Imaging of renal medullary carcinoma in children and young adults: a report from the Children's Oncology Group.
Renal medullary carcinoma is a rare renal malignancy of childhood. There are no large series describing the imaging appearance of renal medullary carcinoma in children. To characterize the clinical and imaging features of pediatric renal medullary carcinoma at initial presentation. We retrospectively analyzed images of 25 pediatric patients with renal medullary carcinoma enrolled in the Children's Oncology Group renal tumors classification, biology and banking study (AREN03B2) from March 2006 to August 2016. Imaging findings of the primary mass, and patterns of locoregional and distant spread were evaluated in correlation with pathological and surgical findings. Median age at presentation was 13 years (range: 6-21 years), with a male predominance (3.2:1). The overall stage of disease at initial presentation was stage 1 in 1, stage 2 in 2 and stage 4 in 22. Maximum diameter of the primary renal mass ranged from 1.6 to 10.3 cm (mean: 6.6 cm) with a slight right side predilection (1.5:1). Enlarged (>1 cm short axis) retroperitoneal lymph nodes were identified at initial staging in 20/25 (80%) cases, 10 of which were histologically confirmed while the others did not undergo surgical sampling. Enlarged lymph nodes were also identified in the mediastinum (14/25; 56%) and supraclavicular regions (4/25; 16%). Metastatic disease was present in the lungs in 19/25 (76%) and liver in 6/25 (24%). The pattern of lung metastases was pulmonary lymphangitic carcinomatosis: 10 cases (9 bilateral, 1 unilateral), pulmonary nodules with indistinct margins: 6 cases, pulmonary nodules with distinct margins: 2 cases, while 1 case had pulmonary nodules with both indistinct and distinct margins. Pulmonary lymphangitic carcinomatosis was pathologically confirmed in 4/10 cases. All cases with pulmonary lymphangitic carcinomatosis had associated enlarged mediastinal lymph nodes. Renal medullary carcinoma in children and young adults presents at an advanced local and distant stage in the majority of patients. The diagnosis of renal medullary carcinoma should be considered when a child or young adult presents with a poorly defined/infiltrative, centrally located renal mass, especially in the setting of known sickle cell hemoglobinopathy. Distant metastases are common at initial presentation in the lungs, distant lymph nodes and liver and often involve multiple sites simultaneously. Pulmonary lymphangitic carcinomatosis, a distinctive and uncommon form of lung metastasis in children, is common in this patient population.


Youth Screen Time and Behavioral Health Problems: The Role of Sleep Duration and Disturbances.
The purpose of this study was to examine the indirect effect of youth screen time (e.g., television, computers, smartphones, video games, and tablets) on behavioral health problems (i.e., internalizing, externalizing, and peer problems) through sleep duration and disturbances. The authors assessed a community sample of parents with a child in one of the following three developmental stages: young childhood (3-7 yrs; N = 209), middle childhood (8-12 yrs; N = 202), and adolescence (13-17 yrs; N = 210). Path analysis was used to test the hypothesized indirect effect model. Findings indicated that, regardless of the developmental stage of the youth, higher levels of youth screen time were associated with more sleep disturbances, which, in turn, were linked to higher levels of youth behavioral health problems. Children who have increased screen time are more likely to have poor sleep quality and problem behaviors.


Vitamin D insufficiency is common in Ugandan children and is associated with severe malaria.
Vitamin D plays an increasingly recognized role in the innate and adaptive immune response to infection. Based on demonstrated roles in up-regulating innate immunity, decreasing inflammation, and reducing the severity of disease in illnesses such as tuberculosis and influenza, we hypothesized that poor vitamin D status would be associated with severe malaria. We measured 25-hydroxyvitamin D [25(OH)D] by immunoassay in a sample of Ugandan children aged 18 months-12 years with severe malaria (cerebral malaria or severe malarial anemia, n = 40) and in healthy community children (n = 20). Ninety-five percent of children with severe malaria (n = 38) and 80% of control children (n = 16) were vitamin D-insufficient [plasma 25(OH)D <30 ng/mL]. Mean plasma 25(OH)D levels were significantly lower in children with severe malaria than in community children (21.2 vs. 25.3 ng/mL, p = 0.03). Logistic regression revealed that for every 1 ng/mL increase in plasma 25(OH)D, the odds of having severe malaria declined by 9% [OR = 0.91 (95% CI: 0.84, 1.0)]. These preliminary results suggest that vitamin D insufficiency may play a role in the development of severe malaria. Further prospective studies in larger cohorts are indicated to confirm the relationship of vitamin D levels to severity of malaria infection and to investigate causality.


Safety of non-steroidal anti-inflammatory drugs, including aspirin and paracetamol (acetaminophen) in people receiving methotrexate for inflammatory arthritis (rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, other spondyloarthritis).
Methotrexate is routinely used in the treatment of inflammatory arthritis. There have been concerns regarding the safety of using concurrent non-steroidal anti-inflammatory drugs (NSAIDs), including aspirin, or paracetamol (acetaminophen), or both, in these people. To systematically appraise and summarise the scientific evidence on the safety of using NSAIDs, including aspirin, or paracetamol, or both, with methotrexate in inflammatory arthritis; and to identify gaps in the current evidence, assess the implications of those gaps and to make recommendations for future research to address these deficiencies. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, second quarter 2010); MEDLINE (from 1950); EMBASE (from 1980); the Cochrane Database of Systematic Reviews (CDSR) and the Database of Abstracts of Reviews of Effects (DARE). We also handsearched the conference proceedings for the American College of Rheumatology (ACR) and European League against Rheumatism (EULAR) (2008 to 2009) and checked the websites of regulatory agencies for reported adverse events, labels and warnings. Randomised controlled trials and non-randomised studies comparing the safety of methotrexate alone to methotrexate with concurrent NSAIDs, including aspirin, or paracetamol, or both, in people with inflammatory arthritis. Two authors independently assessed the search results, extracted data and assessed the risk of bias of the included studies. Seventeen publications out of 8681 identified studies were included in the review, all of which included people with rheumatoid arthritis using various NSAIDs, including aspirin. There were no identified studies for other forms of inflammatory arthritis.For NSAIDs, 13 studies were included that used concurrent NSAIDs, of which nine studies examined unspecified NSAIDs. The mean number of participants was 150.4 (range 19 to 315), mean duration 2182.9 (range 183 to 5490) days, although the study duration was not always clearly defined, and the studies were mainly of low to moderate quality. Two of these studies reported no evidence for increased risk of methotrexate-induced pulmonary disease; one study assessed the effect of concurrent NSAIDs on renal function and found no adverse effect; one study identified no adverse effect on liver function; three studies demonstrated no increase in methotrexate withdrawal; and one study showed no increase in all adverse events, including major toxic reactions. However, transient thrombocytopenia was demonstrated in one study, specifically when NSAIDs were taken on the same week day as methotrexate. This study was a retrospective review that involved small numbers only and was of moderate quality; these finding have not been replicated since.Four studies looked at specific NSAIDs (etodolac, piroxicam, celecoxib and etoricoxib), with a mean number of participants of 25.8 (range 14 to 50) and mean study duration of 16.8 (range 14 to 23) days. These studies were mainly of moderate quality. The studies were primarily pharmacokinetic studies but also reported adverse events as secondary outcomes. There were no clinically significant adverse effects with concomitant piroxicam or etodolac; and only mild adverse events with celecoxib or etoricoxib, such as nausea and vomiting, and headaches.For aspirin, seven studies provided data on adverse events with the use of aspirin and methotrexate. These studies included a mean number of participants of 100 (range 11 to 232), had a mean duration of 1325 (range 8 to 2928) days and were mainly of low to moderate quality. Two of the studies reported no evidence for increased risk of methotrexate-induced pulmonary disease and two studies showed no increase in all adverse events including major toxic reactions; however, none of these studies specified the dose of aspirin that was used. One study demonstrated that concurrent aspirin adversely affected liver function at a mean dose of 6.84 tablets of aspirin per day, which is a possible daily dose of 2.1 g presuming that 300 mg aspirin tablets were given. A further study described a partially reversible decline in renal function with 2 g daily of aspirin. One study reported no increase in adverse events with 975 g aspirin daily, however the study duration was only one week.For paracetamol, no studies were identified for inclusion. In the management of rheumatoid arthritis, the concurrent use of NSAIDs with methotrexate appears to be safe provided appropriate monitoring is performed. The use of anti-inflammatory doses of aspirin should be avoided.


