Measurement of gas-phase temperatures in flames with a point-diffraction interferometer.
Experiments were performed to evaluate the performance of a point-diffraction interferometry (PDI) system to measure gas-phase temperatures in flames. PDI is an interferometric technique that creates the reference beam after the laser beam passes through the test section and directly provides the index of refraction in two dimensions. PDI-based temperature measurements were compared with thermocouple measurements of two-dimensional and axisymmetric thermal boundary layers, as well as two-dimensional and axisymmetric diffusion flames. The PDI system provided excellent agreement in the measurement of thermal profiles in the boundary layers and was within the uncertainties that are due to the radiation corrections for the thermocouple-based flame temperature measurements.


Consistent changes in the taxonomic structure and functional attributes of bacterial communities during primary succession.
Ecologists have long studied primary succession, the changes that occur in biological communities after initial colonization of an environment. Most of this work has focused on succession in plant communities, laying the conceptual foundation for much of what we currently know about community assembly patterns over time. Because of their prevalence and importance in ecosystems, an increasing number of studies have focused on microbial community dynamics during succession. Here, we conducted a meta-analysis of bacterial primary succession patterns across a range of distinct habitats, including the infant gut, plant surfaces, soil chronosequences, and aquatic environments, to determine whether consistent changes in bacterial diversity, community composition, and functional traits are evident over the course of succession. Although these distinct habitats harbor unique bacterial communities, we were able to identify patterns in community assembly that were shared across habitat types. We found an increase in taxonomic and functional diversity with time while the taxonomic composition and functional profiles of communities became less variable (lower beta diversity) in late successional stages. In addition, we found consistent decreases in the rRNA operon copy number and in the high-efficient phosphate assimilation process (Pst system) suggesting that reductions in resource availability during succession select for taxa adapted to low-resource conditions. Together, these results highlight that, like many plant communities, microbial communities also exhibit predictable patterns during primary succession.


If we are all cultural Darwinians what's the fuss about? Clarifying recent disagreements in the field of cultural evolution.
Cultural evolution studies are characterized by the notion that culture evolves accordingly to broadly Darwinian principles. Yet how far the analogy between cultural and genetic evolution should be pushed is open to debate. Here, we examine a recent disagreement that concerns the extent to which cultural transmission should be considered a preservative mechanism allowing selection among different variants, or a transformative process in which individuals recreate variants each time they are transmitted. The latter is associated with the notion of "cultural attraction". This issue has generated much misunderstanding and confusion. We first clarify the respective positions, noting that there is in fact no substantive incompatibility between cultural attraction and standard cultural evolution approaches, beyond a difference in focus. Whether cultural transmission should be considered a preservative or reconstructive process is ultimately an empirical question, and we examine how both preservative and reconstructive cultural transmission has been studied in recent experimental research in cultural evolution. Finally, we discuss how the relative importance of preservative and reconstructive processes may depend on the granularity of analysis and the domain being studied.


Ligand-induced ubiquitination of the epidermal growth factor receptor involves the interaction of the c-Cbl RING finger and UbcH7.
c-Cbl plays a negative regulatory role in tyrosine kinase signaling by an as yet undefined mechanism. We demonstrate here, using the yeast two-hybrid system and an in vitro binding assay, that the c-Cbl RING finger domain interacts with UbcH7, a ubiquitin-conjugating enzyme (E2). UbcH7 interacted with the wild-type c-Cbl RING finger domain but not with a RING finger domain that lacks the amino acids that are deleted in 70Z-Cbl, an oncogenic mutant of c-Cbl. The in vitro interaction was enhanced by sequences on both the N- and C-terminal sides of the RING finger. In vivo and in vitro experiments revealed that c-Cbl and UbcH7 synergistically promote the ligand-induced ubiquitination of the epidermal growth factor receptor (EGFR). In contrast, 70Z-Cbl markedly reduced the ligand-induced, UbcH7-mediated ubiquitination of the EGFR. MG132, a proteasome inhibitor, significantly prolonged the ligand-induced phosphorylation of both the EGFR and c-Cbl. Thus, c-Cbl plays an essential role in the ligand-induced ubiquitination of the EGFR by a mechanism that involves an interaction of the RING finger domain with UbcH7. This mechanism participates in the down-regulation of tyrosine kinase receptors and loss of this function, as occurs in the naturally occurring 70Z-Cbl isoform, probably contributes to oncogenic transformation.


Association between physical fitness, cardiovascular risk factors, and Parkinson's disease.
Objective Exercise is a cornerstone of therapy for Parkinson's disease. This study addressed the association between physical fitness and the onset of Parkinson's disease and association with cardiovascular risk factors. Patients and methods Male veterans ( N = 7347, 59.0 ± 11.2 years) from the Veterans Exercise Testing Study cohort were evaluated. Physical fitness was measured objectively by maximal exercise testing. Onset of Parkinson's disease was abstracted from the Veterans Affairs computerized patient records system. Results After a mean follow-up of 12.5 ± 6.3 years, a total of 94 (1.3%) developed Parkinson's disease. Incidence was 86 cases per 100,000 person-years. The strongest multivariate factors associated with incidence of Parkinson's disease were higher age (hazard ratio: 1.067, 95% confidence interval (CI): 1.043-1.093, p < .001), current smoking (hazard ratio: 0.511, 95% CI: 0.274-0.953, p = .035) and physical fitness (high vs. low: hazard ratio: 0.239, 95% CI: 0.079-0.725, p = .011). Compared with patients with no or only one of these risk factors, patients with two risk factors had a 3.7-fold ( p < .001) increased risk for incidence of Parkinson's disease; those with all three risk factors had a 7.8-fold ( p < .001) higher risk. Conclusions High physical fitness, current smoking and younger age were associated with a lower incidence of Parkinson's disease. These findings parallel those of several epidemiological studies focusing on physical activity and the onset of Parkinson's disease. Together, these observations provide strong support for recommending physical activity to diminish risk of Parkinson's disease.


The Influence of Depression on Health Care Expenditures Among Adults with Spondylosis, Intervertebral Disc Disorders, and Other Back Problems in the United States.
Back pain is a very prevalent complaint, affecting two-thirds of the US population, and it accounts for $100 billion annually in health care expenditures. The occurrence of depression has been reported in existing literature among patients with back pain, but there is limited information regarding health care expenditures among patients with back pain and concurrent depression. To assess excess total and subtypes of health care expenditures among adults with spondylosis, intervertebral disc disorders, and other back problems who reported having depression compared with those without depression in the United States. We utilized a cross-sectional design, pooling Medical Expenditure Panel Survey data from 2010-2012. The eligible study sample included adults (age ≥18 years) who reported positive health care expenditure. Total and subtypes of health care expenditures constituted the dependent variable. Ordinary least squares (OLS) regressions on logged expenditures were performed. Four models were developed to assess influence of demographics, functional ability, and concurrent diagnoses on health care expenditures. A total of 6,739 adults with spondylosis, intervertebral disc disorders, and other back problems were assessed, 20.2% (N = 1,316) of whom had concurrent depression. Adults with concurrent depression had significantly higher total health care expenditures ($13,153) compared with the nondepression group ($7,477, P < 0.001). Outpatient and prescription expenditures showed similar findings. After adjusting for demographics, functional disabilities, and comorbidities, excess cost remained higher in the group reporting concurrent depression (46%). This study demonstrates that the presence of depression in adults with spondylosis, intervertebral disc disorders, and other back problems is associated with greater economic burden. These findings remained consistent after adjusting for all independent sets of variables. The study's findings suggest that interventions resulting in better management of depression have the potential to significantly reduce the economic burden in this population.


Bile acid binding to dietary casein: a study in vitro and in vivo.
1. Studies were carried out in vitro using an ultracentrifugation method to quantify bile acid binding to the different components of a Lundh test meal, and to determine what factors influence bile acid binding to one of the components (casein). We validated the ultracentrifugation method by showing good agreement with the equilibrium dialysis method. Studies were carried out in vivo on jejunal aspirate from 10 ileal resection patients in order to determine whether bile acid binding to casein could be demonstrated, and whether this influenced aqueous-phase bile acid and fatty acid concentrations. 2. In vitro, the Lundh test meal was found to adsorb bile acid. The protein content of the meal (casein) alone accounted for this binding, which was abolished by use of casein hydrolysate. The binding to casein was a saturable process. Both binding affinity and binding capacity were significantly greater for taurocholate at pH 4.5 than at pH 6.5, and for dihydroxylated than for trihydroxylated bile acid, suggesting that hydrophobic bonding was involved. 3. In vivo, jejunal samples aspirated at pH greater than 6 from 10 ileal resection patients showed 25% binding of bile acid to protein. On substitution of amino acids for casein, mean binding was reduced to 16% (P less than 0.05), residual binding being attributed to endogenous protein. This was associated with an increase in fatty acid solubilization from 28% to 60% (P less than 0.025).(ABSTRACT TRUNCATED AT 250 WORDS)


Prognostic Factors for Adverse Outcomes in COVID-19 Infection.
Whilst COVID-19 infection generally run a mild course in up to 80% of those affected, a number of pre-existing co-morbidities determine the severity of infection and the outcome in an individual patient. The most important of these co-morbidities that have consistently emerged in studies from across the globe, are the patients age and sex. Other important co-morbidities that adversely affect outcomes include pre-existing diabetes, obesity, hypertension, chronic lung disease and malignancy. This comprehensive review discusses the impact of these co-morbidities and the role of laboratory predictors of poor patient outcomes.


Diversification of human plasmacytoid predendritic cells in response to a single stimulus.
Innate immune cells adjust to microbial and inflammatory stimuli through a process termed environmental plasticity, which links a given individual stimulus to a unique activated state. Here, we report that activation of human plasmacytoid predendritic cells (pDCs) with a single microbial or cytokine stimulus triggers cell diversification into three stable subpopulations (P1-P3). P1-pDCs (PD-L1+CD80-) displayed a plasmacytoid morphology and specialization for type I interferon production. P3-pDCs (PD-L1-CD80+) adopted a dendritic morphology and adaptive immune functions. P2-pDCs (PD-L1+CD80+) displayed both innate and adaptive functions. Each subpopulation expressed a specific coding- and long-noncoding-RNA signature and was stable after secondary stimulation. P1-pDCs were detected in samples from patients with lupus or psoriasis. pDC diversification was independent of cell divisions or preexisting heterogeneity within steady-state pDCs but was controlled by a TNF autocrine and/or paracrine communication loop. Our findings reveal a novel mechanism for diversity and division of labor in innate immune cells.


