in places with limited access to health care, as shown in Gambian study in which PCV reduced childhood mortality by 16%. In addition to the direct effects of PCV, there is a substantial reduction in disease burden through indirect protection of non-vaccinated populations. PCV is immunogenic in HIV-infected children and provides protection against invasive disease or pneumonia in a substantial number of children. Although the efficacy of PCV for prevention of invasive disease or pneumonia is lower in HIV-infected compared to -uninfected children, the overall burden of disease prevented is much greater in HIV-infected children because of the higher burden of pneumococcal disease in these children. Consequently, vaccine-preventable invasive disease is almost 60 times higher in HIV-infected compared to -uninfected children, while the reduction in pneumonia in HIV-infected children is 15 times greater. However, the long-term efficacy of PCV wanes in HIV-infected children who are not taking antiretroviral therapy, and booster doses are probably indicated. Although there is concern about the potential for replacement disease due to non-vaccine serotypes, a substantial and sustained reduction in invasive disease has occurred overall in populations with widespread childhood immunisation. Routine childhood immunisation is now the standard of care in most developed countries. However, PCV is much less accessible to children in developing countries due to cost and availability. Cost-effectiveness analysis indicates that use of PCV is potentially highly cost-effective, at tiered pricing, even in very low-income countries. Widespread availability and vaccination with PCV is urgently needed for all children under 2 years of age in South Africa. In addition, the use of PCV for all HIV-infected children under 9 years should be prioritised.


Nonlinear source-filter coupling in phonation: vocal exercises.
Nonlinear source-filter coupling has been demonstrated in computer simulations, in excised larynx experiments, and in physical models, but not in a consistent and unequivocal way in natural human phonations. Eighteen subjects (nine adult males and nine adult females) performed three vocal exercises that represented a combination of various fundamental frequency and formant glides. The goal of this study was to pinpoint the proportion of source instabilities that are due to nonlinear source-tract coupling. It was hypothesized that vocal fold vibration is maximally destabilized when F(0) crosses F(1), where the acoustic load changes dramatically. A companion paper provides the theoretical underpinnings. Expected manifestations of a source-filter interaction were sudden frequency jumps, subharmonic generation, or chaotic vocal fold vibrations that coincide with F(0)-F(1) crossovers. Results indicated that the bifurcations occur more often in phonations with F(0)-F(1) crossovers, suggesting that nonlinear source-filter coupling is partly responsible for source instabilities. Furthermore it was observed that male subjects show more bifurcations in phonations with F(0)-F(1) crossovers, presumably because in normal speech they are less likely to encounter these crossovers as much as females and hence have less practice in suppressing unwanted instabilities.


Predicting Home and Community Walking Activity Poststroke.
Walking ability poststroke is commonly assessed using gait speed categories developed by Perry et al. The purpose of this study was to reexamine factors that predict home and community ambulators determined from real-world walking activity data using activity monitors. Secondary analyses of real-world walking activity from 2 stroke trials. Home (100-2499 steps/d), most limited community (2500-4499 steps/d), least limited community (5000-74 999), and full community (≥7500 steps/d) walking categories were developed based on normative data. Independent variables to predict walking categories were comfortable and fast gait speed, 6-minute walk test, Berg Balance Scale, Fugl Meyer, and Stroke Impact Scale. Data were analyzed using multivariate analyses to identify significant variables associated with walking categories, bootstrap method to select the most stable model and receiver-operating characteristic to identify cutoff values. Data from 441 individuals poststroke were analyzed. The 6-minute walk test, Fugl Meyer, and Berg Balance Scale combined were the strongest predictors of home versus community and limited versus unlimited community ambulators. The 6-minute walk test was the strongest individual variable in predicting home versus community (receiver-operating characteristic area under curve=0.82) and limited versus full community ambulators (receiver-operating characteristic area under curve=0.76). A comfortable gait speed of 0.49 m/s discriminated between home and community and a comfortable gait speed of 0.93 m/s discriminated between limited community and full community ambulators. The 6-minute walk test was better able to discriminate among home, limited community, and full community ambulators than comfortable gait speed. Gait speed values commonly used to distinguish between home and community walkers may overestimate walking activity.