Predictive Value of Blood N-Terminal Pro-Brain Natriuretic Peptide Concentrations for Early Patent Ductus Closure in Very Preterm Infants.
It has been shown that blood concentrations of NT-proBNP may be useful in identifying preterm infants at risk of hemodynamically significant patent ductus arteriosus and its complications. The aim of the study was to assess predictive value of serum NT-proBNP levels for early ductus arteriosus (DA) closure in very preterm newborns. Fifty-two infants <32 weeks' gestation aged <72 hours with patent ductus arteriosus (PDA) diameter >1.5 mm were involved in a randomized study. Twenty-seven (52%) of them were treated with ibuprofen or paracetamol starting within the first 3 days of life. Expectant management was applied to 25 (48%) infants. All patients underwent planned echocardiographic (daily) and two serum NT-proBNP measurements within the first 10 days after birth. Depending on the DA closure within the first 10 days of life, 2 groups of patients were formed retrospectively, with closed (n = 30) or patent (n = 22) DA by this age. In the first 10 days of life, DA closure occurred in 19 (70%) treated infants and in 11 (44%) infants managed expectantly (p > 0,05). Initial concentrations of NT-proBNP were significantly higher in infants that had patent ductus arteriosus (PDA) at 10 days of life. By the eighth day, median NT-proBNP values in both groups significantly decreased but remained considerably higher in newborns with PDA. NT-proBNP serum concentrations on the second day of life could reliably predict DA closure within the first 10 days after birth in treated babies (the AUC was significant 0.81 [95% CI: 0.58-1.03], p < 0.05) but not in infants who were managed expectantly. Serum NT-proBNP concentrations on the second day of life could reliably predict early PDA closure in treated but not in expectantly managed very preterm infants.


Master of the master gland: Choh Hao Li, the University of California, and science, migration, and race.
This essay examines the origins of the relationship between Choh Hao Li and the University of California, Berkeley. Li came to the United States from China in 1935 for graduate study at the University of Michigan, but ended up enrolling at Berkeley. Over the course of the next two decades, Li went from being a foreign graduate student in chemistry on a temporary visa to an internationally recognized leader in the biochemistry of endocrinology at the head of his own laboratory and a naturalized citizen of the United States. At what was otherwise a dark time for Americans of Chinese descent, Li was garnering adulation in the popular press. He was called the "master of the master gland" for his successes both in isolating and in synthesizing pituitary hormones. Specifically, the essay explores the making of the "master of the master gland" from the perspectives of the history of science and the history of race and migration in the United States, tracing the interplay among Li's scientific work, his migrations, his career aspirations, and his legal status in the United States. A Chinese intellectual cast adrift by the shifting geopolitics of World War II and the early Cold War, Li danced delicately along the margins of membership in American society during the 1940s, only arriving at what turned out to be his final destination after careful and protracted negotiations with officials of the U.S. government, with influential members of the international scientific community, and with representatives of the University of California, Berkeley.


Identification of potential target genes for RFX4_v3, a transcription factor critical for brain development.
Regulatory factor X4 variant transcript 3 (Rfx4_v3) gene disruption in mice demonstrated that interruption of a single allele (heterozygous, +/-) prevented formation of the subcommissural organ, resulting in congenital hydrocephalus, while interruption of two alleles (homozygous, -/-) caused fatal failure of dorsal midline brain structure formation. To identify potential target genes for RFX4_v3, we used microarray analysis to identify differentially expressed genes in Rfx4_v3-deficient mouse brains at embryonic day 10.5, before gross structural changes were apparent. Of 109 differentially expressed transcripts, 24 were chosen for validation and 22 were confirmed by real-time PCR. Many validated genes encoded critical proteins involved in brain morphogenesis, such as the signaling components in the Wnt, bone morphogenetic protein (BMP) and retinoic acid (RA) pathways. Cx3cl1, a CX3C-type chemokine gene that is highly expressed in brain, was down-regulated in the Rfx4_v3-null mice. Both human and mouse Cx3cl1 proximal promoters contained highly conserved X-boxes, known cis-acting elements for RFX protein binding. Using the Cx3cl1 promoter as an example of a target gene, we demonstrated direct binding of RFX4_v3 to the Cx3cl1 promoter, and trans-acting activity of RFX4_v3 protein to stimulate gene expression. These data suggest that RFX4_v3 may act upstream of critical signaling pathways in the process of brain development.


Measurements of fluorine in contemporary urban Canadians: a comparison of the levels found in human bone using in vivo and ex vivo neutron activation analysis.
Non-invasive in vivo neutron activation analysis (NAA) was used to measure the fluorine concentration in 35 people in Hamilton, Ontario, Canada. Measurement and precision data of this second generation NAA system were determined in 2013, and the results were compared with the performance of a first generation system used in a pilot study of 33 participants from the Hamilton area in 2008. Improvements in precision in line with those predicted by phantom studies were observed, but the use of fewer technicians during measurement seemed adversely to affect performance. We compared the levels of fluorine observed in people between the two studies and found them to be comparable. The average fluorine concentration in bone was found to be 3 ± 0.3 mg and 3.5 ± 0.4 mg F/g Ca for 2013 and 2008 measurements respectively. Ten people were measured in both studies; the observed average change in bone fluorine in this subgroup was consistent with that predicted by the observation of the relationship between bone fluorine and age in the wider group. In addition, we observed differences in the relationship between bone fluorine level and age between men and women, which may be attributable either to sex or gender differences. The rate of increase in fluorine content for men was found to be 0.096 ± 0.022 mg F/g Ca per year while the rate of increase for women was found to be slightly less than half that of men, 0.041 ± 0.017 mg F/g Ca per year. A discontinuity in the rate of increase in fluorine content with age was observed in women at around age 50. Bone fluorine content was significantly lower ([Formula: see text]) in women age 50 to 59 than in women age 40 to 49, which we suggest may be attributable to bone metabolism changes associated with menopause. We also observed increased fluorine levels in tea drinkers as compared to non-tea drinkers, suggesting tea may be a significant source of exposure in Canada. The rate of increase in fluorine content of the tea drinkers and the non-tea drinkers were found to be 0.127 (± 0.029) and 0.050 (± 0.009) mg F/g Ca per year respectively. Finally, we also obtained twelve bone samples from cadavers' skulls. Neutron activation analysis was used to determine the fluorine levels in these ex vivo samples. The rate of increase of fluorine content versus age for in vivo and ex vivo measurements were found to be 0.078 ± 0.014 and 0.078 ± 0.050 mg F/g Ca per year respectively. Excellent agreement was found between the fluorine levels determined in vivo and ex vivo using the two separate systems, providing confidence in the fluorine concentration data being measured in vivo.


Dry-coated live viral vector vaccines delivered by nanopatch microprojections retain long-term thermostability and induce transgene-specific T cell responses in mice.
The disadvantages of needle-based immunisation motivate the development of simple, low cost, needle-free alternatives. Vaccine delivery to cutaneous environments rich in specialised antigen-presenting cells using microprojection patches has practical and immunological advantages over conventional needle delivery. Additionally, stable coating of vaccine onto microprojections removes logistical obstacles presented by the strict requirement for cold-chain storage and distribution of liquid vaccine, or lyophilised vaccine plus diluent. These attributes make these technologies particularly suitable for delivery of vaccines against diseases such as malaria, which exerts its worst effects in countries with poorly-resourced healthcare systems. Live viral vectors including adenoviruses and poxviruses encoding exogenous antigens have shown significant clinical promise as vaccines, due to their ability to generate high numbers of antigen-specific T cells. Here, the simian adenovirus serotype 63 and the poxvirus modified vaccinia Ankara--two vectors under evaluation for the delivery of malaria antigens to humans--were formulated for coating onto Nanopatch microprojections and applied to murine skin. Co-formulation with the stabilising disaccharides trehalose and sucrose protected virions during the dry-coating process. Transgene-specific CD8(+) T cell responses following Nanopatch delivery of both vectors were similar to intradermal injection controls after a single immunisation (despite a much lower delivered dose), though MVA boosting of pre-primed responses with Nanopatch was found to be less effective than the ID route. Importantly, disaccharide-stabilised ChAd63 could be stored for 10 weeks at 37°C with less than 1 log10 loss of viability, and retained single-dose immunogenicity after storage. These data support the further development of microprojection patches for the deployment of live vaccines in hot climates.


Instrumental variable analysis to compare effectiveness of stents in the extremely elderly.
Evaluating novel therapies is challenging in the extremely elderly. Instrumental variable methods identify variables associated with treatment allocation to perform adjusted comparisons that may overcome limitations of more traditional approaches. Among all patients aged ≥85 years undergoing percutaneous coronary intervention in nonfederal hospitals in Massachusetts between 2003 and 2009 (n=2690), we identified quarterly drug-eluting stent (DES) use rates as an instrumental variable. We estimated risk-adjusted differences in outcomes for DES versus bare metal stents using a 2-stage least squares instrumental variable analysis method. Quarterly DES use ranged from 15% to 88%. Unadjusted 1-year mortality rates were 14.5% for DES versus 23.0% for bare metal stents (risk difference, -8.5%; P<0.001), an implausible finding compared with randomized trial results. Using instrumental variable analysis, DES were associated with no difference in 1-year mortality (risk difference, -0.8%; P=0.76) or bleeding (risk difference, 2.3%; P=0.33) and with significant reduction in target vessel revascularization (risk difference, -8.3%; P<0.0001). Using an instrumental variable analysis, DES were associated with similar mortality and bleeding and a significant reduction in target vessel revascularization compared with bare metal stents in the extremely elderly. Variation in use rates may be useful as an instrumental variable to facilitate comparative effectiveness in groups underrepresented in randomized trials.