Maintenance of mating cell integrity requires the adhesin Fig2p.
Fungal adhesins represent a large family of serine/threonine-rich secreted glycoproteins. Adhesins have been shown to play roles in heterotypic and homotypic cell-cell adhesion processes, morphogenetic pathways and invasive/pseudohyphal growth, frequently in response to differentiation cues. Here we address the role of the Saccharomyces cerevisiae mating-specific adhesin Fig2p. Cells lacking FIG2 possess a variety of mating defects that relate to processes involving the cell wall, including morphogenetic defects, cell fusion defects, and alterations in agglutination activities. We found that mating-specific morphogenetic defects caused by the absence of FIG2 are suppressible by increased external osmolarity and that, during mating, fig2delta cells display reduced viability relative to wild-type cells. These defects result from alterations in signaling activated by the mating and cell integrity pathways. Finally, we show that fig2delta zygotes also have defects in zygotic spindle positioning that are osmoremedial, whereas the requirements for FIG2 in normal cell-cell agglutination and cell fusion during mating are insensitive to changes in the extracellular osmotic environment. We conclude that FIG2 performs distinct functions in the mating cell wall that are separable with respect to their ability to be suppressed by changes in external osmolarity and that a fundamental role of FIG2 in mating cells is the maintenance of cell integrity.


Scrub typhus: surveillance, clinical profile and diagnostic issues in Shandong, China.
To elucidate the epidemic status, clinical profile, and current diagnostic issues of scrub typhus in Shandong Province, we analyzed the surveillance data of scrub typhus from 2006 to 2011 and conducted a hospital-based disease survey in 2010. Scrub typhus was clustered in mountainous and coastal areas in Shandong Province, with an epidemic period from September to November. The most common manifestations were fever (100%), eschar or skin ulcer (86.3%), fatigue (71.6%), anorexia (71.6%), and rash (68.6%). Predominant complications included bronchopneumonia, toxic hepatitis, and acute cholecystitis in 21.6%, 3.9%, and 2.9% of the cases, respectively. Severe complications including toxic myocarditis, heart failure, pneumonedema, pleural effusion, and emphysema were first reported in Shandong. Missed and delayed diagnosis of scrub typhus was common in local medical institutions. Alarm should be raised for changes of clinical features and current diagnostic issues of scrub typhus in newly developed endemic areas.


Muscle ultrastructural characteristics of elite powerlifters and bodybuilders.
Muscle ultrastructure of a group of subjects possessing extreme hypertrophy was compared with that of a control group which had undergone 6 months of heavy resistance training. Two needle biopsies were taken from triceps brachii of two international calibre powerlifters and five elite bodybuilders. In addition, samples were taken from five healthy volunteers before and after 6 months of training of the elbow extensors. One biopsy was prepared for electron microscopy and analyzed stereologically, and the other was stained for myosin ATPase activity and photographed under the light microscope. Despite large differences in elbow extension strength and arm girth there was no significant difference in fibre areas or percentages of fibre types between the elite group and the trained controls. This suggests that the elite group possessed a greater total number of muscle fibres than the controls did. Mitochondrial volume density of the elite group was similar to that of the control group following training but significantly less (p less than 0.05) than the pretraining control measurements. Myofibrillar volume density was significantly lower and cytoplasmic volume density significantly higher in the elite group than in the trained controls. There was a considerably higher incidence of structural abnormalities including central nuclei and atrophied fibres in the elite group than in the control group, which might possibly have been associated with the use of anabolic steroids by the elite group.


3D-QSAR and docking studies of pentacycloundecylamines at the sigma-1 (σ1) receptor.
Pentacycloundecylamine (PCU) derived compounds have been shown to be promising lead structures for the development of novel drug candidates aimed at a variety of neurodegenerative and psychiatric diseases. Here we show for the first time a 3D quantitative structure-activity relationship (3D-QSAR) for a series of aza-PCU-derived compounds with activity at the sigma-1 (σ1) receptor. A comparative molecular field analysis (CoMFA) model was developed with a partial least squares cross validated (q(2)) regression value of 0.6, and a non-cross validated r(2) of 0.9. The CoMFA model was effective at predicting the sigma-1 activities of a test set with an r(2) >0.7. We also describe here the docking of the PCU-derived compounds into a homology model of the sigma-1 (σ1) receptor, which was developed to gain insight into binding of these cage compounds to the receptor. Based on docking studies we evaluated in a [(3)H]pentazocine binding assay an oxa-PCU, NGP1-01 (IC50=1.78μM) and its phenethyl derivative (IC50=1.54μM). Results from these studies can be used to develop new compounds with specific affinity for the sigma-1(σ1) receptor.


Risk assessment for atypical spitzoid melanocytic neoplasms using FISH to identify chromosomal copy number aberrations.
Risk assessment for atypical Spitz tumors remains an enigma for physicians. Many prognosticators including sentinel lymph node biopsy fail to show the same prognostic significance in these tumors as seen in conventional melanoma. We conducted a case-controlled collaborative study involving multiple major melanoma treatment centers in the United States and Australia. Sixty-four atypical Spitz tumors with 5 years of uneventful follow-up and 11 atypical Spitz tumors resulting in advanced locoregional disease, distant metastasis, or death were evaluated by fluorescence in situ hybridization using 2 probe sets targeting 6 chromosomal loci. Predetermined criteria were utilized to detect the presence or absence of copy number aberrations for each locus. Logistic regression analysis, Fisher exact test, and multivariate analysis were performed to determine chromosomal copy number aberrations with statistically significant association with aggressive clinical behavior. Gains in 6p25 or 11q13 and homozygous deletions in 9p21 had statistically significant association with aggressive clinical behavior with P-values of 0.02, 0.02, and <0.0001, respectively. In multivariate analysis, homozygous 9p21 deletion was highly associated with clinically aggressive behavior (P<0.0001) and death due to disease (P=0.003). Fluorescence in situ hybridization detecting a limited number of chromosomal copy number aberrations can provide clinically useful and statistically significant risk assessment for atypical Spitz tumors. Cases with homozygous 9p21 deletions have the greatest risk. Cases with 6p25 or 11q13 gains also have higher risk for aggressive clinical behavior than FISH-negative atypical Spitz tumors or cases with 6q23 deletions.


Medicolegal liability in pathology: an international perspective.
An inevitable outcome of modern Medicine in any country is that some patients will experience adverse events, some of which would have been preventable. Different nations have developed various approaches to such cases; their legal efficacies are probably dissimilar and dependent on a number of disparate variables. An international "snapshot" of the results of the interacting forces can be obtained by asking physicians in several countries how they view selected subjective facets of their tort systems. In the U.S., many physicians view the structure of malpractice torts as unfair, and that belief is shared by at least some pathologists. The American Medical Association has declared that a multiregional malpractice "crisis" exists which raises medical costs and threatens access to care. Furthermore, malpractice tort decisions are often flawed scientifically because lay jurors and judges cannot properly evaluate the quality of "expert" testimony given by adversarial witnesses. Despite these factors, there has been little effort to investigate the views of pathologists on malpractice actions outside the U.S. In this paper, the authors have collected the responses of an international group of pathologists to a questionnaire on that topic. The respondents practice in academic centers in 15 countries outside the U.S. As expected, a range of views was represented, with some pathologists reporting that malpractice litigation was uncommon and others noting a worrisome trend toward its growth. Interestingly, so-called "defensive medicine" was found to be relatively common in pathology in many countries.


Enantioselective Synthesis of Five-Membered-Ring Atropisomers with a Chiral Rh(III) Complex.
Axially chiral atropisomeric compounds are widely applied in asymmetric catalysis and medicinal chemistry, and efficient methods for their synthesis are in high demand. This applies in particular to atropisomers derived from five-membered aromatic rings because their lower barrier for rotation among the biaryl axis limits their asymmetric synthesis. We report here an enantioselective C-H functionalization method using our chiral RhJasCp complex for the synthesis of the biaryl atropisomer types that can be accessed from three different five-membered-ring heterocycles.


Retinopathy of prematurity in extremely premature infants: multiple births versus single births
Background/aim: This study aimed to compare the incidence of any stage of retinopathy of prematurity (ROP) and type 1 ROP between extremely preterm multiple- and single-birth infants. Materials and methods: In this retrospective study, we included extremely preterm infants who were ≤27 weeks of gestational age at birth. The screened infants were divided into two groups: single and multiple births. The incidence of any stage of ROP and type 1 ROP was compared between the groups. Results: This study included 301 infants; 225 were in the single-birth group and 76 were in multiple-birth group. The incidences of any stage of ROP and type 1 ROP among all infants were 70.7% (213 of 301) and 16.6% (50 of 301), respectively. Regression analysis showed that lower birth weight (OR = 0.99, P = 0.004) and longer length of stay in hospital (OR = 1.02, P = 0.002) were significantly correlated with any stage of ROP. Compared to single-birth infants, the risk of any stage of ROP and type 1 ROP did not statistically increase for multiple-birth infants (P > 0.05). Conclusion: This study showed that multiple birth had no significant correlation with ROP development in extremely preterm infants.


Pan-Cancer Survey of Tumor Mass Dormancy and Underlying Mutational Processes.
Tumor mass dormancy is the key intermediate step between immune surveillance and cancer progression, yet due to its transitory nature it has been difficult to capture and characterize. Little is understood of its prevalence across cancer types and of the mutational background that may favor such a state. While this balance is finely tuned internally by the equilibrium between cell proliferation and cell death, the main external factors contributing to tumor mass dormancy are immunological and angiogenic. To understand the genomic and cellular context in which tumor mass dormancy may develop, we comprehensively profiled signals of immune and angiogenic dormancy in 9,631 cancers from the Cancer Genome Atlas and linked them to tumor mutagenesis. We find evidence for immunological and angiogenic dormancy-like signals in 16.5% of bulk sequenced tumors, with a frequency of up to 33% in certain tissues. Mutations in the CASP8 and HRAS oncogenes were positively selected in dormant tumors, suggesting an evolutionary pressure for controlling cell growth/apoptosis signals. By surveying the mutational damage patterns left in the genome by known cancer risk factors, we found that aging-induced mutations were relatively depleted in these tumors, while patterns of smoking and defective base excision repair were linked with increased tumor mass dormancy. Furthermore, we identified a link between APOBEC mutagenesis and dormancy, which comes in conjunction with immune exhaustion and may partly depend on the expression of the angiogenesis regulator PLG as well as interferon and chemokine signals. Tumor mass dormancy also appeared to be impaired in hypoxic conditions in the majority of cancers. The microenvironment of dormant cancers was enriched in cytotoxic and regulatory T cells, as expected, but also in macrophages and showed a reduction in inflammatory Th17 signals. Finally, tumor mass dormancy was linked with improved patient survival outcomes. Our analysis sheds light onto the complex interplay between dormancy, exhaustion, APOBEC activity and hypoxia, and sets directions for future mechanistic explorations.