Microfluidic chips for point-of-care immunodiagnostics.
We might be at the turning point where research in microfluidics undertaken in academia and industrial research laboratories, and substantially sponsored by public grants, may provide a range of portable and networked diagnostic devices. In this Progress Report, an overview on microfluidic devices that may become the next generation of point-of-care (POC) diagnostics is provided. First, we describe gaps and opportunities in medical diagnostics and how microfluidics can address these gaps using the example of immunodiagnostics. Next, we conceptualize how different technologies are converging into working microfluidic POC diagnostics devices. Technologies are explained from the perspective of sample interaction with components of a device. Specifically, we detail materials, surface treatment, sample processing, microfluidic elements (such as valves, pumps, and mixers), receptors, and analytes in the light of various biosensing concepts. Finally, we discuss the integration of components into accurate and reliable devices.


Degradation kinetics of benzyl nicotinate in aqueous solution.
The degradation of benzyl nicotinate in aqueous solution over a pH range of 2.0-10.0 at 50+/-0.2 degrees was studied. The degradation was determined by high performance liquid chromatography. The degradation was observed to follow apparent first-order rate kinetics and the rate constant for the decomposition at 25 degrees was estimated by extrapolation. The reaction was shown to be hydroxide ion catalyzed and the Arrhenius plots showed the temperature dependence of benzyl nicotinate degradation. A significant increase in the stability of benzyl nicotinate was observed when glycerol or polyethylene glycol 400 was incorporated into the aqueous solution.


Diffusion-sensitized ophthalmic magnetic resonance imaging free of geometric distortion at 3.0 and 7.0 T: a feasibility study in healthy subjects and patients with intraocular masses.
This study is designed to examine the feasibility of diffusion-sensitized multishot split-echo rapid acquisition with relaxation enhancement (RARE) for diffusion-weighted ophthalmic imaging free of geometric distortions at 3.0 and 7.0 T in healthy volunteers and patients with intraocular masses. A diffusion-sensitized multishot split-echo RARE (ms-RARE) variant is proposed as an alternative imaging strategy for diffusion-weighted imaging. It is compared with standard single-shot echo planar imaging (EPI) and readout-segmented EPI in terms of geometric distortions in a structure phantom as well as in vivo at 3.0 and 7.0 T. To quantify geometric distortions, center of gravity analysis was carried out. Apparent diffusion coefficient (ADC) mapping in a diffusion phantom was performed to verify the diffusion sensitization within ms-RARE. An in vivo feasibility study in healthy volunteers (n = 10; mean age, 31 ± 7 years; mean body mass index, 22.6 ± 1.7 kg/m²) was conducted at 3.0 and 7.0 T to evaluate clinical feasibility of ms-RARE. As a precursor to a broader clinical study, patients (n = 6; mean age, 55 ± 12 years; mean body mass index, 27.5 ± 4.7 kg/m²) with an uveal melanoma and/or retinal detachment were examined at 3.0 and 7.0 T. In 1 case, the diseased eye was enucleated as part of the therapy and imaged afterward with magnetic resonance microscopy at 9.4 T. Macrophotography and histological investigation was carried out. For qualitative assessment of the image distortion, 3 independent readers reviewed and scored ms-RARE in vivo images for all subjects in a blinded reading session. Statistical significance in the difference of the scores (a) obtained for the pooled ms-RARE data with b = 0 and 300 s/mm² and (b) for the 3 readers was analyzed using the nonparametric Mann-Whitney test. The assessment of geometric integrity in phantom imaging revealed the ability of ms-RARE to produce distortion-free images. Unlike ms-RARE, modest displacements (2.3 ± 1.4 pixels) from the fast low angle shot imaging reference were observed for readout-segmented EPI, which were aggravated for single-shot EPI (8.3 ± 5.7 pixels). These observations were confirmed in the in vivo feasibility study including distortion-free diffusion-weighted ophthalmic images with a 0.5 × 0.5 × 5 mm³ spatial resolution at 3.0 T and as good as 0.2 × 0.2 × 2 mm³ at 7.0 T. The latter represents a factor of 40 enhancement in spatial resolution versus clinical protocols recently reported for diffusion-weighted imaging of the eye at 1.5 T. Mean ADC values within the vitreous body were (2.91 ± 0.14) × 10⁻³ mm²/s at 3.0 T and (2.93 ± 0.41) × 10⁻³ mm²/s at 7.0 T. Patient data showed severe retinal detachment in the anatomical images. Whereas the tumor remained undetected in T1-weighted and T2-weighted imaging at 3.0/7.0 T, in vivo ADC mapping using ms-RARE revealed the presence of a uveal melanoma with a significant contrast versus the surrounding subretinal hemorrhage. This observation was confirmed by high-resolution ex vivo magnetic resonance microscopy and histology. Qualitative analysis of image distortion in ms-RARE images obtained for all subjects yielded a mean ± SD image quality score of 1.06 ± 0.25 for b = 0 s/mm² and of 1.17 ± 0.49 for b = 300 s/mm². No significant interreader differences were observed for ms-RARE with a diffusion sensitization of b = 0 s/mm² and 300 s/mm². This work demonstrates the capability of diffusion-sensitized ms-RARE to acquire high-contrast, high-spatial resolution, distortion-free images of the eye and the orbit at 3.0 and 7.0 T. Geometric distortions that are observed for EPI-based imaging approaches even at lower field strengths are offset by fast spin-echo-based imaging techniques. The benefits of this improvement can be translated into the assessment of spatial arrangements of the eye segments and their masses with the ultimate goal to provide guidance during diagnostic treatment of ophthalmological diseases.