HIV prevalence and incidence in rural Tanzania: results from 10 years of follow-up in an open-cohort study.
Tanzanian antenatal clinic surveillance data suggest stabilizing HIV levels. Data from an open cohort in northern Tanzania provide robust estimates of prevalence and incidence. Between 1994 and 2004, 19 rounds of household-based demographic surveillance and 4 rounds of individually linked HIV serologic surveys were conducted. Longitudinal knowledge of individuals' testing histories is used to allow for effects of selective participation on prevalence estimates; multiple imputation procedures allow for interval censoring effects on incidence. A total of 16,820 adults donated blood for HIV testing in at least 1 of 4 serologic surveys. HIV prevalence increased steadily from 6.0% in 1994/1995 to 8.3% in 2000/2001, leveling out thereafter. HIV incidence increased sharply from 0.8% in 1994 to 1997 to 1.2% per thousand in 1997 to 2000, remaining high (1.1%) in 2000 to 2003. In roadside areas, incidence fell in the last interval, especially among women, but in remote rural areas, incidence rose slightly. HIV spread is continuing in rural areas, suggesting a need for more intensive HIV prevention efforts and antiretroviral interventions. The leveling off in prevalence is attributable to a combination of high mortality among HIV-infected persons and a slight decrease in incidence in roadside villages.


Folding pathway of the b1 domain of protein G explored by multiscale modeling.
The understanding of the folding mechanisms of single-domain proteins is an essential step in the understanding of protein folding in general. Recently, we developed a mesoscopic CA-CB side-chain protein model, which was successfully applied in protein structure prediction, studies of protein thermodynamics, and modeling of protein complexes. In this research, this model is employed in a detailed characterization of the folding process of a simple globular protein, the B1 domain of IgG-binding protein G (GB1). There is a vast body of experimental facts and theoretical findings for this protein. Performing unbiased, ab initio simulations, we demonstrated that the GB1 folding proceeds via the formation of an extended folding nucleus, followed by slow structure fine-tuning. Remarkably, a subset of native interactions drives the folding from the very beginning. The emerging comprehensive picture of GB1 folding perfectly matches and extends the previous experimental and theoretical studies.


Monitoring of organochlorine pesticides in blood of women with uterine cervix cancer.
In Yucatan, Mexico, chronic exposure of Mayan population to pesticides is expected as about 30 per cent are drinking polluted water. Residues of organochlorine pesticides (OCP) were monitored in 18 municipalities of Yucatan with high mortality rates due to uterine cervix cancer. 70 blood samples collected from Mayan women living in livestock, agricultural and metropolitan area were analyzed for OCP. Solid Phase Extraction was performed on C18 cartridges and analyzed by Gas Chromatography with Electron Capture Detector. The results showed that the highest OCP levels were detected in blood of women living in the livestock area. OCP detected were endosulfan I (7.35 μg/mL), aldrin (3.69 μg/mL), 4,4' DDD (2.33 μg/mL), 1.39 and 1.46 μg/mL of δ-HCH. Women from the agricultural area had high concentrations of OCP in their blood, particularly dieldrin (1.19 μg/mL), and 1.26 μg/mL of 4,4' DDE. In the metropolitan area, 0.080 μg/mL of γ-HCH and 0.064 μg/mL of heptachlore were detected. This monitoring study was also based on epidemiological data of uterine cervical cancer. It was found that environmental factors may have facilitated the infiltration of OCP to the aquifer used for potable water supply. These factors in addition to poverty can have impacts on public health. This first exploratory study suggests that monitoring of OCP in human is important for the establishment of health promotion programs. The integrative analysis of both, environmental and social factors would be helpful to characterize the bioaccumulation of pesticides in humans.


Emerging roles for centromere-associated proteins in DNA repair and genetic recombination.
Centromere proteins CENP-S and CENP-X are members of the constitutive centromere-associated network, which is a conserved group of proteins that are needed for the assembly and function of kinetochores at centromeres. Intriguingly CENP-S and CENP-X have alter egos going by the names of MHF1 (FANCM-associated histone-fold protein 1) and MHF2 respectively. In this guise they function with a DNA translocase called FANCM (Fanconi's anemia complementation group M) to promote DNA repair and homologous recombination. In the present review we discuss current knowledge of the biological roles of CENP-S and CENP-X and how their dual existence may be a common feature of CCAN (constitutive centromere-associated network) proteins.


Emerging biomarkers in head and neck cancer in the era of genomics.
Head and neck cancer (HNC) broadly includes carcinomas arising from the mucosal epithelia of the head and neck region as well as various cell types of salivary glands and the thyroid. As reflected by the multiple sites and histologies of HNC, the molecular characteristics and clinical outcomes of this disease vary widely. In this Review, we focus on established and emerging biomarkers that are most relevant to nasopharyngeal carcinoma and head and neck squamous-cell carcinoma (HNSCC), which includes primary sites in the oral cavity, oropharynx, hypopharynx and larynx. Applications and limitations of currently established biomarkers are discussed along with examples of successful biomarker development. For emerging biomarkers, preclinical or retrospective data are also described in the context of recently completed comprehensive molecular analyses of HNSCC, which provide a broad genetic landscape and molecular classification beyond histology and clinical characteristics. We will highlight the ongoing effort that will see a shift from prognostic to predictive biomarker development in HNC with the goal of delivering individualized cancer therapy.


Wavelength independent multimode interference coupler.
We propose an ultra-broadband multimode interference (MMI) coupler with a wavelength range exceeding the O, E, S, C, L and U optical communication bands. For the first time, the dispersion property of the MMI section is engineered using a subwavelength grating structure to mitigate wavelength dependence of the device. We present a 2 × 2 MMI design with a bandwidth of 450nm, an almost fivefold enhancement compared to conventional designs, maintaining insertion loss, power imbalance and MMI phase deviation below 1dB, 0.6dB and 3°, respectively. The design is performed using an in-house tool based on the 2D Fourier Eigenmode Expansion Method (F-EEM) and verified with a 3D Finite Difference Time Domain (FDTD) simulator.


Two-year, randomized, controlled study of safinamide as add-on to levodopa in mid to late Parkinson's disease.
In a 6-month double-blind, placebo-controlled study of Parkinson's disease patients with motor fluctuations, safinamide 50 and 100 mg/d significantly increased ON-time without increasing dyskinesia. Further long-term safinamide use in these patients was evaluated over an additional 18 months. Patients continued on their randomized placebo, 50, or 100 mg/d safinamide. The primary endpoint was change in Dyskinesia Rating Scale total score during ON-time over 24 months. Other efficacy endpoints included change in ON-time without troublesome dyskinesia, changes in individual diary categories, depressive symptoms, and quality of life measures. Change in Dyskinesia Rating Scale was not significantly different in safinamide versus placebo groups, despite decreased mean total Dyskinesia Rating Scale with safinamide compared with an almost unchanged score in placebo. Ad hoc subgroup analysis of moderate to severe dyskinetic patients at baseline (36% of patients) showed a decrease with safinamide 100 mg/d compared with placebo (P = 0.0317). Improvements in motor function, activities of daily living, depressive symptoms, clinical status, and quality of life at 6 months remained significant at 24 months. Adverse events and discontinuation rates were similar with safinamide and placebo. This 2-year, controlled study of add-on safinamide in mid-to-late Parkinson's disease with motor fluctuations, although not demonstrating an overall difference in dyskinesias between patients and controls, showed improvement in dyskinesia in patients at least moderately dyskinetic at baseline. The study additionally demonstrated significant clinical benefits in ON-time (without troublesome dyskinesia), OFF-time, activities of daily living, motor symptoms, quality of life, and symptoms of depression.


Mobility and Reactivity of Cu+ Species in Cu-CHA Catalysts under NH3-SCR-NOx Reaction Conditions: Insights from AIMD Simulations.
The mobility of the copper cations acting as active sites for the selective catalytic reduction of nitrogen oxides with ammonia in Cu-CHA catalysts varies with temperature and feed composition. Herein, the migration of [Cu(NH3)2]+ complexes between two adjacent cavities of the chabazite structure, including other reactant molecules (NO, O2, H2O, and NH3), in the initial and final cavities is investigated using ab initio molecular dynamics (AIMD) simulations combined with enhanced sampling techniques to describe hopping events from one cage to the other. We find that such diffusion is only significantly hindered by the presence of excess NH3 or NO in the initial cavity, since both reactants form with [Cu(NH3)2]+ stable intermediates which are too bulky to cross the 8-ring windows connecting the cavities. The presence of O2 modifies strongly the interaction of NO with Cu+. At low temperatures, we observe NO detachment from Cu+ and increased mobility of the [Cu(NH3)2]+ complex, while at high temperatures, NO reacts spontaneously with O2 to form NO2. The present simulations give evidence for recent experimental observations, namely, an NH3 inhibition effect on the SCR reaction at low temperatures, and transport limitations of NO and NH3 at high temperatures. Our first principle simulations mimicking operating conditions support the existence of two different reaction mechanisms operating at low and high temperatures, the former involving dimeric Cu(NH3)2-O2-Cu(NH3)2 species and the latter occurring by direct NO oxidation to NO2 in one single cavity.