The chromatin Remodeler CHD8 is required for activation of progesterone receptor-dependent enhancers.
While the importance of gene enhancers in transcriptional regulation is well established, the mechanisms and the protein factors that determine enhancers activity have only recently begun to be unravelled. Recent studies have shown that progesterone receptor (PR) binds regions that display typical features of gene enhancers. Here, we show by ChIP-seq experiments that the chromatin remodeler CHD8 mostly binds promoters under proliferation conditions. However, upon progestin stimulation, CHD8 re-localizes to PR enhancers also enriched in p300 and H3K4me1. Consistently, CHD8 depletion severely impairs progestin-dependent gene regulation. CHD8 binding is PR-dependent but independent of the pioneering factor FOXA1. The SWI/SNF chromatin-remodelling complex is required for PR-dependent gene activation. Interestingly, we show that CHD8 interacts with the SWI/SNF complex and that depletion of BRG1 and BRM, the ATPases of SWI/SNF complex, impairs CHD8 recruitment. We also show that CHD8 is not required for H3K27 acetylation, but contributes to increase accessibility of the enhancer to DNaseI. Furthermore, CHD8 was required for RNAPII recruiting to the enhancers and for transcription of enhancer-derived RNAs (eRNAs). Taken together our data demonstrate that CHD8 is involved in late stages of PR enhancers activation.


Identification of an infectious progenitor for the multiple-copy HERV-K human endogenous retroelements.
Human Endogenous Retroviruses are expected to be the remnants of ancestral infections of primates by active retroviruses that have thereafter been transmitted in a Mendelian fashion. Here, we derived in silico the sequence of the putative ancestral "progenitor" element of one of the most recently amplified family - the HERV-K family - and constructed it. This element, Phoenix, produces viral particles that disclose all of the structural and functional properties of a bona-fide retrovirus, can infect mammalian, including human, cells, and integrate with the exact signature of the presently found endogenous HERV-K progeny. We also show that this element amplifies via an extracellular pathway involving reinfection, at variance with the non-LTR-retrotransposons (LINEs, SINEs) or LTR-retrotransposons, thus recapitulating ex vivo the molecular events responsible for its dissemination in the host genomes. We also show that in vitro recombinations among present-day human HERV-K (also known as ERVK) loci can similarly generate functional HERV-K elements, indicating that human cells still have the potential to produce infectious retroviruses.


Seasonal variation in hospital admission for road traffic injuries in England: analysis of hospital statistics.
To report on seasonal variation in hospital admissions for traffic injuries to car and truck occupants, motorcyclists, cyclists, and pedestrians. Descriptive study of hospital admission statistics in England, 1999-2004. national average monthly admissions for injury; severity of injury, defined as death in hospital or a hospital admission lasting four days or more. Admissions for car occupants were highest in the winter months but seasonal variation was not great (highest and lowest months: December, 16% above monthly average; June, 5% below). There was a summer peak and winter trough in admissions for adult cyclists (June, 34% above average; December, 27% below) and motorcyclists (August, 33% above average; January, 43% below). Admissions for child pedestrians were highest in late spring and lowest in mid-winter (May, 24% above average; December, 28% below). By contrast, admissions for adult pedestrians were higher in winter than summer (December, 33% above average; July, 17% below). From April to September, there were more admissions for pedestrians and cyclists in England (44 875 in the six years of the study) than for car occupants (34 582). For cyclists, proportionally more injuries in the winter months were severe. Severity of injuries to car occupants did not show seasonal variation. The public health "toll" of traffic injuries, measured as total numbers of people injured, varies substantially by season. Although it is important to reduce all injuries, the safety of pedestrians and cyclists, as unprotected road users, needs particular attention.


MicroRNAs as biomarkers in pituitary tumors.
The use of extracellular microRNAs (miRNAs) as circulating biomarkers is currently leading to relevant advances in the diagnosis and assessment of prognosis of several diseases. Specific miRNAs have also been shown to play a role in the pathophysiology of many neoplastic and non-neoplastic diseases. A number of studies have demonstrated that miRNAs show differential expression in various tumors, such as in the prostate, ovary, lung, breast, brain, and pituitary. Recent findings have built connections between miRNAs that are deregulated within the tumor and their presence in peripheral blood. MiRNAs have been shown to be stable in the blood where they are present in either free and/or uncomplexed form, as well as packed in microvesicles, exosomes, and apoptotic bodies, or bound to different proteins. Because the pituitary is a highly vascularized organ that releases hormones into the circulation, miRNAs would be useful biomarkers for the diagnosis of pituitary tumors, as well as for predicting or detecting recurrence after surgery. Here we review the biological significance of miRNAs in pituitary tumors and the potential value of circulating miRNAs as biomarkers.


Radiation dose reduction to the breast in thoracic CT: comparison of bismuth shielding, organ-based tube current modulation, and use of a globally decreased tube current.
The purpose of this work was to evaluate dose performance and image quality in thoracic CT using three techniques to reduce dose to the breast: bismuth shielding, organ-based tube current modulation (TCM) and global tube current reduction. Semi-anthropomorphic thorax phantoms of four different sizes (15, 30, 35, and 40 cm lateral width) were used for dose measurement and image quality assessment. Four scans were performed on each phantom using 100 or 120 kV with a clinical CT scanner: (1) reference scan; (2) scan with bismuth breast shield of an appropriate thickness; (3) scan with organ-based TCM; and (4) scan with a global reduction in tube current chosen to match the dose reduction from bismuth shielding. Dose to the breast was measured with an ion chamber on the surface of the phantom. Image quality was evaluated by measuring the mean and standard deviation of CT numbers within the lung and heart regions. Compared to the reference scan, dose to the breast region was decreased by about 21% for the 15-cm phantom with a pediatric (2-ply) shield and by about 37% for the 30, 35, and 40-cm phantoms with adult (4-ply) shields. Organ-based TCM decreased the dose by 12% for the 15-cm phantom, and 34-39% for the 30, 35, and 40-cm phantoms. Global lowering of the tube current reduced breast dose by 23% for the 15-cm phantom and 39% for the 30, 35, and 40-cm phantoms. In phantoms of all four sizes, image noise was increased in both the lung and heart regions with bismuth shielding. No significant increase in noise was observed with organ-based TCM. Decreasing tube current globally led to similar noise increases as bismuth shielding. Streak and beam hardening artifacts, and a resulting artifactual increase in CT numbers, were observed for scans with bismuth shields, but not for organ-based TCM or global tube current reduction. Organ-based TCM produces dose reduction to the breast similar to that achieved with bismuth shielding for both pediatric and adult phantoms. However, organ-based TCM does not affect image noise or CT number accuracy, both of which are adversely affected by bismuth shielding. Alternatively, globally decreasing the tube current can produce the same dose reduction to the breast as bismuth shielding, with a similar noise increase, yet without the streak artifacts and CT number errors caused by the bismuth shields. Moreover, globally decreasing the tube current reduces the dose to all tissues scanned, not simply to the breast.


Intestinal epithelial barrier dysfunction and dendritic cell redistribution during early stages of inflammation in the rat: role for TLR-2 and -4 blockage.
Dendritic cell (DC) redistribution during early stages of enteritis may be related to ileal barrier dysfunction. We used a rat model of ileitis to examine this hypothesis. Sprague-Dawley rats were injected with indomethacin or saline and euthanized 2, 6, 12, or 24 hours later. Ileal segments and mesenteric lymph nodes were obtained for morphological, bacterial, or functional studies. To determine the role of Toll-like receptor (TLR)-2 and -4 blockages, rats were pretreated with normal IgG, anti-TLR-2, or anti-TLR-4 antibodies prior to indomethacin or saline, and ileal segments were collected 24 hours later. In control rats, CD103+DC were mainly located in the lamina propria (LP) and some expressed TLR-2. TLR-4+ cells with different morphology and distribution from CD103+DC were also detected. In indomethacin-treated rats at 6-24 hours, inflammation was evident as was redistribution of CD103+DC from LP to Peyer's patches. We also observed TLR-2+ monocyte depletion and changes in TLR-4 distribution. At 2-6 hours we detected opened tight junctions as well as abnormal trans- and para-epithelial enteric bacterial infiltration, while macromolecular permeability was not significantly enhanced until 24 hours. In the absence of indomethacin, anti-TLR-2 blockage induced a significant increase of LP CD103+DC, while in the presence of indomethacin, anti-TLR-2 or -4 blockages significantly inhibited (P < 0.05) the reduction of LP CD103+DC. During the early stages of indomethacin-induced ileitis, epithelial barrier damage and abnormal bacterial infiltration into the mucosa occurred in conjunction with initial redistribution of CD103+DC. Furthermore, we showed that TLR-2 and -4 blockade regulates CD103+DC distribution during early phases in this experimental model.


Exploring palliative care provision for recipients of allogeneic hematopoietic stem cell transplantation who relapsed.
To quantify the characteristics of patients who die in the hospital from relapse after allogeneic hematopoietic stem cell transplantation (alloHSCT), explore palliative care integration and end-of-life (EOL) care, and benchmark standards of care. Retrospective chart review cohort study; a cross-sectional survey design guided a national survey. A chart review was conducted in a large tertiary hospital in Australia. The survey was distributed to leading alloHSCT centers in Australia and New Zealand. The chart review sample group was patients in the hematology department who had received an alloHSCT, relapsed, and died in the hospital (N = 40). The survey sample group was the most advanced nurse involved in patient care at each facility (N = 14). A quantitative data collection tool created for chart review, as well as patient notes written by the physician, were examined. The quantitative data collection tool was created for the survey, which was conducted via email or telephone. The chart review measured patient demographics, palliative care integration, EOL care, and symptoms. Survey topics included services available, referrals to palliative care services, EOL discussions, and symptom management. About half of the patients were seen by the palliative care service. Many patients experienced severe symptoms in the terminal phase. Survey participants felt EOL discussions were left until the terminal phase. Participants believed early palliative care integration was beneficial for patients and their family. The chart review demonstrated late integration of palliative care and poor standards of EOL care. Survey results reiterated this and reflected that nurses are supportive of earlier integration of palliative care and improving EOL care. Palliative care should be integrated earlier, and nursing roles have the potential to address unmet needs for these patients.