Isotype commitment in the in vivo immune responses. I. Antigen-dependent specific and polyclonal plaque-forming cell responses by B lymphocytes induced to extensive proliferation.
The random recombination and deletion hypothesis for the control of isotype commitment in antibody responses was directly tested in a serial transfer system in vivo. Normal or hyperimmune spleen cells were used in weekly serial transfers with antigen into irradiated recipients until clonal senescence was observed. Antigen-specific and -nonspecific plaque-forming cells of all isotypes were determined at each transfer time. No major changes in the isotypes of specific antibodies were observed for the whole life-span of the transferred cells (9-10 wk), and no indication was obtained for the accumulation of cells transcribing the most 3' members of the C-gene cluster with sustained proliferation. Rather, the dominant isotypes were found throughout the response to be IgG1, IgG2b, and IgG2a. The results imply isotype-specific regulatory mechanisms in the control of Ig class production. These appear to operate as well in the antigen-nonspecific component of the immune response.


Acupuncture Decreases Blood Pressure Related to Hypothalamus Functional Connectivity with Frontal Lobe, Cerebellum, and Insula: A Study of Instantaneous and Short-Term Acupuncture Treatment in Essential Hypertension.
The therapeutic effects of acupuncture in decreasing blood pressure are ambiguous and underlying acupuncture in hypertension treatment has not been investigated. Our objective was to observe the change of quality of life and compare the differences in brain functional connectivity by investigating instantaneous and short-term acupuncture treatment in essential hypertension patients. A total of 30 patients were randomly divided into the LR3 group and sham acupoint group. Subjects received resting-state fMRI among preacupuncture, postinstantaneous, and short-term acupuncture treatment in two groups. Hypothalamus was selected as the seed point to analyze the changes in connectivity. We found three kinds of results: (1) There was statistical difference in systolic blood pressure in LR3 group after the short-term treatment and before acupuncture. (2) Compared with sham acupoint, acupuncture at LR3 instantaneous effects in the functional connectivity with seed points was more concentrated in the frontal lobe. (3) Compared with instantaneous effects, acupuncture LR3 short-term effects in the functional connectivity with seed points had more regions in frontal lobe, cerebellum, and insula. These brain areas constituted a neural network structure with specific functions that could explain the mechanism of therapy in hypertension patients by LR3 acupoint.


Innovative approach to the difficult ventricular shunt using pleural access device for maintenance drainage: case report.
Patients with complex medical problems and multiple failed ventricular shunts require continued innovation for hydrocephalus management. The authors report the case of a 4-year-old boy with refractory hydrocephalus and secondary reduced ability to absorb CSF in both the pleural and peritoneal cavities following renal transplantation. A novel management approach was devised with split shunting to pleural and peritoneal targets as well as prophylactic pleural port placement to provide a method for minimally invasive thoracentesis should symptomatic pleural effusions develop. Fluid was successfully aspirated via the pleural port with relief of symptoms over a period of 16 months without complication. The authors demonstrate that a previously undescribed approach to distal shunting can prevent neurological sequelae of shunt failure and permit noninvasive maintenance drainage for patients in whom symptomatic pleural effusion is a recurrent complication.