Population attributable fractions of psychopathology and suicidal behaviour associated with childhood adversities in Northern Ireland.
Childhood adversities are strong predictors of psychopathology and suicidality. However, specific adversities are associated with different outcomes, with cross-national variations reported. The current study examined rates of adversities reported in Northern Ireland (NI), and associations between adverse childhood experiences and psychopathology and suicidal behaviour were explored. Data was obtained from the Northern Ireland Study of Health and Stress (NISHS), conducted as part of the World Mental Health (WMH) survey initiative (2004-2008); response rate 68.4% (n = 1,986). The on-line survey used, the WHO Composite International Diagnostic Interview (CIDI) to examine psychopathology and associated risk factors in the NI population. Prevalence rates of retrospectively reported childhood adversities were calculated, with gender and age variations explored. Females were more likely to experience sexual abuse. Individuals who grew up during the worst years of the civil conflict in NI experienced elevated levels of childhood adversities. Participants who endured childhood adversities were more likely to have mental health problems but variations in risk factors were found for different disorders. Parental mental illness was associated with all disorders however, with ORs ranging from 2.20 for mood disorders to 4.07 for anxiety disorders. Population attributable fractions (PAF) estimated the reduction in psychopathology and suicidal behaviour in the population if exposure to adverse childhood events had not occurred. The highest PAF values were revealed for parental mental illness and sexual abuse. The findings indicate that a substantial proportion of psychopathology and suicide risk in NI are attributable to childhood adversities, providing support for early intervention and prevention initiatives.


Simulating Hamiltonian dynamics with a truncated Taylor series.
We describe a simple, efficient method for simulating Hamiltonian dynamics on a quantum computer by approximating the truncated Taylor series of the evolution operator. Our method can simulate the time evolution of a wide variety of physical systems. As in another recent algorithm, the cost of our method depends only logarithmically on the inverse of the desired precision, which is optimal. However, we simplify the algorithm and its analysis by using a method for implementing linear combinations of unitary operations together with a robust form of oblivious amplitude amplification.


A study of properties and abundance of the components of liver carnitine palmitoyltransferases in mitochondrial inner and outer membranes. Effects of hypothyroidism, fasting and a ketotic diabetic state.
1. Liver mitochondrial outer and inner membranes were isolated from normal, 48 h-fasted, streptozotocin-diabetic and hypothyroid rats. 2. Relative to membrane protein, fasting and diabetes substantially increased the activity of carnitine palmitoyltransferase (CPT) in outer membranes. Inner-membrane CPT specific activity was only slightly altered, being increased in diabetes and decreased in hypothyroidism. Abundance of an inner-membrane Mr-68,000 polypeptide that cross-reacted with an anti-CPT serum was significantly increased in diabetes and hypothyroidism. Relative to inner-membrane CPT activity, this cross-reactivity was increased by 37% in diabetes and by 400% in hypothyroidism, suggesting modification of the intrinsic activity of the CPT in these states. 3. CPT in outer membranes was inhibitable by malonyl-CoA, whereas inner-membrane CPT was insensitive to malonyl-CoA. Fasting and diabetes increased the IC50 (concentration of malonyl-CoA causing 50% inhibition) for outer-membrane CPT, whereas the IC50 was decreased in hypothyroidism. 4. Binding of [14C]malonyl-CoA was observed with both outer and inner membranes and was fitted to two-site models in each case. Fasting, diabetes and hypothyroidism changed the KD for binding at the higher-affinity site in outer membranes in a manner that correlated closely with changes in IC50 for inhibition of outer-membrane CPT by malonyl-CoA. Fasting and diabetes increased the abundance of this outer-membrane high-affinity malonyl-CoA-binding site, whereas hypothyroidism decreased its abundance.


Human echo perception.
It has been shown that human test subjects have the ability, under controlled laboratory conditions, to use echoes to detect the presence or absence of targets placed before them. In addition, blind and sighted persons have been able to detect a target monaurally, to make simple shape discriminations, and to locate a target in space. Signal, environmental, and individual variability affect performance in a measurable fashion. This research is an initial step in measuring the limits of a human being's ability to use echoes as a source of information about his physical surroundings. At this point it seems unlikely that the unaided human ear can rival the bat's auditory system for echo perception. It may be, however, that modern technology can partially bridge the evolutionary gap and bring more useful echoes to man's ear than those it now receives. Such an accomplishment would allow us to examine the extent to which man might benefit from this means of sensing his environment.


Tachycardia-Induced J-Wave Changes in Patients With and Without Idiopathic Ventricular Fibrillation.
To know the underlying mechanisms of J waves, the response to atrial pacing was studied in patients with idiopathic ventricular fibrillation (IVF) and patients with non-IVF. In 8 patients with IVF, the J-wave amplitude was measured before, during, and after atrial pacing. All patients had episodes of ventricular fibrillation without structural heart disease. The responses of J waves were compared with those of the 17 non-IVF control subjects who revealed J waves but no history of cardiac arrest and underwent electrophysiological study. The IVF patients were younger than the non-IVF patients (28±10 versus 52±14 years, respectively; P=0.002) and had larger J waves with more extensive distribution. J waves decreased from 0.35±0.26 to 0.22±0.23 mV (P=0.025) when the RR intervals were shortened from 782±88 to 573±162 ms (P=0.001). A decrease (≥0.05 mV) in the J-wave amplitude was observed in 6 of the 8 patients. In addition, 1 patient showed a distinct reduction of J waves in the unipolar epicardial leads. In contrast, J waves were augmented in the 17 non-IVF subjects from 0.27±0.09 to 0.38±0.10 mV (P<0.001): augmented in 9 and unchanged in the 8 subjects. The different response patterns of J waves to rapid pacing suggest different mechanisms: early repolarization in IVF patients and conduction delay in non-IVF patients. The response to atrial pacing was different between the IVF and non-IVF patients, which suggests the presence of different mechanisms for the genesis of J waves.


Subcutaneous nodules as the first clinical manifestation of sarcoidosis.
We report the case of a 61-year-old male who presented with a febrile illness accompanied by arthralgia and myalgia. Two months later he developed multiple subcutaneous nodules and enlarged parotid glands. Later two erythematous plaques, clinically compatible with erythema nodosum (EN), were observed. Laboratory investigations revealed abnormal levels of angiotensin converting enzyme and chest radiography showed bilateral hilar enlargement. The biopsy of the cutaneous lesions demonstrated multiple non-caseating granulomas in the subcutaneous tissue without any alterations in the epidermis and the dermis. The cultures for Mycobacteria and fungi were both negative. The clinical picture and histopathological findings were compatible with subcutaneous nodular sarcoidosis. The response to steroid treatment was satisfactory.


An unusual cause for hyponatremia with seizures.
A 50-year-old Asian Indian female with known hypertension presented with persistent vomiting but no other symptoms of meningism. Clinical examination and basic laboratory parameters were entirely normal except for significant hyponatremia. Further investigation was suggestive of the syndrome of inappropriate antidiuretic hormone (SIADH) secretion. Subsequently, despite steady correction of hyponatremia, the patient developed generalised seizures. Cerebrospinal fluid (CSF) analysis performed was inconclusive. Screening for a chronic meningitis underlying SIADH, yielded positive blood and CSF titres for venereal disease research laboratory (VDRL), which were confirmed by Treponema pallidum haemagglutination (TPHA). The patient was treated for neurosyphilis and made a complete recovery. Hyponatremia resolved and she had no further episodes of seizures. She was tested for HIV infection which was negative. On follow-up, she remained TPHA positive but VDRL titres became negative.