Pazopanib Maintenance Therapy in East Asian Women With Advanced Epithelial Ovarian Cancer: Results From AGO-OVAR16 and an East Asian Study.
The recent phase 3 trial AGO-OVAR16 demonstrated that pazopanib maintenance improved median progression-free survival in patients with ovarian cancer whose disease did not progress during first-line treatment. However, this improvement was not seen in the subset of East Asian patients. The current analysis evaluated the efficacy and safety of pazopanib maintenance in East Asian patients from AGO-OVAR16 and a separate East Asian study. East Asian patients from AGO-OVAR16 (n = 209) and the East Asian study (N = 145) were randomized 1:1 to receive pazopanib 800 mg/d or placebo for up to 24 months. The primary end point for each study was progression-free survival by RECIST (Response Evaluation Criteria in Solid Tumors) based on investigator assessment. Clinical and genetics data were analyzed separately by study or pooled according to separate predetermined statistical plans. Pazopanib maintenance had a detrimental effect on median progression-free survival versus placebo in East Asian patients from the combined studies (n = 354; 17.9 vs 21.5 months; hazard ratio, 1.114; 95% confidence interval, 0.818-1.518; P = 0.4928). Pazopanib maintenance showed a disadvantage in overall survival in East Asian patients from AGO-OVAR16 versus placebo (hazard ratio, 1.706; 95% confidence interval, 1.010-2.883; P = 0.0465); overall survival analysis was not performed in the East Asian study because of insufficient event numbers. Pazopanib-treated patients had a significantly higher incidence of grade 3 or higher hypertension (27%) and neutropenia (13%) versus placebo. The treatment effect of maintenance pazopanib in East Asian patients seemed to differ from that in non-Asian patients. In study-specific and pooled analyses, none of the potential factors analyzed could satisfactorily explain the different efficacy results of pazopanib in East Asian patients.


A randomized, double-blind, placebo-controlled study of ziprasidone monotherapy in bipolar disorder with co-occurring lifetime panic or generalized anxiety disorder.
Bipolar disorder often co-occurs with anxiety disorders. Evidence suggests that second-generation antipsychotics (SGAs) may be useful in treating both conditions. This study examined the efficacy of ziprasidone in the treatment of these disorders. This 3-site, randomized, double-blind, placebo-controlled, parallel group, 8-week trial of ziprasidone monotherapy examined 49 subjects with bipolar disorder and lifetime panic disorder (with or without agoraphobia) or generalized anxiety disorder (GAD) experiencing moderately severe anxiety symptoms at entrance into the study. Both bipolar disorder and anxiety diagnoses were based on DSM-IV-TR criteria. Patients were screened and randomized from June 25, 2010, through August 23, 2011. Primary outcome measures were the Clinical Global Impressions-21 Anxiety Scale (CGI-21 Anxiety) and the Sheehan Disability Scale (SDS), with secondary measures monitoring anxiety and mood symptoms. Last-observation-carried-forward analyses demonstrated that patients in the ziprasidone group did not improve significantly more than those in the placebo group on the CGI-21 Anxiety (F1 = 0.34; P = .564) or SDS (F1 = 0.26; P = .611). Secondary analysis using hierarchical linear modeling found similar results (CGI-21 Anxiety: F1 = 1.82; P = .178; and SDS: F1 = 0.70; P = .408). Regardless of group, time in the study was associated with significant decrease in anxiety (F1 = 11.08; P = .001) and total disability (F1 = 26.16; P < .001). Patients in the ziprasidone group showed a greater increase in abnormal involuntary movement, and 81.8% (n = 9) of the subjects who withdrew from the study due to adverse events, serious adverse events, or side effects were in the ziprasidone group. Results suggest that ziprasidone monotherapy was not associated with a clinically significant improvement in anxiety symptoms or improved function for patients with bipolar disorder, lifetime panic disorder or GAD, and concurrent moderately severe anxiety symptoms, and it was associated with a more negative side-effect profile relative to placebo. ClinicalTrials.gov identifier: NCT01172652.


Occupational risk factors for the development of systemic lupus erythematosus.
There have been few studies of occupational exposures and systemic lupus erythematosus (SLE). We examined the association between the risk of SLE and occupational exposures (mercury, solvents, and pesticides), specific jobs (ever worked in teaching, healthcare, and cosmetology), and working night or rotating shifts. Patients with recently diagnosed SLE (n = 265) were recruited through 4 university based and 30 community based rheumatology practices in North Carolina and South Carolina, USA. Controls (n = 355) were identified through driver's license records and were frequency matched to patients by age, sex, and state. Data collection included an in-person interview with detailed farming and work histories. Associations were seen with self-reported occupational exposure to mercury (OR 3.6, 95% CI 1.3, 10.0), mixing pesticides for agricultural work (OR 7.4, 95% CI 1.4, 40.0), and among dental workers (OR 7.1, 95% CI 2.2, 23.4). Although these associations were fairly strong and statistically significant, the prevalence of these exposures was very low and thus these estimates are based on a small number of exposed cases and controls. Weaker associations were seen between SLE and shift work (OR 1.6, 95% CI 0.99, 2.7) and among healthcare workers with patient contact (OR 1.7, 95% CI 0.99, 2.9). There was no association of SLE with use of solvents or among teachers or cosmetologists. This study reveals the potential contribution of occupational exposures to the development of SLE, and highlights some exposures and experiences that should be examined in other studies using more extensive exposure assessment techniques and in experimental studies of autoimmunity.


The diagnostic test accuracy of magnetic resonance imaging, magnetic resonance arthrography and computer tomography in the detection of chondral lesions of the hip.
The purpose of this study was to assess the diagnostic test accuracy of magnetic resonance imaging (MRI), magnetic resonance arthrography (MRA) and multidetector arrays in CT arthrography (MDCT) for assessing chondral lesions in the hip joint. A review of the published and unpublished literature databases was performed to identify all studies reporting the diagnostic test accuracy (sensitivity/specificity) of MRI, MRA or MDCT for the assessment of adults with chondral (cartilage) lesions of the hip with surgical comparison (arthroscopic or open) as the reference test. All included studies were reviewed using the quality assessment of diagnostic accuracy studies appraisal tool. Pooled sensitivity, specificity, likelihood ratios and diagnostic odds ratios were calculated with 95 % confidence intervals using a random-effects meta-analysis for MRI, MRA and MDCT imaging. Eighteen studies satisfied the eligibility criteria. These included 648 hips from 637 patients. MRI indicated a pooled sensitivity of 0.59 (95 % CI: 0.49-0.70) and specificity of 0.94 (95 % CI: 0.90-0.97), and MRA sensitivity and specificity values were 0.62 (95 % CI: 0.57-0.66) and 0.86 (95 % CI: 0.83-0.89), respectively. The diagnostic test accuracy for the detection of hip joint cartilage lesions is currently superior for MRI compared with MRA. There were insufficient data to perform meta-analysis for MDCT or CTA protocols. Based on the current limited diagnostic test accuracy of the use of magnetic resonance or CT, arthroscopy remains the most accurate method of assessing chondral lesions in the hip joint.


[The role of omega-3 fatty acids in the treatment of bipolar disorders: the current situation].
There is great interest in the use of omega-3 fatty acids in the treatment of various psychiatric disorders. Epidemiological investigations show that a high consumption of omega-3 fatty acids is in inverse proportion to the prevalence of affective disorders. To provide an overview of current research reports on the use of omega-3 fatty acids and bipolar disorders. Medline was searched with the following MeSH terms: 'mood disorders', 'affective disorders', 'bipolar disorders', 'fish oil', 'unsaturated dietary fats', 'omega-3 fatty acids', 'eicosapentaenoic acid', 'docosahexaenoic acid' and 'alpha-linolenic acid'. results To date, articles have been published about four randomized controlled trials and one open-label study. Omega-3 fatty acids, when added to an existing psychopharmacological maintenance treatment for bipolar disorder, can have a slight beneficial effect on depressive symptoms. There is no clear evidence that this combination has a beneficial effect on manic symptoms. Current data on the efficacy of docosahexaenoic acid (dha) and eicosapentaenoic acid (epa) in the treatment of bipolar disorder are insufficient for us to draw definite conclusions that can guide clinical practice. Further investigations are required into the effects of omega-3 fatty acids on the various phases of bipolar disorder.


Computational modeling of the arterial wall based on layer-specific histological data.
Arterial walls typically have a heterogeneous structure with three different layers (intima, media, and adventitia). Each layer can be modeled as a fiber-reinforced material with two families of relatively stiff collagenous fibers symmetrically arranged within an isotropic soft ground matrix. In this paper, we present two different modeling approaches, the embedded fiber (EF) approach and the angular integration (AI) approach, to simulate the anisotropic behavior of individual arterial wall layers involving layer-specific data. The EF approach directly incorporates the microscopic arrangement of fibers that are synthetically generated from a random walk algorithm and captures material anisotropy at the element level of the finite element formulation. The AI approach smears fibers in the ground matrix and treats the material as homogeneous, with material anisotropy introduced at the constitutive level by enhancing the isotropic strain energy with two anisotropic terms. Both approaches include the influence of fiber dispersion introduced by fiber angular distribution (departure of individual fibers from the mean orientation) and take into consideration the dispersion caused by fiber waviness, which has not been previously considered. By comparing the numerical results with the published experimental data of different layers of a human aorta, we show that by using histological data both approaches can successfully capture the anisotropic behavior of individual arterial wall layers. Furthermore, through a comprehensive parametric study, we establish the connections between the AI phenomenological material parameters and the EF parameters having straightforward physical or geometrical interpretations. This study provides valuable insight for the calibration of phenomenological parameters used in the homogenized modeling based on the fiber microscopic arrangement. Moreover, it facilitates a better understanding of individual arterial wall layers, which will eventually advance the study of the structure-function relationship of arterial walls as a whole.