Potential drug development candidates for human soil-transmitted helminthiases.
Few drugs are available for soil-transmitted helminthiasis (STH); the benzimidazoles albendazole and mebendazole are the only drugs being used for preventive chemotherapy as they can be given in one single dose with no weight adjustment. While generally safe and effective in reducing intensity of infection, they are contra-indicated in first-trimester pregnancy and have suboptimal efficacy against Trichuris trichiura. In addition, drug resistance is a threat. It is therefore important to find alternatives. We searched the literature and the animal health marketed products and pipeline for potential drug development candidates. Recently registered veterinary products offer advantages in that they have undergone extensive and rigorous animal testing, thus reducing the risk, cost and time to approval for human trials. For selected compounds, we retrieved and summarised publicly available information (through US Freedom of Information (FoI) statements, European Public Assessment Reports (EPAR) and published literature). Concomitantly, we developed a target product profile (TPP) against which the products were compared. The paper summarizes the general findings including various classes of compounds, and more specific information on two veterinary anthelmintics (monepantel, emodepside) and nitazoxanide, an antiprotozoal drug, compiled from the EMA EPAR and FDA registration files. Few of the compounds already approved for use in human or animal medicine qualify for development track decision. Fast-tracking to approval for human studies may be possible for veterinary compounds like emodepside and monepantel, but additional information remains to be acquired before an informed decision can be made.


Anthracnose Caused by Discula fraxinea on the New Host Chinese Fringetree and White Ash in Delaware.
Leaf blight or anthracnose symptoms have been noted on the current year's growth of Chinese fringetree (Chionanthus retusis L.) since the early 1990s in Newark, DE. Symptoms begin as dark, greenish brown, water-soaked lesions on the edges of young leaves. With time, lesions enlarge, turn darker brown, and coalesce with necrotic areas turning dry and light brown. Isolations from infected leaves consistently yielded a golden brown fungal culture on acidified potato dextrose agar. Similar symptoms were observed on white ash (Fraxinus americana L.), from which a similar fungus was isolated. C. retusis and F. americana belong to the Oleaceae, the olive family. Acervuli were inconspicuous on leaves, but conidia were easily observed. Conidia were small, non-septate, ellipsoidal, hyaline, and averaged 5.5 × 3.5 μm. In culture, the fungus formed conspicuous, concentric zones of flocculent mycelium and spherical conidiomata when exposed to diurnal light. Isolates from C. retusis and ash were identified as Discula fraxinea (Peck) Redlin & Stack, the anamorph of Gnomoniella fraxini Redlin & Stack (Gnomoniaceae, Diaporthales) (3). Sequences of the internal transcribed spacer region (ITS) of rDNA indicated that the isolates from C. retusis and white ash (GenBank Accession No. AY455810-AY455818) were conspecific with D. fraxinea isolates from Maryland and Oregon, with six or fewer base pair substitutions or insertion/deletions (indels) across all isolates. Ash anthracnose has been reported from the central and eastern United States and California, the prairie provinces in Canada, and recently from British Columbia, usually under the synonyms of Gloeosporium aridum and G. fraxineum (1,2). Koch's postulates were completed when isolates of D. fraxinea from C. retusis, green ash (F.pennsylvanica Marsh.), and white ash were inoculated onto 3- to 4-year-old trees of C. retusis and F. americana in 2000 and 2001. Seven replicate branches with emerging leaves were sprayed to runoff with a conidial suspension (60,000 conidia per ml) and covered with plastic bags for 24 h. After 20 days, 85% of C. retusis branches inoculated with a C. retusis isolate developed symptoms, and D. fraxinea was isolated from 78.6% of symptomatic leaves. Isolates from green ash in Maryland and white ash in Delaware produced symptoms on 57% of C. retusis branches. Only 37% of white ash branches inoculated with isolates from C. retusis and white ash developed symptoms, but D. fraxinea was isolated from 100% of symptomatic leaves. No symptoms developed on control branches. To our knowledge, this is the first report of D. fraxinea on C. retusis or on any member of that plant genus (1,2). In addition, D. fraxinea has not previously been reported on F. americana in Delaware. Specimens and cultures of D. fraxinea from C. retusis (BPI 746408, CBS 114058) and F. americana (BPI 746411, CBS 114051) were deposited at the U.S. National Fungus Collection and the Centraalbureau voor Schimmelcultures, The Netherlands. References: (1) D. F. Farr et al. Fungi on Plants and Plant Products in the United States. The American Phytopathological Society, St. Paul, MN, 1989. (2) D. F. Farr et al. Fungal Databases. Systematic Botany and Mycology Laboratory, On-line publication. ARS, USDA, 2003. (3) S. C. Redlin and R. W. Stack. Mycotaxon 32:175, 1988.