Estradiol 17 beta-D-glucuronide is a high-affinity substrate for oatp organic anion transporter.
Although substantial evidence indicates that estradiol-17 beta (E2) is conjugated to the glucuronide in the kidney and then excreted by a direct tubular secretory route and that the liver transports E2 glucuronides via carrier-mediated mechanisms, the transporters involved in these processes have not been identified. The so-called "organic anion-transporting polypeptide" (i.e., oatp) has a number of known substrates, including bromosulfophthalein (BSP) and taurocholic acid (TCA) (E. Jacquemin, B. Hagenbuch, B. Stieger, A. W. Wolkoff, and P. J. Meier. Proc. Natl. Acad. Sci. USA 91: 133-137, 1994). In a companion study, we determined that steroid hormones represent a class of hormones that interact strongly with oatp when the latter is transiently expressed in vitro. Here, we studied more extensively steroids and steroid anion conjugates as candidate oatp substrates. In HeLa cell monolayers transfected with a full-length oatp cDNA, [3H]estradiol 17 beta-D-glucuronide ([3H]E2-17G) was transported with a signal-to-noise ratio of 15:1 over that of monolayers transfected with a control plasmid. The affinity of oatp for [3H]E2-17G was significantly higher than that for TCA (K(m) of 3 microM vs. 27 microM, respectively). In contrast to E2-17G, unconjugated estradiol (E2) was not significantly transported by oatp. Several unconjugated steroids and anionic steroid conjugates were tested for their ability to compete with tracer E2-17G for oatp-mediated transport. Conjugation at the 17 or 3 position with the anion of a strong acid (sulfate) resulted in a greater degree of inhibition of tracer E2-17G transport than did conjugation at the 17 or 3 position with an uncharged group (acetate), suggesting that the strength of the negative charge at these positions is an important determinant of the affinity of a given steroid conjugate for oatp. We conclude that the preferred substrates for oatp are steroids with a strong 17- or 3-position anionic group. Since steroid sulfotransferases and glucuronosyltransferases are expressed in the proximal tubule, as is oatp, the transporter may serve as an apical exit pathway for steroids following their conjugation within the tubule cell.


Retrotaxis of human neutrophils during mechanical confinement inside microfluidic channels.
The current paradigm of unidirectional migration of neutrophils from circulation to sites of injury in tissues has been recently challenged by observations in zebrafish showing that neutrophils can return from tissues back into the circulation. However, the relevance of these observations to human neutrophils remains unclear, the forward and reverse migration of neutrophils is difficult to quantify, and the precise conditions modulating the reverse migration cannot be isolated. Here, we designed a microfluidic platform inside which we observed human neutrophil migration in response to chemoattractant sources inside channels, simulating the biochemical and mechanical confinement conditions at sites of injury in tissues. We observed that, after initially following the direction of chemoattractant gradients, more than 90% of human neutrophils can reverse their direction and migrate persistently and for distances longer than one thousand micrometers away from chemoattractant sources (retrotaxis). Retrotaxis is enhanced in the presence of lipoxin A4 (LXA4), a well-established mediator of inflammation resolution, or Tempol, a standard antioxidant. Retrotaxis stops after neutrophils encounter targets which they phagocytise or on surfaces presenting high concentrations of fibronectin. Our microfluidic model suggests a new paradigm for neutrophil accumulation at sites of inflammation, which depends on the balance of three simultaneous processes: chemotaxis along diffusion gradients, retrotaxis following mechanical guides, and stopping triggered by phagocytosis.


Intestinal absorption of S-(pentachlorobutadienyl)glutathione and S-(pentachlorobutadienyl)-L-cysteine, the glutathione and cysteine S-conjugates of hexachlorobuta-1,3-diene.
The bioactivation of the nephrotoxin hexachlorobuta-1,3-diene (HCBD) involves hepatic formation and biliary excretion of S-(pentachlorobutadienyl)glutathione (PCBG). The intestinal absorption of PCBG was studied in vivo by introducing PCBG or its metabolite, S-(pentachlorobutadienyl)-L-cysteine (PCBC), into rat intestines via a biliary cannula and measuring PCBG and PCBC concentrations in portal blood. When PCBG was infused into the intestine, both PCBG and PCBC were found in the blood; the highest metabolite concentrations (0.9 nmol/ml for PCBG and 1 nmol/ml for PCBC) were observed 30 min after infusing the S-conjugate. Higher blood PCBC concentrations were observed after PCBC infusion than after PCBG infusion. Transport studies in CaCo-2 cells, a human intestinal cell line, showed that application of PCBG (0.1 mM) to the apical side of the cells resulted in a 2.4-fold accumulation of PCBG in the basolateral chamber after 24 hr; in this time, the cells metabolized 69% of the applied PCBG to PCBC. Addition of glutathione (1 mM), gamma-glutamyl-p-nitroanilide (1 mM), or probenecid (1 mM) to the apical chamber diminished the active transport of PCBG. With PCBC, no active apical or basolateral transport was observed. The experiments are the first demonstration of the intestinal absorption of the S-conjugates of HCBD, which is an important step in their translocation from the liver to the kidney.


Good weight loss responders and poor weight loss responders after Roux-en-Y gastric bypass: clinical and nutritional profiles.
Bariatric surgery is one of the main treatments for severity obesity, but weight regain after surgery is an important issue. To compare the clinical and nutritional profiles of good and poor weight loss responders in the late postoperative period after bariatric surgery. A cross-sectional study with patients undergoing Roux-en-Y gastric bypass in a University Hospital. Patients were divided into good weight loss responders (GWLR) and poor weight loss responders (PWLR) defined as ≥ 50% or < 50% excess weight loss (EWL), respectively, at least 2 years post-surgery. The sample included 204 individuals (87.7% women; mean age 50.15 ± 11.1 years; mean time after surgery 67.38 ± 30.76 months). Two years post-surgery, 71.1% were considered GWLR and 28.9% PWLR (mean EWL 72.33% ± 13.86%, and 35.06% ± 12.10%, respectively; p = 0.000). Weight regain was < 10% for 36.3% of patients, 10.1-20% for 36.3%, and > 20% for 21.3%, compared with the lowest post-surgery weight. Among PWLR, 49.0% regained > 20% of the lowest post-surgery weight. GWLR lost most weight at all time points analyzed (p < 0.05). GWLR presented improvement or remission of diabetes, dyslipidemia and hypertension more frequently compared to PWLR (p < 0.05). Eating patterns was similar between GWLR and PWLR (p > 0.05, study's power 100%). Quality of life improved in 79.5% of the total study sample, with greater improvements in the GWLR (p < 0.05). Greater weight loss correlated with improved remission in comorbidities and better quality of life.


Evaluation of entomopathogenic fungi against chilli thrips, Scirtothrips dorsalis.
Commercial strains of entomopathogenic fungi were evaluated for control of chilli thrips, Scirtothrips dorsalis Hood (Thysanoptera: Thripidae), an invasive pest of ornamental and vegetable plants in the Caribbean and southeastern United States. In laboratory assays, LC50 values against adult S. dorsalis were 5.1 × 10(4) CFU/mL for Beauveria bassiana GHA, with higher values 3.1 × 10(5) for Metarhizium brunneum F52 and 3.8 × 10(5) for Isaria fumosorosea Apopka 97. Second instars were comparatively less susceptible to all isolates, ostensibly due to moulting, with LC50 values of 1.1 × 10(8), 7.0 × 10(5), and 9.9 × 10(5) CFU/spores per mL for GHA, F52, and Apopka 97 strains, respectively. In greenhouse cages, compared with controls, three applications of mycoinsecticides and other biorational insecticides at 7 to 14 day intervals reduced overall S. dorsalis populations on pepper plants Capsicum annuum cv. California Wonder: spinosad reduced populations by 94-99%, M. brunneum F52 by 84-93%, B. bassiana GHA by 81-94%, I. fumosorosea PFR-97 by 62-66%, and different horticultural oils by 58-85%. The proportion of marketable fruit was significantly increased by M. brunneum F52, B. bassiana GHA, and 2% SuffOil-X treatments. Slightly lower levels of control were observed in nursery tests with ornamental rose shrubs, Rosa sp. Red Double Knock Out®, during hot sunny conditions. Four applications reduced thrips populations over 10 weeks: spinosad by an average of 91%, M. brunneum F52 by an average of 81%, B. bassiana GHA by an average of 62%, SuffOil-X by an average of 50%, and I. fumosorosea PFR-97 by an average of 44%. The data show that mycoinsecticides can be used in management strategies for low to moderate populations of S. dorsalis and provide resistance management tools for the limited number of insecticides that are effective against this pest.


Multiple sclerosis and ionizing radiation.
The etiology of multiple sclerosis (MS) may involve exposure to infectious, chemical or physical agents damaging the blood-brain barrier and an autoimmune reaction against myelin breakdown products. Here we report a pooled analysis of 174 MS cases and 815 population controls from two case-control studies with regard to such a potentially damaging exposure, namely X-ray examinations, radiological work and treatment with ionizing radiation. Exposure was assessed by questionnaires to the subjects. We obtained odds ratios of 4.4 (95% confidence interval, CI, 1.6-11.6) and 1.8 (95% CI 1.2-2.6) for radiological work and X-ray examinations, respectively; 5 cases, but no controls, in one of the studies had been treated with ionizing radiation. Our data and some other observations reported in the literature suggest a contributory role for ionizing radiation to the development of MS in some cases.