Neural Signatures of the Processing of Temporal Patterns in Sound.
The ability to detect regularities in sound (i.e., recurring structure) is critical for effective perception, enabling, for example, change detection and prediction. Two seemingly unconnected lines of research concern the neural operations involved in processing regularities: one investigates how neural activity synchronizes with temporal regularities (e.g., frequency modulation; FM) in sounds, whereas the other focuses on increases in sustained activity during stimulation with repeating tone-frequency patterns. In three electroencephalography studies with male and female human participants, we investigated whether neural synchronization and sustained neural activity are dissociable, or whether they are functionally interdependent. Experiment I demonstrated that neural activity synchronizes with temporal regularity (FM) in sounds, and that sustained activity increases concomitantly. In Experiment II, phase coherence of FM in sounds was parametrically varied. Although neural synchronization was more sensitive to changes in FM coherence, such changes led to a systematic modulation of both neural synchronization and sustained activity, with magnitude increasing as coherence increased. In Experiment III, participants either performed a duration categorization task on the sounds, or a visual object tracking task to distract attention. Neural synchronization was observed regardless of task, whereas the sustained response was observed only when attention was on the auditory task, not under (visual) distraction. The results suggest that neural synchronization and sustained activity levels are functionally linked: both are sensitive to regularities in sounds. However, neural synchronization might reflect a more sensory-driven response to regularity, compared with sustained activity which may be influenced by attentional, contextual, or other experiential factors.SIGNIFICANCE STATEMENT Optimal perception requires that the auditory system detects regularities in sounds. Synchronized neural activity and increases in sustained neural activity both appear to index the detection of a regularity, but the functional interrelation of these two neural signatures is unknown. In three electroencephalography experiments, we measured both signatures concomitantly while listeners were presented with sounds containing frequency modulations that differed in their regularity. We observed that both neural signatures are sensitive to temporal regularity in sounds, although they functionally decouple when a listener is distracted by a demanding visual task. Our data suggest that neural synchronization reflects a more automatic response to regularity compared with sustained activity, which may be influenced by attentional, contextual, or other experiential factors.


Interleukin 7 generates antitumor cytotoxic T lymphocytes against murine sarcomas with efficacy in cellular adoptive immunotherapy.
Interleukin 7 (IL-7) is a 25-kD cytokine that was initially described as a pre-B cell growth factor. This cytokine has also been shown to have T cell proliferative and differentiation effects. In this report, we demonstrate that antitumor cytotoxic T lymphocytes (CTL) generated by secondary in vitro sensitization of draining lymph node cells in IL-7 are effective in treating 3-day syngeneic methylcholanthrene (MCA) sarcoma pulmonary metastases in mice. In vivo titrations comparing IL-7 to IL-2 antitumor CTL show that they have equivalent potency in adoptive immunotherapy. IL-7 antitumor CTL generated against MCA sarcomas of weak immunogeneity are also tumor specific in their in vivo efficacy. This study represents the first successful use of a cytokine other than IL-2 for the generation of cells with in vivo efficacy in cellular adoptive transfer.


Identification of novel candidate disease genes from de novo exonic copy number variants.
Exon-targeted microarrays can detect small (<1000 bp) intragenic copy number variants (CNVs), including those that affect only a single exon. This genome-wide high-sensitivity approach increases the molecular diagnosis for conditions with known disease-associated genes, enables better genotype-phenotype correlations, and facilitates variant allele detection allowing novel disease gene discovery. We retrospectively analyzed data from 63,127 patients referred for clinical chromosomal microarray analysis (CMA) at Baylor Genetics laboratories, including 46,755 individuals tested using exon-targeted arrays, from 2007 to 2017. Small CNVs harboring a single gene or two to five non-disease-associated genes were identified; the genes involved were evaluated for a potential disease association. In this clinical population, among rare CNVs involving any single gene reported in 7200 patients (11%), we identified 145 de novo autosomal CNVs (117 losses and 28 intragenic gains), 257 X-linked deletion CNVs in males, and 1049 inherited autosomal CNVs (878 losses and 171 intragenic gains); 111 known disease genes were potentially disrupted by de novo autosomal or X-linked (in males) single-gene CNVs. Ninety-one genes, either recently proposed as candidate disease genes or not yet associated with diseases, were disrupted by 147 single-gene CNVs, including 37 de novo deletions and ten de novo intragenic duplications on autosomes and 100 X-linked CNVs in males. Clinical features in individuals with de novo or X-linked CNVs encompassing at most five genes (224 bp to 1.6 Mb in size) were compared to those in individuals with larger-sized deletions (up to 5 Mb in size) in the internal CMA database or loss-of-function single nucleotide variants (SNVs) detected by clinical or research whole-exome sequencing (WES). This enabled the identification of recently published genes (BPTF, NONO, PSMD12, TANGO2, and TRIP12), novel candidate disease genes (ARGLU1 and STK3), and further confirmation of disease association for two recently proposed disease genes (MEIS2 and PTCHD1). Notably, exon-targeted CMA detected several pathogenic single-exon CNVs missed by clinical WES analyses. Together, these data document the efficacy of exon-targeted CMA for detection of genic and exonic CNVs, complementing and extending WES in clinical diagnostics, and the potential for discovery of novel disease genes by genome-wide assay.


Improved detection of proteolytically cleaved high molecular weight kininogen by immunoblotting using an antiserum against its reduced 47 kDa light chain.
Several ligand blotting or immunoblotting assays for the detection of single-chain and proteolytically cleaved two-chain high molecular weight kininogen (HK) in whole plasma have been described. Since they may suffer from poor sensitivity for the light chain species of cleaved HK on reduced blots, an antiserum against the reduced and alkylated 47 kDa light chain of HK was raised in rabbits allowing improved immunodetection of HK species on blots of reduced electropherograms. This immunoblotting method is highly specific and sensitive, permitting detection of 0.2 ng single-chain HK or the light chains of 2 ng proteolytically cleaved HK in whole plasma. Thus, this immunoblotting technique is at least 50-100 times more sensitive than ligand blotting with radiolabelled factor XI overlay. A similar cleavage pattern was observed following in vitro activation of normal human plasma by dextran sulphate and after plasma kallikrein-induced proteolysis of purified HK. However, bands of different molecular weights were generated after HK had been cleaved by purified leukocyte elastase. During acute attack in a patient with hereditary angioedema, high levels of in vivo cleaved HK were noticed, whereas concentration of cleaved HK in plasma samples and synovial fluids from patients suffering from various inflammatory conditions were not substantially higher than those in normal plasma. During in vitro cold activation of plasma samples of pregnant women concomitant HK cleavage and plasma kallikrein generation were observed.


ACG Clinical Guideline: Diagnosis and Management of Pancreatic Cysts.
Pancreatic cysts are very common with the majority incidentally identified. There are several types of pancreatic cysts; some types can contain cancer or have malignant potential, whereas others are benign. However, even the types of cysts with malignant potential rarely progress to cancer. At the present time, the only viable treatment for pancreatic cysts is surgical excision, which is associated with a high morbidity and occasional mortality. The small risk of malignant transformation, the high risks of surgical treatment, and the lack of high-quality prospective studies have led to contradictory recommendations for their immediate management and for their surveillance. This guideline will provide a practical approach to pancreatic cyst management and recommendations for cyst surveillance for the general gastroenterologist.


Regulation of mucociliary clearance in health and disease.
Airway secretions are cleared by mucociliary clearance (MCC), in addition to other mechanisms such as cough, peristalsis, two-phase gas-liquid flow and alveolar clearance. MCC comprises the cephalad movement of mucus caused by the cilia lining the conducting airways until it can be swallowed or expectorated. MCC is a very complex process in which many variables are involved, all of which may modify the final outcome. The structure, number, movement and co-ordination of the cilia present in the airways as well as the amount, composition and rheological properties of the periciliary and mucus layers are determinants of MCC. Physiological factors such as age, sex, posture, sleep and exercise are reported to influence MCC due to a change in the cilia, the mucus or the periciliary layer, or a combination of these. Environmental pollution is suspected to have a depressant effect on MCC dependent on different factors such as pollutant concentration and the duration of exposure. Most studies focus on sulphur dioxide, sulphuric acid, nitrogen dioxide and ozone. Tobacco smoke and hairspray have been noted to have a negative influence on MCC. Some diseases are known to affect MCC, mostly negatively. The underlying mechanism differs from one illness to another. Immotile cilia syndrome, asthma, bronchiectasis, chronic bronchitis, cystic fibrosis and some acute respiratory tract infections are among the most frequently reported. The present paper reviews normal mucociliary clearance and the effects of diseases on this process.


Medications, Deep Brain Stimulation, and Other Factors Influencing Impulse Control Disorders in Parkinson's Disease.
Impulse control disorders (ICDs) in Parkinson's disease (PD) have a high cumulative incidence and negatively impact quality of life. ICDs are influenced by a complex interaction of multiple factors. Although it is now well-recognized that dopaminergic treatments and especially dopamine agonists underpin many ICDs, medications alone are not the sole cause. Susceptibility to ICD is increased in the setting of PD. While causality can be challenging to ascertain, a wide range of modifiable and non-modifiable risk factors have been linked to ICDs. Common characteristics of PD patients with ICDs have been consistently identified across many studies; for example, males with an early age of PD onset and dopamine agonist use have a higher risk of ICD. However, not all cases of ICDs in PD can be directly attributable to dopamine, and studies have concluded that additional factors such as genetics, smoking, and/or depression may be more predictive. Beyond dopamine, other ICD associations have been described but remain difficult to explain, including deep brain stimulation surgery, especially in the setting of a reduction in dopaminergic medication use. In this review, we will summarize the demographic, genetic, behavioral, and clinical contributions potentially influencing ICD onset in PD. These associations may inspire future preventative or therapeutic strategies.


Prospective double-blind trial of synthetic steroid (Org OD 14) for preventing postmenopausal osteoporosis.
A double-blind trial of Org OD 14, a synthetic steroid with an unusual endocrine profile, was conducted on 100 postmenopausal women; of these, 63 completed two years' treatment (33 Org OD 14; 30 placebo). A dose of 2.5 mg/day successfully prevented bone loss over two years, whereas a significant reduction in bone mineral content occurred in women taking placebo, the rate being comparable to that in earlier studies (p less than 0.01). At the dosage used (2.5 mg/day) Org OD 14 also significantly reduced the severity of menopausal complaints (flushing, sweating, etc). Vabra aspiration curettage in 20 cases 6-18 months after starting active treatment showed no evidence of endometrial hyperplasia, though weak proliferation of the endometrium was seen in three. Org OD 14 may provide a new approach to hormonal prevention of bone loss in postmenopausal women without inducing appreciable endometrial stimulation; the potential value of Org OD 14 in osteoporosis and other post-climacteric complaints warrants further investigation.