Burden of tension-type headache in the Middle East and North Africa region, 1990-2019.
Tension-type headache (TTH) is the most prevalent neurological disorder. As there is a gap in the literature regarding the disease burden attributable to TTH in the Middle East and North Africa (MENA) region, the aim of the present study was to report the epidemiological indicators of TTH in MENA, from 1990 to 2019, by sex, age and socio-demographic index (SDI). Publicly available data on the point prevalence, annual incidence and years lived with disability (YLDs) were retrieved from the global burden of disease (GBD) 2019 study for the 21 countries and territories in MENA, between 1990 and 2019. The results were presented with numbers and age-standardised rates per 100000 population, along with their corresponding 95% uncertainty intervals (UIs). In 2019, the age-standardised point prevalence and annual incidence rates for TTH in the MENA region were 24504.5 and 8680.1 per 100000, respectively, which represents a 2.0% and a 0.9% increase over 1990-2019, respectively. The age-standardised YLD rate of TTH in this region in 2019 was estimated to be 68.1 per 100000 population, which has increased 1.0% since 1990. Iran [29640.4] had the highest age-standardised point prevalence rate for TTH, while Turkey [21726.3] had the lowest. In 2019, the regional point prevalence of TTH was highest in the 35-39 and 70-74 age groups, for males and females, respectively. Furthermore, the number of prevalent cases was estimated to be highest in those aged 35-39 and 25-29 years, in both males and females, respectively. Moreover, the burden of TTH was not observed to have a clear association with SDI. While the prevalence of TTH in the MENA region increased from 1990 to 2019, the incidence rate did not change. In addition, the burden of TTH in MENA was higher than at the global level for both sexes and all age groups. Therefore, prevention of TTH would help alleviate the attributable burden imposed on the hundreds of millions of people suffering from TTH around the region.


Attenuated activation of pulmonary immune cells in mRNA-1273-vaccinated hamsters after SARS-CoV-2 infection.
The mRNA-1273 vaccine is effective against SARS-CoV-2 and was granted emergency use authorization by the FDA. Clinical studies, however, cannot provide the controlled response to infection and complex immunological insight that are only possible with preclinical studies. Hamsters are the only model that reliably exhibits severe SARS-CoV-2 disease similar to that in hospitalized patients, making them pertinent for vaccine evaluation. We demonstrate that prime or prime-boost administration of mRNA-1273 in hamsters elicited robust neutralizing antibodies, ameliorated weight loss, suppressed SARS-CoV-2 replication in the airways, and better protected against disease at the highest prime-boost dose. Unlike in mice and nonhuman primates, low-level virus replication in mRNA-1273-vaccinated hamsters coincided with an anamnestic response. Single-cell RNA sequencing of lung tissue permitted high-resolution analysis that is not possible in vaccinated humans. mRNA-1273 prevented inflammatory cell infiltration and the reduction of lymphocyte proportions, but enabled antiviral responses conducive to lung homeostasis. Surprisingly, infection triggered transcriptome programs in some types of immune cells from vaccinated hamsters that were shared, albeit attenuated, with mock-vaccinated hamsters. Our results support the use of mRNA-1273 in a 2-dose schedule and provide insight into the potential responses within the lungs of vaccinated humans who are exposed to SARS-CoV-2.


Serum-free growth of normal and transformed fibroblasts in milk: differential requirements for fibronectin.
Bovine milk may be used as a supplement for the serum-free growth of certain fibroblastic cells in culture. The growth properties of three representative cell types in milk-supplemented medium were examined; fibroblastic cell strains, fibroblastic cell lines, and transformed fibroblasts. Transformed fibroblasts, which included RNA and DNA tumor virus-transformed cells and carcinogen-transformed cells, grew in milk. Instead of growing attached to the culture dishes, as they normally do in serum, transformed fibroblasts grew in milk as large clusters in suspension. In contrast, nontransformed fibroblastic cell strains and cell lines did not grow in milk-supplemented medium. Fibroblasts transformed by a temperature-sensitive transformation mutant of Rous sarcoma virus were temperature-sensitive for growth in milk. The failure of cells to adhere to the substratum in milk-supplemented medium suggested that milk might be deficient in attachment factors for fibroblasts. When the attachment of fibroblastic cells in milk-supplemented medium was facilitated by pretreating culture dishes with fibronectin, (a) transformed cells grew attached rather than in suspension, (b) normal cell lines attached and grew to confluence, and (c) normal cell strains adhered and survived but did not exhibit appreciable cell proliferation.