Association between inflammatory biomarkers and all-cause, cardiovascular and cancer-related mortality.
The inflammatory biomarker α1-acid glycoprotein (AGP) was found to have the strongest association with 5-year mortality in a recent study of 106 biomarkers. We examined whether AGP is a better biomarker of mortality risk than the more widely used inflammatory biomarkers interleukin-6 (IL-6) and C-reactive protein (CRP). We analyzed data for 6545 men and women aged 45-69 (mean 55.7) years from the Whitehall II cohort study. We assayed AGP, IL-6 and CRP levels from fasting serum samples collected in 1997-1999. Mortality followup was until June 2015. Cox regression analysis was used to model associations of inflammatory biomarkers with all-cause, cardiovascular and cancer-related mortality. Over the mean follow-up of 16.7 years, 736 deaths occurred, of which 181 were from cardiovascular disease and 347 from cancer. In the model adjusted for all covariates (age, sex, socioeconomic status, body mass index, health behaviours and chronic disease), AGP did not predict mortality beyond the first 5 years of follow-up; over this period, IL-6 and CRP had stronger associations with mortality. When we considered all covariates and biomarkers simultaneously, AGP no longer predicted all-cause mortality over the entire follow-up period (adjusted hazard ratio [HR] 0.99, 95% confidence interval [CI] 0.90-1.08). Only IL-6 predicted all-cause mortality (adjusted HR 1.22, 95% CI 1.12-1.33) and cancer-related mortality (adjusted HR 1.13, 95% CI 1.00-1.29) over the entire follow-up period, whereas CRP predicted only cardiovascular mortality (adjusted HR 1.30, 95% CI 1.06-1.61). Our findings suggest that AGP is not a better marker of short-or long-term mortality risk than the more commonly used biomarkers IL-6 and CRP.


Low density lipoprotein-cholesterol levels affect vertebral fracture risk in female patients with primary hyperparathyroidism.
Although increased arterial sclerosis and dyslipidemia were observed in primary hyperparathyroidism (pHPT) patients in previous studies, it still remains unclear about the relationships between lipid and bone metabolism in pHPT patients, especially about fracture risk. The present study was performed to examine the relationships between lipid metabolism parameters including body composition and bone metabolism in 116 female patients with pHPT and 116 age-matched control subjects. Bone mineral density (BMD) and body composition were measured by dual-energy x-ray absorptiometry. Serum low density lipoprotein (LDL)-cholesterol (Chol) levels were negatively related to only z-score of BMD at femoral neck and serum creatinine levels. Serum levels of LDL-Chol were significantly lower in the group with vertebral fractures in pHPT patients, although body composition parameters were not significantly different. In univariate logistic regression analyses, age, height, BMD at lumbar spine and radius, serum levels of creatinine, total-Chol and LDL-Chol were significantly selected as a predictor of vertebral fractures. LDL-Chol was related to vertebral fractures independently of the other parameters. In conclusion, the present study demonstrated that lower serum LDL-Chol levels were related to vertebral fracture risk independent of renal function, age, body size, bone metabolism parameters and the severity of the disease in pHPT women.


Corticosteroid-induced diabetes in palliative care.
Corticosteroids are one of the most commonly used medications in palliative care. Although the benefit of corticosteroids generally outweighs the risk in the palliative population, side effects are common and necessitate careful consideration prior to prescribing. In March of 2010, a guideline for monitoring blood glucose values was implemented as part of our standard care within our two inpatient tertiary palliative care units. A retrospective study was conducted, the aim of which was twofold. First, we hoped to determine a prevalence rate for steroid-induced diabetes mellitus (SDM) in palliative care and whether or not screening glucose levels twice weekly was appropriate or required. Second, we wanted to determine if possible predictors existed for the development of SDM in a palliative population, thereby identifying the patients most at risk who would benefit from ongoing glucose monitoring. We found that SDM is more common in palliative care patients than previously thought. Our study showed a higher likelihood of developing hyperglycaemia with higher doses of dexamethasone. But although dose is correlated with hyperglycemia, patients without high doses were also at risk. Further study is currently underway with slight modifications to the guideline to more accurately assess the physical burden, as well as the emotional and financial cost of a hyperglycemia screening protocol.


Avoiding bias effects in NMR experiments for heteronuclear dipole-dipole coupling determinations: principles and application to organic semiconductor materials.
Carbon-proton dipole-dipole couplings between bonded atoms represent a popular probe of molecular dynamics in soft materials or biomolecules. Their site-resolved determination, for example, by using the popular DIPSHIFT experiment, can be challenged by spectral overlap with nonbonded carbon atoms. The problem can be solved by using very short cross-polarization (CP) contact times, however, the measured modulation curves then deviate strongly from the theoretically predicted shape, which is caused by the dependence of the CP efficiency on the orientation of the CH vector, leading to an anisotropic magnetization distribution even for isotropic samples. Herein, we present a detailed demonstration and explanation of this problem, as well as providing a solution. We combine DIPSHIFT experiments with the rotor-directed exchange of orientations (RODEO) method, and modifications of it, to redistribute the magnetization and obtain undistorted modulation curves. Our strategy is general in that it can also be applied to other types of experiments for heteronuclear dipole-dipole coupling determinations that rely on dipolar polarization transfer. It is demonstrated with perylene-bisimide-based organic semiconductor materials, as an example, in which measurements of dynamic order parameters reveal correlations of the molecular dynamics with the phase structure and functional properties.


Molecular genetic dissection of the sex-specific and vital functions of the Drosophila melanogaster sex determination gene fruitless.
A multibranched hierarchy of regulatory genes controls all aspects of somatic sexual development in Drosophila melanogaster. One branch of this hierarchy is headed by the fruitless (fru) gene and functions in the central nervous system, where it is necessary for male courtship behavior as well as the differentiation of a male-specific abdominal structure, the muscle of Lawrence (MOL). A preliminary investigation of several of the mutations described here showed that the fru gene also has a sex-nonspecific vital function. The fru gene produces a complex set of transcripts through the use of four promoters and alternative splicing. Only the primary transcripts produced from the most distal (P1) promoter are sex-specifically spliced under direction of the sex-determination hierarchy. We have analyzed eight new fru mutations, created by X-ray mutagenesis and P-element excision, to try to gain insight into the relationship of specific transcript classes to specific fru functions. Males that lack the P1-derived fru transcripts show a complete absence of sexual behavior, but no other defects besides the loss of the MOL. Both males and females that have reduced levels of transcripts from the P3 promoter develop into adults but frequently die after failing to eclose. Analysis of the morphology and behavior of adult escapers showed that P3-encoded functions are required for the proper differentiation and eversion of imaginal discs. Furthermore, the reduction in the size of the neuromuscular junctions on abdominal muscles in these animals suggests that one of fru's sex-nonspecific functions involves general aspects of neuronal differentiation. In mutants that lack all fru transcripts as well as a small number of adjacent genes, animals die at an early pupal stage, indicating that fru's function is required only during late development. Thus, fru functions both in the sex-determination regulatory hierarchy to control male sexual behavior through sex-specific transcripts and sex-nonspecifically to control the development of imaginal discs and motorneuronal synapses during adult development through sex-nonspecific transcript classes.


3D chemical imaging of the brain using quantitative IR spectro-microscopy.
Three-dimensional (3D) histology is the next frontier for modern anatomo-pathology. Characterizing abnormal parameters in a tissue is essential to understand the rationale of pathology development. However, there is no analytical technique, in vivo or histological, that is able to discover such abnormal features and provide a 3D distribution at microscopic resolution. Here, we introduce a unique high-throughput infrared (IR) microscopy method that combines automated image correction and subsequent spectral data analysis for 3D-IR image reconstruction. We performed spectral analysis of a complete organ for a small animal model, a mouse brain with an implanted glioma tumor. The 3D-IR image is reconstructed from 370 consecutive tissue sections and corrected using the X-ray tomogram of the organ for an accurate quantitative analysis of the chemical content. A 3D matrix of 89 × 106 IR spectra is generated, allowing us to separate the tumor mass from healthy brain tissues based on various anatomical, chemical, and metabolic parameters. We demonstrate that quantitative metabolic parameters can be extracted from the IR spectra for the characterization of the brain vs. tumor metabolism (assessing the Warburg effect in tumors). Our method can be further exploited by searching for the whole spectral profile, discriminating tumor vs. healthy tissue in a non-supervised manner, which we call 'spectromics'.


Antibiotic use in ambulatory care for acutely ill children in high-income countries: a systematic review and meta-analysis.
To determine the rate and appropriateness of antibiotic prescribing for acutely ill children in ambulatory care in high-income countries. On 10 February 2021, we systematically searched articles published since 2000 in MEDLINE, Embase, CENTRAL, Web Of Science and grey literature databases. We included cross-sectional and longitudinal studies, time-series analyses, randomised controlled trials and non-randomised studies of interventions with acutely ill children up to and including 12 years of age in ambulatory care settings in high-income countries. Pooled antibiotic prescribing and appropriateness rates were calculated using random-effects models. Meta-regression was performed to describe the relationship between the antibiotic prescribing rate and study-level covariates. We included 86 studies comprising 11 114 863 children. We found a pooled antibiotic prescribing rate of 45.4% (95% CI 38.2% to 52.8%) for all acutely ill children, and 85.6% (95% CI 73.3% to 92.9%) for acute otitis media, 37.4% (95% CI 30.9% to 44.3%) for respiratory tract infections, and 40.4% (95% CI 29.9% to 51.9%) for other diagnoses. Considerable heterogeneity can only partly be explained by differences in diagnoses. The overall pooled appropriateness rate is 68.5% (95% CI 55.8% to 78.9%, I²=99.8%; 19 studies, 119 995 participants). 38.3% of all prescribed antibiotics were aminopenicillins. Antibiotic prescribing rates for acutely ill children in ambulatory care in high-income countries remain high. Large differences in prescription rates between studies can only partly be explained by differences in diagnoses. Better registration and further research are needed to investigate patient-level data on diagnosis and appropriateness.