Effect of intranasal capsaicin on symptoms and mediator release.
Differential nasal responsiveness to environmental tobacco smoke (ETS) has been documented in humans and we hypothesized that this reflects differential responsiveness to c-fiber stimulation. We compared the response to intranasal capsaicin in subjects with and without a history of ETS-rhinitis. We challenged 10 ETS-sensitive and 11 ETS-nonsensitive subjects intranasally with 25 mg of lactose powder followed by 25 pg to 25 ng of capsaicin in 25 mg of lactose. Subjects rated nasal symptoms and underwent nasal lavage. In each lavage, the concentrations of albumin (an index of vascular permeability), kinins and histamine (a marker of mast cell activation) were measured. Nasal lavage tosyl-L-arginine methyl ester (TAME)-esterase activity, which can be a reflection of mast cell activation, increased vascular permeability or glandular secretion, was also determined. Subjects with a history of ETS-rhinitis reported more rhinorrhea than subjects without a history of ETS-rhinitis (P less than .01). No significant increase occurred in nasal lavage histamine, albumin or kinins in either subject group. TAME-esterase activity (presumably a reflection of increased glandular secretion) increased greater than 1000 cpm in 12/21 subjects (designated "TAME-producers"), but this was unrelated to ETS-sensitivity. TAME producers showed a dose-dependent increase in TAME-esterase activity, whereas TAME nonproducers showed no change at any capsaicin dose. We conclude that capsaicin causes nasal symptoms and glandular stimulation without evidence of increased vascular permeability or mast cell activation. ETS-rhinorrhea symptoms in humans appear related to c-fiber stimulation. The absence of c-fiber-induced glandular secretion, although not related to ETS-sensitivity, was associated with decreased sneezing and increased symptoms of capsaicin-induced nasal burning.


Glutamine in the mechanism of ammonia-induced astrocyte swelling.
Brain edema and the subsequent increase in intracranial pressure are the major neurological complications in fulminant hepatic failure (FHF). Brain edema in FHF is predominantly "cytotoxic" due principally to astrocyte swelling. It is generally believed that ammonia plays a key role in this process, although the mechanism by which ammonia brings about such swelling is yet to be defined. It has been postulated that glutamine accumulation in astrocytes subsequent to ammonia detoxification results in increased osmotic forces leading to cell swelling. While the hypothesis is plausible and has gained support, it has never been critically tested. In this study, we examined whether a correlation exists between cellular glutamine levels and the degree of cell swelling in cultured astrocytes exposed to ammonia. Cultured astrocytes derived from rat brain cortices were exposed to ammonia (5 mM) for different time periods and cell swelling was measured. Cultures treated with ammonia for 1-3 days showed a progressive increase in astrocyte cell volume (59-127%). Parallel treatment of astrocyte cultures with ammonia showed a significant increase in cellular glutamine content (60-80%) only at 1-4 h, a time when swelling was absent, while glutamine levels were normal at 1-3 days, a time when peak cell swelling was observed. Thus no direct correlation between cell swelling and glutamine levels was detected. Additionally, acute increase in intracellular levels of glutamine by treatment with the glutaminase inhibitor 6-diazo-5-oxo-L-norleucine (DON) after ammonia exposure also did not result in swelling. On the contrary, DON treatment significantly blocked (66%) ammonia-induced astrocyte swelling at a later time point (24 h), suggesting that some process resulting from glutamine metabolism is responsible for astrocyte swelling. Additionally, ammonia-induced free radical production and induction of the mitochondrial permeability transition (MPT) were significantly blocked by treatment with DON, suggesting a key role of glutamine in the ammonia-induced free radical generation and the MPT. In summary, our findings indicate a lack of direct correlation between the extent of cell swelling and cellular levels of glutamine. While glutamine may not be acting as an osmolyte, we propose that glutamine-mediated oxidative stress and/or the MPT may be responsible for the astrocyte swelling by ammonia.


Postoperative deterioration in health related quality of life as predictor for survival in patients with glioblastoma: a prospective study.
Studies indicate that acquired deficits negatively affect patients' self-reported health related quality of life (HRQOL) and survival, but the impact of HRQOL deterioration after surgery on survival has not been explored. Assess if change in HRQOL after surgery is a predictor for survival in patients with glioblastoma. Sixty-one patients with glioblastoma were included. The majority of patients (n = 56, 91.8%) were operated using a neuronavigation system which utilizes 3D preoperative MRI and updated intraoperative 3D ultrasound volumes to guide resection. HRQOL was assessed using EuroQol 5D (EQ-5D), a generic instrument. HRQOL data were collected 1-3 days preoperatively and after 6 weeks. The mean change in EQ-5D index was -0.05 (95% CI -0.15-0.05) 6 weeks after surgery (p = 0.285). There were 30 patients (49.2%) reporting deterioration 6 weeks after surgery. In a Cox multivariate survival analysis we evaluated deterioration in HRQOL after surgery together with established risk factors (age, preoperative condition, radiotherapy, temozolomide and extent of resection). There were significant independent associations between survival and use of temozolomide (HR 0.30, p = 0.019), radiotherapy (HR 0.26, p = 0.030), and deterioration in HRQOL after surgery (HR 2.02, p = 0.045). Inclusion of surgically acquired deficits in the model did not alter the conclusion. Early deterioration in HRQOL after surgery is independently and markedly associated with impaired survival in patients with glioblastoma. Deterioration in patient reported HRQOL after surgery is a meaningful outcome in surgical neuro-oncology, as the measure reflects both the burden of symptoms and treatment hazards and is linked to overall survival.


Clinical, molecular, and genotype-phenotype correlation studies from 25 cases of oral-facial-digital syndrome type 1: a French and Belgian collaborative study.
Oral-facial-digital syndrome type 1 (OFD1) is characterised by an X linked dominant mode of inheritance with lethality in males. Clinical features include facial dysmorphism with oral, tooth, and distal abnormalities, polycystic kidney disease, and central nervous system malformations. Large interfamilial and intrafamilial clinical variability has been widely reported, and 18 distinct mutations have been previously reported within OFD1. A French and Belgian collaborative study collected 25 cases from 16 families. OFD1 was analysed using direct sequencing and phenotype-genotype correlation was performed using chi2 test. X inactivation studies were performed on blood lymphocytes. In 11 families, 11 novel mutations, including nine frameshift, one nonsense, and one missense mutation were identified, which spanned nine different exons. A combination of our results with previously reported cases showed that the majority of mutations (65.5%) was located in exons 3, 8, 9, 13, and 16. There was phenotype-genotype correlation between (a) polycystic kidney disease and splice mutations; (b) mental retardation and mutations located in exons 3, 8, 9, 13, and 16; and (c) tooth abnormalities and mutations located in coiled coil domains. Comparing the phenotype of the families with a pathogenic mutation to families with absence of OFD1 mutation, polycystic kidneys and short stature were significantly more frequent in the group with no OFD1 mutation, whereas lingual hamartomas were significantly more frequent in the group with OFD1 mutation. Finally, an X inactivation study showed non-random X inactivation in a third of the samples. Differential X inactivation between mothers and daughters in two families with high intrafamilial variability was of particular interest. Slight phenotype-genotype correlations were established, and X inactivation study showed that skewed X inactivation could be partially involved in the pathogenesis of intrafamilial clinical variability.


Transparent conducting silver nanowire networks.
We present a transparent conducting electrode composed of a periodic two-dimensional network of silver nanowires. Networks of Ag nanowires are made with wire diameters of 45-110 nm and a pitch of 500, 700, and 1000 nm. Anomalous optical transmission is observed, with an averaged transmission up to 91% for the best transmitting network and sheet resistances as low as 6.5 Ω/sq for the best conducting network. Our most dilute networks show lower sheet resistance and higher optical transmittance than an 80 nm thick layer of ITO sputtered on glass. By comparing measurements and simulations, we identify four distinct physical phenomena that govern the transmission of light through the networks: all related to the excitation of localized surface plasmons and surface plasmon polaritons on the wires. The insights given in this paper provide the key guidelines for designing high-transmittance and low-resistance nanowire electrodes for optoelectronic devices, including thin-film solar cells. For the latter, we discuss the general design principles to use the nanowire electrodes also as a light trapping scheme.


A quantitative link between face discrimination deficits and neuronal selectivity for faces in autism.
Individuals with Autism Spectrum Disorder (ASD) appear to show a general face discrimination deficit across a range of tasks including social-emotional judgments as well as identification and discrimination. However, functional magnetic resonance imaging (fMRI) studies probing the neural bases of these behavioral differences have produced conflicting results: while some studies have reported reduced or no activity to faces in ASD in the Fusiform Face Area (FFA), a key region in human face processing, others have suggested more typical activation levels, possibly reflecting limitations of conventional fMRI techniques to characterize neuron-level processing. Here, we test the hypotheses that face discrimination abilities are highly heterogeneous in ASD and are mediated by FFA neurons, with differences in face discrimination abilities being quantitatively linked to variations in the estimated selectivity of face neurons in the FFA. Behavioral results revealed a wide distribution of face discrimination performance in ASD, ranging from typical performance to chance level performance. Despite this heterogeneity in perceptual abilities, individual face discrimination performance was well predicted by neural selectivity to faces in the FFA, estimated via both a novel analysis of local voxel-wise correlations, and the more commonly used fMRI rapid adaptation technique. Thus, face processing in ASD appears to rely on the FFA as in typical individuals, differing quantitatively but not qualitatively. These results for the first time mechanistically link variations in the ASD phenotype to specific differences in the typical face processing circuit, identifying promising targets for interventions.