Closing the manufacturing process of dendritic cell vaccines transduced with adenovirus vectors.
Anticancer immunotherapy using dendritic cell (DC) based vaccines provides an adjuvant therapeutic strategy that is not cross reactive with conventional therapeutics. However, manufacturing of DC vaccines requires stringent adherence to Good Manufacturing Practice (GMP) methods and rigorous standardization. Optimally this includes a closed system for monocyte isolation, in combination with closed culture and washing systems and an effective vector transduction strategy. In this study, we used the Gambro Elutra to enrich monocytes from non-mobilized leukapheresis products collected from healthy donors. This approach enriched monocytes from an average frequency of 13.6+3.2% (mean+SEM), to an average frequency of 79.5+4.3% following enrichment with a yield of 79 to 100%. The monocytes were then cultured in a closed system using gas permeable Vuelife fluoroethylene propylene (FEP) bags and X-vivo-15 media containing 10 ng/ml granulocyte-macrophage colony-stimulation factor (GM-CSF) and 5 ng/ml Interleukin (IL) 4. The cultures were re-fed on days two and four, with a 25% media volume and cytokines. Following culture for seven days, the cells were harvested using a Cobe-2991 and concentrated using a bench centrifuge retrofitted with blocks to allow centrifugation of 72 ml bags and supernatant removed using a plasma extractor. This approach reduced the media volume to an average of 17.4 ml and an average DC concentration of 6.3+1.0x10(7) cells/ml, a viability of 93.8+2.2%, a purity of 88.9+3.3% and a total yield of 8.5+1.4x10(8) DCs. Based on the identification of DR+ cells as DCs we had an average yield of 46+8% using a calculation based on the number of monocytes in the apheresis product and the resulting DCs differentiated from monocytes. The use of DCs as a vaccine, required transduction with an adenovirus (Adv) vector with the tumor suppressor, p53 transgene (Adv5CMV-p53) as the antigen at a DC concentration of 9x10(6) DCs/ml at an Ad5CMV-p53: DC ratio of 20,000:1, and a 2 or 3 hour co-culture, followed by a 1:10 dilution with media and an additional 16-22 hour incubation. Following incubation, the DCs were washed twice and the supernatants removed using a plasma extractor. The average viability after infection with Ad5CMV-p53 was 87.9+/-2.6% with an average of 20.3+5.4% of the DCs expressing p53. The calculated yield of DCs following Ad5CMV-p53 transduction, based on the number of monocytes in the apheresis products, averaged 12.4+3.8%. We conclude that it is possible to efficiently manufacture Adv transduced DCs using a functionally closed system.


Bloodborne pathogen exposures: Difference in reporting rates and individual predictors among health care personnel.
Employees in health care settings are at varying risk for bloodborne pathogen (BBP) exposures. We compared differences in reporting rates of BBP exposures among health care personnel during 2 different time periods, assessing job category, years of experience, and sex as potential predictors for exposure. A retrospective review of the employee health department BBP database at 2 time periods (September 1, 2012-April 30, 2013, and September 1, 2013-April 30, 2014) in which 2 different reporting protocols (call center vs pager) was used. A survey was administered to assess reported and unreported exposures within a 12-month period. BBP exposures were highest among residents and lowest among students. Physicians' reporting rate doubled when the call center was no longer used (relative risk, 2.40; 95% confidence interval [CI], 1.04-5.52). Percutaneous injuries were the most common (78.3%), and most occurred in the operating room or postanesthesia unit (30.8%) and patient rooms (28.9%). Of 1,105 survey respondents, 103 (9.3%) recalled some type of exposure, but only 80 (77.7%) reported these exposures. When accounting for years of experience and sex, job category was significantly associated with injury or exposure within the previous 12 months (P < .001). Risk of exposure among residents was 3 times higher (odds ratio, 3.10; 95 CI, 1.60-6.00) than nurses. Risk and reporting behaviors of BBP exposures vary widely across different providers. Training and education to prevent BBP exposures may need to be tailored toward different provider types.


Scaling up complex interventions: insights from a realist synthesis.
Preventing chronic diseases, such as cancer, cardiovascular disease and diabetes, requires complex interventions, involving multi-component and multi-level efforts that are tailored to the contexts in which they are delivered. Despite an increasing number of complex interventions in public health, many fail to be 'scaled up'. This study aimed to increase understanding of how and under what conditions complex public health interventions may be scaled up to benefit more people and populations.A realist synthesis was conducted and discussed at an in-person workshop involving practitioners responsible for scaling up activities. Realist approaches view causality through the linkages between changes in contexts (C) that activate mechanisms (M), leading to specific outcomes (O) (CMO configurations). To focus this review, three cases of complex interventions that had been successfully scaled up were included: Vibrant Communities, Youth Build USA and Pathways to Education. A search strategy of published and grey literature related to each case was developed, involving searches of relevant databases and nominations from experts. Data extracted from included documents were classified according to CMO configurations within strategic themes. Findings were compared and contrasted with guidance from diffusion theory, and interpreted with knowledge users to identify practical implications and potential directions for future research.Four core mechanisms were identified, namely awareness, commitment, confidence and trust. These mechanisms were activated within two broad scaling up strategies, those of renewing and regenerating, and documenting success. Within each strategy, specific actions to change contexts included building partnerships, conducting evaluations, engaging political support and adapting funding models. These modified contexts triggered the identified mechanisms, leading to a range of scaling up outcomes, such as commitment of new communities, changes in relevant legislation, or agreements with new funding partners.This synthesis applies and advances theory, realist methods and the practice of scaling up complex interventions. Practitioners may benefit from a number of coordinated efforts, including conducting or commissioning evaluations at strategic moments, mobilising local and political support through relevant partnerships, and promoting ongoing knowledge exchange in peer learning networks. Action research studies guided by these findings, and studies on knowledge translation for realist syntheses are promising future directions.


Changing trends in antimicrobial susceptibility of Streptococcus pneumoniae isolates in Taiwan, 2006-2007.
Multiple antibiotic-resistant clones of Streptococcus pneumoniae have spread throughout the world and continue to evolve under the selective pressure of antibiotics and vaccines. The aim of this study is to assess the susceptibility of S. pneumoniae isolates and to analyze the resistance trends in Taiwan. Antimicrobial susceptibility tests were performed on 152 nonmeningeal isolates of S. pneumoniae that were collected from 13 different hospitals around Taiwan from 2006-2007. Tests were performed using the broth microdilution method according to recommendations of the Clinical and Laboratory Standards Institute. The minimal inhibitory concentrations (MIC(50)/MIC(90)) of penicillin, cefotaxime, vancomycin, and moxifloxacin were 0.5/1.0, 0.25/1.0, 0.25/0.5, and 0.06/0.12 μg/mL, respectively. The susceptibility rates of penicillin, cefotaxime, vancomycin, and moxifloxacin were 99.3%, 99.3%, 100%, and 98.7%, respectively. However, if the meningitis breakpoints were applied to these nonmeningeal isolates, the susceptibility rates of penicillin and cefotaxime were reduced to 18.4% and 76.3%, respectively. Compared with the findings from previous studies in Taiwan, our results show that the percentage of S. pneumoniae isolates with a penicillin MIC of 0.12-1.0 μg/mL increased from 43.3% in 1996-1997 to 73.7% in 2006-2007 (p < 0.001). The percentage of S. pneumoniae isolates with a cefotaxime MIC of 1.0 μg/mL increased from 11.3% in 1996-1997 to 23.0% in 2006-2007 (p < 0.001). Regarding the serial MIC intervals of the four antimicrobial agents, there was no significant difference between bacteremic and nonbacteremic isolates. Although nonmeningeal S. pneumoniae isolates remained susceptible to penicillin, the proportion of isolates with a penicillin MIC of 0.12-1.0 μg/mL or cefotaxime MIC of 1.0 μg/mL increased during the past decade in Taiwan. The ever-increasing resistance of S. pneumoniae has a great impact on the treatment of meningitis.