Hand hygiene in the intensive care unit: prospective observations of clinical practice.
Adherence to hand hygiene recommendations in the intensive care unit (ICU) is variable and moderate, at best. To measure adherence to hand hygiene recommendations among ICU clinicians in a prospective observational study in 6 multidisciplinary ICUs among 4 hospitals. We observed 115 clinicians (64 nurses, 21 respiratory therapists, 18 residents and 12 physicians) during 1 patient encounter, each. Clinicians were unaware that they were under observation. We documented use of gloves, soap, and alcohol solution before and after patient encounters for purposes of physical examination or patient care. The rate of adherence to current recommendations was 20% (95% CI 13.7-28.2). All 23 clinicians adhering to recommendations used gloves followed by washing with soap or alcohol solution. 57.4% (95% CI 48.3-66.0) of clinicians used some form of hand hygiene without fully adhering to recommendations, whereas 42.6% did not appear to attend to hand hygiene at all during observation. By univariate analysis, with nurses as the reference group, we found trends suggesting lowest adherence rates among residents (odds ratio [OR] 0.32, 95% CI 0.11-0.96) and intensivists (OR 0.46, 95% CI, 0.13-1.60), and highest adherence among respiratory therapists (OR 2.05, 95% CI 0.67-6.30). We also observed a center effect (p = 0.04). However, multivariate analysis showed no relationship of hand hygiene to clinician group (p = 0.06) nor ICU (p = 0.05). Multidisciplinary, multimethod approaches to improving hand hygiene are likely necessary to improve the modest adherence to hand hygiene that we observed.


Genetic analysis of the orthologous crt and mdr1 genes in Plasmodium malariae from Thailand and Myanmar.
Plasmodium malariae is a widely spread but neglected human malaria parasite, which causes chronic infections. Studies on genetic polymorphisms of anti-malarial drug target genes in P. malariae are limited. Previous reports have shown polymorphisms in the P. malariae dihydrofolate reductase gene associated with pyrimethamine resistance and linked to pyrimethamine drug pressure. This study investigated polymorphisms of the P. malariae homologous genes, chloroquine resistant transporter and multidrug resistant 1, associated with chloroquine and mefloquine resistance in Plasmodium falciparum. The orthologous P. malariae crt and mdr1 genes were studied in 95 patients with P. malariae infection between 2002 and 2016 from Thailand (N = 51) and Myanmar (N = 44). Gene sequences were analysed using BioEdit, MEGA7, and DnaSP programs. Mutations and gene amplifications were compared with P. falciparum and Plasmodium vivax orthologous genes. Protein topology models derived from the observed pmcrt and pmmdr1 haplotypes were constructed and analysed using Phyre2, SWISS MODEL and Discovery Studio Visualization V 17.2. Two non-synonymous mutations were observed in exon 2 (H53P, 40%) and exon 8 (E278D, 44%) of pmcrt. The topology model indicated that H53P and E278D were located outside of the transmembrane domain and were unlikely to affect protein function. Pmmdr1 was more diverse than pmcrt, with 10 non-synonymous and 3 synonymous mutations observed. Non-synonymous mutations were located in the parasite cytoplasmic site, transmembrane 11 and nucleotide binding domains 1 and 2. Polymorphisms conferring amino acid changes in the transmembrane and nucleotide binding domains were predicted to have some effect on PmMDR1 conformation, but were unlikely to affect protein function. All P. malariae parasites in this study contained a single copy of the mdr1 gene. The observed polymorphisms in pmcrt and pmmdr1 genes are unlikely to affect protein function and unlikely related to chloroquine drug pressure. Similarly, the absence of pmmdr1 copy number variation suggests limited mefloquine drug pressure on the P. malariae parasite population, despite its long time use in Thailand for the treatment of falciparum malaria.


Regularized Semipaired Kernel CCA for Domain Adaptation.
Domain adaptation learning is one of the fundamental research topics in pattern recognition and machine learning. This paper introduces a regularized semipaired kernel canonical correlation analysis formulation for learning a latent space for the domain adaptation problem. The optimization problem is formulated in the primal-dual least squares support vector machine setting where side information can be readily incorporated through regularization terms. The proposed model learns a joint representation of the data set across different domains by solving a generalized eigenvalue problem or linear system of equations in the dual. The approach is naturally equipped with out-of-sample extension property, which plays an important role for model selection. Furthermore, the Nyström approximation technique is used to make the computational issues due to the large size of the matrices involved in the eigendecomposition feasible. The learned latent space of the source domain is fed to a multiclass semisupervised kernel spectral clustering model that can learn from both labeled and unlabeled data points of the source domain in order to classify the data instances of the target domain. Experimental results are given to illustrate the effectiveness of the proposed approaches on synthetic and real-life data sets.


Effects of aging on human leukocytes (part I): immunophenotyping of innate immune cells.
Immunosenescence is a hallmark of the aging immune system, leading to increased susceptibility to infections in the aged population and decreased ability to eradicate infectious pathogens. These effects, in turn, result in an increased burden on the healthcare system due to elevated frequency and duration of hospital visits. Growing evidence suggests that cells of the innate immune system are central modulators for the initiation and maintenance of an adequate pathogen-specific response through the adaptive immune system. While there are many reports on age-dependent alterations and dysfunctions of the adaptive immune system, the underlying mechanisms and effects of natural aging on the composition of the innate immune system remain unknown. Here, we present the results obtained from the comprehensive immunophenotyping of innate leukocyte populations, examined for age-related alterations within different sub-populations assessed using multi-parametric flow cytometry. We compared peripheral blood mononuclear cells from 24 young (aged 19-30 years) and 26 elderly (aged 53-67 years) donors. For classical CD16(+)CD56(dim) NK cells, the fraction of CD62L(+)CD57(+) was diminished in the elderly donors compared with young individuals, while the other investigated NK subsets remained unaffected by age. Both transitional monocytes and non-classical CD14(+-)CD16(++) monocytes were increased in the elderly compared with the young. The populations of pDCs and mDC2 were decreased among the elderly. These data demonstrate that the dynamics of the mDC subsets might counteract decreased virus surveillance. Furthermore, these data show that the maturation of NK cells might gradually slow down.


De novo gene disruptions in children on the autistic spectrum.
Exome sequencing of 343 families, each with a single child on the autism spectrum and at least one unaffected sibling, reveal de novo small indels and point substitutions, which come mostly from the paternal line in an age-dependent manner. We do not see significantly greater numbers of de novo missense mutations in affected versus unaffected children, but gene-disrupting mutations (nonsense, splice site, and frame shifts) are twice as frequent, 59 to 28. Based on this differential and the number of recurrent and total targets of gene disruption found in our and similar studies, we estimate between 350 and 400 autism susceptibility genes. Many of the disrupted genes in these studies are associated with the fragile X protein, FMRP, reinforcing links between autism and synaptic plasticity. We find FMRP-associated genes are under greater purifying selection than the remainder of genes and suggest they are especially dosage-sensitive targets of cognitive disorders.


SSRI and SNRI withdrawal symptoms reported on an internet forum.
Antidepressant withdrawal symptoms are well-recognised, but their potential duration remains uncertain. We aimed to describe the characteristics of withdrawal associated with two popular classes of antidepressants, including duration. We analysed the content of a sample of posts on an antidepressant withdrawal website. We compared the characteristics of withdrawal associated with SSRIs and SNRIs, including time of onset, duration and nature of symptoms. 110 posts about SSRI withdrawal, and 63 concerning SNRI withdrawal, were analysed. The mean duration of withdrawal symptoms was significantly longer with SSRIs than SNRIs: 90.5 weeks (standard deviation, SD, 150.0) and 50.8 weeks (SD 76.0) respectively; p = 0.043). Neurological symptoms, such as 'brain zaps,' were more common among SNRI users (p = 0.023). Psychosexual/genitourinary symptoms may be more common among SSRI users (p = 0.054). The website aims to help people with antidepressant withdrawal, and is therefore likely to attract people who have difficulties. Length of prior use of antidepressants was long, with a mean of 252.2 weeks (SD 250.8). People accessing antidepressant withdrawal websites report experiencing protracted withdrawal symptoms. There are some differences in the characteristics of withdrawal associated with different classes of antidepressants.


Steroid receptor coactivator 3 is a coactivator for myocardin, the regulator of smooth muscle transcription and differentiation.
Abnormal proliferation of vascular smooth muscle cells (VSMCs) constitutes a key event in atherosclerosis, neointimal hyperplasia, and the response to vascular injury. Estrogen receptor alpha (ERalpha) mediates the protective effects of estrogen in injured blood vessels and regulates ligand-dependent gene expression in vascular cells. However, the molecular mechanisms mediating ERalpha-dependent VSMC gene expression and VSMC proliferation after vascular injury are not well defined. Here, we report that the ER coactivator steroid receptor coactivator 3 (SRC3) is also a coactivator for the major VSMC transcription factor myocardin, which is required for VSMC differentiation to the nonproliferative, contractile state. The N terminus of SRC3, which contains a basic helix-loop-helix/Per-ARNT-Sim protein-protein interaction domain, binds the C-terminal activation domain of myocardin and enhances myocardin-mediated transcriptional activation of VSMC-specific, CArG-containing promoters, including the VSMC-specific genes SM22 and myosin heavy chain. Suppression of endogenous SRC3 expression by specific small interfering RNA attenuates myocardin transcriptional activation in cultured cells. The SRC3-myocardin interaction identifies a site of convergence for nuclear hormone receptor-mediated and VSMC-specific gene regulation and suggests a possible mechanism for the vascular protective effects of estrogen on vascular injury.


Difference in Detection Rate of Portal Venous Gas via Computed Tomography and Ultrasonography in Pediatric Patients.
This study was performed to compare computed tomography (CT)- and ultrasonography (US)-derived detection rates of portal venous gas (PVG) in pediatric patients and investigate whether discrepancies between these modalities were influenced by patient age and interval between examinations. We included 25 children who underwent both CT and US within 2 days for evaluation of intestinal ischemia. McNemar test was used to compare the detection of PVG between the 2 modalities. The cohort was retrospectively divided into 2 groups based on whether comparable results were obtained via both modalities; the Mann-Whitney U test was used to compare patient age and interval between CT and US between these 2 groups. Among 25 children, CT and US yielded similar results in 17 patients regarding the presence or absence of PVG (median age/interval, 2 years [range, 0-17 years]/51 minutes [range, 2-1196 minutes]; 3/14 detected via both/not both modalities) and different results in 8 (median age/interval, 0 years [range, 0-15 years]/171.5 minutes [range, 64-1486 minutes]; 7/1 detected via US only/via CT only). There was a significant difference in PVG detection rate between US and CT (P = 0.034). Patient age did not differ significantly between the 2 groups (P = 0.206), but the interval between CT and US did (P = 0.025). In conclusion, the detection rate of PVG was higher with US, compared with CT, although the timings of the examinations could have influenced this finding. Ultrasonography could be useful for PVG detection in pediatric patients because it can be performed repeatedly at the bedside without radiation exposure.


Endothelial Mechanosignaling: Does One Sensor Fit All?
Forces are important in the cardiovascular system, acting as regulators of vascular physiology and pathology. Residing at the blood vessel interface, cells (endothelial cell, EC) are constantly exposed to vascular forces, including shear stress. Shear stress is the frictional force exerted by blood flow, and its patterns differ based on vessel geometry and type. These patterns range from uniform laminar flow to nonuniform disturbed flow. Although ECs sense and differentially respond to flow patterns unique to their microenvironment, the mechanisms underlying endothelial mechanosensing remain incompletely understood. A large body of work suggests that ECs possess many mechanosensors that decorate their apical, junctional, and basal surfaces. These potential mechanosensors sense blood flow, translating physical force into biochemical signaling events. Understanding the mechanisms by which proposed mechanosensors sense and respond to shear stress requires an integrative approach. It is also critical to understand the role of these mechanosensors not only during embryonic development but also in the different vascular beds in the adult. Possible cross talk and integration of mechanosensing via the various mechanosensors remain a challenge. Determination of the hierarchy of endothelial mechanosensors is critical for future work, as is determination of the extent to which mechanosensors work together to achieve force-dependent signaling. The role and primary sensors of shear stress during development also remain an open question. Finally, integrative approaches must be used to determine absolute mechanosensory function of potential mechanosensors. Antioxid. Redox Signal. 25, 373-388.


Variability in larval gut pH regulation defines sensitivity to ocean acidification in six species of the Ambulacraria superphylum.
The unusual rate and extent of environmental changes due to human activities may exceed the capacity of marine organisms to deal with this phenomenon. The identification of physiological systems that set the tolerance limits and their potential for phenotypic buffering in the most vulnerable ontogenetic stages become increasingly important to make large-scale projections. Here, we demonstrate that the differential sensitivity of non-calcifying Ambulacraria (echinoderms and hemichordates) larvae towards simulated ocean acidification is dictated by the physiology of their digestive systems. Gastric pH regulation upon experimental ocean acidification was compared in six species of the superphylum Ambulacraria. We observed a strong correlation between sensitivity to ocean acidification and the ability to regulate gut pH. Surprisingly, species with tightly regulated gastric pH were more sensitive to ocean acidification. This study provides evidence that strict maintenance of highly alkaline conditions in the larval gut of Ambulacraria early life stages may dictate their sensitivity to decreases in seawater pH. These findings highlight the importance of identifying and understanding pH regulatory systems in marine larval stages that may contribute to substantial energetic challenges under near-future ocean acidification scenarios.


Transcatheter Interatrial Shunt Device for the Treatment of Heart Failure With Preserved Ejection Fraction (REDUCE LAP-HF I [Reduce Elevated Left Atrial Pressure in Patients With Heart Failure]): A Phase 2, Randomized, Sham-Controlled Trial.
In nonrandomized, open-label studies, a transcatheter interatrial shunt device (IASD, Corvia Medical) was associated with lower pulmonary capillary wedge pressure (PCWP), fewer symptoms, and greater quality of life and exercise capacity in patients with heart failure (HF) and midrange or preserved ejection fraction (EF ≥40%). We conducted the first randomized sham-controlled trial to evaluate the IASD in HF with EF ≥40%. REDUCE LAP-HF I (Reduce Elevated Left Atrial Pressure in Patients With Heart Failure) was a phase 2, randomized, parallel-group, blinded multicenter trial in patients with New York Heart Association class III or ambulatory class IV HF, EF ≥40%, exercise PCWP ≥25 mm Hg, and PCWP-right atrial pressure gradient ≥5 mm Hg. Participants were randomized (1:1) to the IASD versus a sham procedure (femoral venous access with intracardiac echocardiography but no IASD placement). The participants and investigators assessing the participants during follow-up were blinded to treatment assignment. The primary effectiveness end point was exercise PCWP at 1 month. The primary safety end point was major adverse cardiac, cerebrovascular, and renal events at 1 month. PCWP during exercise was compared between treatment groups using a mixed-effects repeated measures model analysis of covariance that included data from all available stages of exercise. A total of 94 patients were enrolled, of whom 44 met inclusion/exclusion criteria and were randomized to the IASD (n=22) and control (n=22) groups. Mean age was 70±9 years, and 50% were female. At 1 month, the IASD resulted in a greater reduction in PCWP compared with sham control (P=0.028 accounting for all stages of exercise). Peak PCWP decreased by 3.5±6.4 mm Hg in the treatment group versus 0.5±5.0 mm Hg in the control group (P=0.14). There were no peri-procedural or 1-month major adverse cardiac, cerebrovascular, and renal events in the IASD group and 1 event (worsening renal function) in the control group (P=1.0). In patients with HF and EF ≥40%, IASD treatment reduces PCWP during exercise. Whether this mechanistic effect will translate into sustained improvements in symptoms and outcomes requires further evaluation. URL: https://clinicaltrials.gov. Unique identifier: NCT02600234.


A High-Efficiency Multispectral Filter Based on Plasmonic Hybridization between Two Cascaded Ultrathin Nanogratings.
Overcoming the disadvantages of low transmission and broad peak bandwidth of previously reported plasmonic color filters, a high-efficiency multispectral plasmonic color filter is theoretically proposed with two cascaded ultrathin metallic nanogratings separated by two heterogeneous dielectric layers, and its optical properties are theoretically investigated using the finite-difference time-domain method. The transmission spectrum presents three near-unity peak bands accompanied with three near-null dip bands adjacent around them. Both transmission efficiencies of above 90% and ultranarrow peak bandwidth of 20 nm are achieved in the visible regime. The peak band positions can be flexibly tailored by varying the structural parameters. The filter selects the visible color with high signal noise ratio at the peak bands. The outstanding spectral properties of this filter indicate significant improvement for the high-accuracy color filtering and multispectral imaging applications. The simulated near-field electromagnetic distributions suggest that the excitation of the hybrid antisymmetric surface plasmon polariton (SPP) leaky mode and metal-insulator-metal waveguide modes are responsible for the peak transmission bands, while the formation of the hybrid SPP bound modes confined on the bottom nanograting makes the dip transmission bands, all of which are the consequence of the plasmonic hybridization between the two neighboring metallic nanogratings.


Buoyancy-Driven Gradients for Biomaterial Fabrication and Tissue Engineering.
The controlled fabrication of gradient materials is becoming increasingly important as the next generation of tissue engineering seeks to produce inhomogeneous constructs with physiological complexity. Current strategies for fabricating gradient materials can require highly specialized materials or equipment and cannot be generally applied to the wide range of systems used for tissue engineering. Here, the fundamental physical principle of buoyancy is exploited as a generalized approach for generating materials bearing well-defined compositional, mechanical, or biochemical gradients. Gradient formation is demonstrated across a range of different materials (e.g., polymers and hydrogels) and cargos (e.g., liposomes, nanoparticles, extracellular vesicles, macromolecules, and small molecules). As well as providing versatility, this buoyancy-driven gradient approach also offers speed (<1 min) and simplicity (a single injection) using standard laboratory apparatus. Moreover, this technique is readily applied to a major target in complex tissue engineering: the osteochondral interface. A bone morphogenetic protein 2 gradient, presented across a gelatin methacryloyl hydrogel laden with human mesenchymal stem cells, is used to locally stimulate osteogenesis and mineralization in order to produce integrated osteochondral tissue constructs. The versatility and accessibility of this fabrication platform should ensure widespread applicability and provide opportunities to generate other gradient materials or interfacial tissues.


Physiological responses of coccolithophores to abrupt exposure of naturally low pH deep seawater.
Upwelling is the process by which deep, cold, relatively high-CO2, nutrient-rich seawater rises to the sunlit surface of the ocean. This seasonal process has fueled geoengineering initiatives to fertilize the surface ocean with deep seawater to enhance productivity and thus promote the drawdown of CO2. Coccolithophores, which inhabit many upwelling regions naturally 'fertilized' by deep seawater, have been investigated in the laboratory in the context of ocean acidification to determine the extent to which nutrients and CO2 impact their physiology, but few data exist in the field except from mesocosms. Here, we used the Porcupine Abyssal Plain (north Atlantic Ocean) Observatory to retrieve seawater from depths with elevated CO2 and nutrients, mimicking geoengineering approaches. We tested the effects of abrupt natural deep seawater fertilization on the physiology and biogeochemistry of two strains of Emiliania huxleyi of known physiology. None of the strains tested underwent cell divisions when incubated in waters obtained from <1,000 m (pH = 7.99-8.08; CO2 = 373-485 p.p.m; 1.5-12 μM nitrate). However, growth was promoted in both strains when cells were incubated in seawater from ~1,000 m (pH = 7.9; CO2 ~560 p.p.m.; 14-17 μM nitrate) and ~4,800 m (pH = 7.9; CO2 ~600 p.p.m.; 21 μM nitrate). Emiliania huxleyi strain CCMP 88E showed no differences in growth rate or in cellular content or production rates of particulate organic (POC) and inorganic (PIC) carbon and cellular particulate organic nitrogen (PON) between treatments using water from 1,000 m and 4,800 m. However, despite the N:P ratio of seawater being comparable in water from ~1,000 and ~4,800 m, the PON production rates were three times lower in one incubation using water from ~1,000 m compared to values observed in water from ~4,800 m. Thus, the POC:PON ratios were threefold higher in cells that were incubated in ~1,000 m seawater. The heavily calcified strain NZEH exhibited lower growth rates and PIC production rates when incubated in water from ~4,800 m compared to ~1,000 m, while cellular PIC, POC and PON were higher in water from 4,800 m. Calcite Sr/Ca ratios increased with depth despite constant seawater Sr/Ca, indicating that upwelling changes coccolith geochemistry. Our study provides the first experimental and field trial of a geoengineering approach to test how deep seawater impacts coccolithophore physiological and biogeochemical properties. Given that coccolithophore growth was only stimulated using waters obtained from >1,000 m, artificial upwelling using shallower waters may not be a suitable approach for promoting carbon sequestration for some locations and assemblages, and should therefore be investigated on a site-by-site basis.