Resilience and Burnout Resources in Respiratory Care Departments.
Burnout is a major problem in health care, with rates of approximately 33% and 50% in nurses and physicians, respectively, prior to the COVID-19 pandemic. Respiratory therapist (RT) burnout rates and drivers have not been specifically examined. The purpose of this project was to determine resilience and burnout resources available within respiratory care departments and to provide an estimate of pre- and post-COVID-19 RT burnout rates. A survey was developed to evaluate resilience and burnout resources in respiratory care departments. The survey was posted online to the AARConnect management, education, adult acute care, neonatal/pediatrics, COVID-19, and help line communities. Data analysis was descriptive. Key drivers of burnout among RTs were identified from qualitative answers. There were 221 responses, and 72% reported experiencing burnout. Ten percent of the departments that responded measured burnout; 36% utilized resilience tools, and 83% offered free employee assistance for those struggling with burnout. In January 2020, 30% of departments reported an estimated burnout rate > 40%, which increased to 44% of departments (P = .007) in the COVID-19 pandemic period. The most common drivers reported were poor leadership (32%), high work load (31%), and staffing (29%); 93% of respondents agreed that burnout is a major problem in health care, 33% agreed that burnout is primarily driven by external factors, 92% agreed that RTs have a similar risk of burnout as other health care professionals, 73% agreed that they were comfortable discussing challenging situations with colleagues, 32% agreed that their leadership provided adequate support for those suffering from burnout, and 79% agreed that they would be open to utilizing resilience tools from the AARC or other professional organizations. Most respondents experienced burnout and few respiratory care departments measured burnout. Resilience resources were not commonly used but employee assistance and wellness programs were common. Key drivers of burnout identified were poor leadership, staffing, and high workloads.


Correlation between env V1/V2 region diversification and neutralizing antibodies during primary infection by simian immunodeficiency virus sm in rhesus macaques.
Evolution of the domain encoding the V1/V2 variable region of the simian immunodeficiency virus sm (SIVsm) envelope (env) gene was analyzed in relation to route of virus challenge, virus load, and neutralizing antibody (NAb) titers during primary infection of rhesus macaques with the pathogenic SIVsmE660 isolate. In this model system animals are initially infected with multiple viruses as evidenced by the presence of multiple V1/V2 genotypic variants that could be resolved by using a heteroduplex tracking assay (HTA). Overlapping subsets of the multiple variants were established in each animal. There was no selection for the establishment of specific variants in comparing intravenous- and intrarectal-challenged macaques at week 2 postinfection, suggesting that no genotypic selection occurred at the mucosal surface. There was an initial period of significant stability of the V1/V2 variants. Macaques challenged intravenously displayed subsequent V1/V2 diversification significantly earlier than macaques challenged intrarectally and well past the initial resolution of viremia. The time when SIVsmE660-specific NAbs reached a threshold titer of 100 was significantly correlated with the timing of V1/V2 diversification, even though antibodies to the Env protein could be detected much earlier. The time when NAbs reached a titer of 400 was significantly correlated with virus load late in infection. These results show that the route of infection affects the timing of V1/V2 diversification and that this diversification is correlated with the maturation of a specific NAb response. However, prior immunization capable of priming an anamnestic Env antibody response did not accelerate V1/V2 diversification. This result suggests that diversification of the SIV env V1/V2 region is the result of a type-specific antibody response.


The spectrum of cortical myoclonus. From focal reflex jerks to spontaneous motor epilepsy.
The purpose of this paper is to draw attention to the wide range of clinical motor phenomena which may be caused by abnormal sensorimotor cortical discharge. Eleven selected patients with cortical myoclonus are described. In all cases the brief muscle jerks appeared to involve cerebral cortical mechanisms, for there were enlarged cerebral evoked potentials to somatosensory or visual stimuli and (in 5 of the 6 cases investigated in this way) a time-locked cortical event preceded spontaneous or action-induced jerking. In some patients, cortical myoclonus occurred only in response to a variety of afferent inputs (cortical reflex myoclonus). In others, the myoclonus occurred only during movement, when cortical mechanisms were activated voluntarily (cortical action myoclonus), or the cortical discharge occurred spontaneously (spontaneous cortical myoclonus and epilepsia partialis continua), and even spread to cause focal motor epilepsy (Jacksonian seizures). Some patients showed combinations of stimulus sensitive and spontaneous myoclonus, epilepsia partialis continua, focal motor epilepsy and generalized grand mal seizures. Such variations probably represent subtle differences in the site of abnormality in sensorimotor cortical neuronal mechanisms.


Highly circularly polarized white light using a combination of white polymer light-emitting diode and wideband cholesteric liquid crystal reflector.
We present a simple and intriguing device that generates highly circularly polarized white light. It comprises white polymer light-emitting diodes (WPLEDs) attached to a wideband cholesteric liquid crystal (CLC) reflector with a wide photonic bandgap (PBG) covering the visible range. The degree of circular polarization realized is very high over the visible range. The wide PBG was realized by introducing a gradient in pitch of the cholesteric helix by controlling the twisting power within the CLC medium. WPLEDs fabricated using a ternary (red, green, and blue) fluorescent polymer blend with the same moiety showed a low turn-on voltage, high brightness, high efficiency, and good color stability.


Seroepidemiology of Toxoplasma gondii Infection among healthy blood donors in Taiwan.
Toxoplasma gondii is an opportunistic, zoonotic pathogen with a worldwide distribution. There are large variations in the seroprevalence of T. gondii infection in different regions of the world. Although toxoplasmosis became a notifiable communicable disease in Taiwan in 2007, little is known about its epidemiology among the general population. This cross-sectional study aimed to survey the seroprevalence of T. gondii infection and its risk factors among healthy blood donors in Taiwan. Through collaborating with the Taiwan Blood Services Foundation, a total of 1,783 healthy blood donors from all six-branch blood service centers participated in this study. The blood samples were tested for the presence of T. gondii antibodies and DNA using enzyme immunoassays and real-time PCR, respectively. Structured questionnaires were used to gather information on risk factors for T. gondii infection. Of the 1,783 participants, 166 (9.3%) tested positive for anti-Toxoplasma IgG, while 5 (0.28%) tested positive for anti-Toxoplasma IgM. The five IgM positive donors had high avidity antibodies suggestive of past infection. No active parasitemia was detected by real-time PCR assays. Multivariate logistic regression showed that undercooked pork meat consumption (adjusted odds ratio [OR] = 2.9; 95% confidence interval [CI]: 1.3-6.5), raw mussels consumption (adjusted OR = 5.3; 95% CI: 1.5-19.1), having a cat in the household (adjusted OR = 2.0; 95% CI: 1.2-3.2), a lower education level (adjusted OR = 1.6; 95% CI: 1.1-2.3), and donation place in eastern Taiwan (adjusted OR = 2.5; 95% CI: 1.6-3.9) were independent risk factors for Toxoplasma seropositivity. These findings provide information on the seroprevalence and epidemiology of T. gondii infection among healthy blood donors in Taiwan.


Displacement of the temporomandibular joint disk: correlation between clinical findings and MRI characteristics.
Disk displacement frequently causes dysfunction of the temporomandibular joint (TMJ). Magnetic resonance imaging (MRI) of the TMJ is 95% accurate in the assessment of disk position and form. Various restorative procedures are used for treatment of disk displacement. However, several authors have noted a lack of correlation between MRI findings of disk displacement and the extent of pain and dysfunction of the TMJ. The purpose of this study was to evaluate whether MRI findings of various degrees of disk displacement could be correlated with the presence of clinical signs and symptoms in patients with a clinical disorder of the TMJ. One hundred and forty-four TMJs (in 72 patients) were imaged. Displacement of the posterior band in relation to the condyle was quantified as mild or significant. Disk displacement was found in 45 (54%) of the 84 symptomatic joints and 13 (22%) of the 60 asymptomatic joints. Among the 84 symptomatic joints, 31 (37%) had disk displacement with reduction and 14 (17%) had disk displacement without reduction. In the latter group, 11 (79%) of the 14 joints had significant displacement of the posterior band (8 or 9 o'clock) and 21% had mild displacement of the posterior band (10 o'clock). Of the 60 clinically asymptomatic joints, 47 (78%) had no signs of disk displacement on MRI, whereas 13 (22%) had disk displacement with reduction. None of the asymptomatic joints had disk displacement without reduction. The difference in occurrence of disk displacement between symptomatic and asymptomatic joints was statistically significant (54% vs. 22%; p < 0.001). However, the difference in occurrence of disk displacement with reduction of the disk on mouth opening was not statistically significant (37% vs. 22%; p = 0.06). Disk displacement on MRI correlated well with clinical symptoms in cases of significant disk displacement and in cases of disk displacement without reduction. When disk displacement with reduction was mild, there was no statistically significant difference between symptomatic and asymptomatic joints, which suggests that other causes should be considered.


Evaluation of experiments with adaptive interim analyses.
A general method for statistical testing in experiments with an adaptive interim analysis is proposed. The method is based on the observed error probabilities from the disjoint subsamples before and after the interim analysis. Formally, an intersection of individual null hypotheses is tested by combining the two p-values into a global test statistic. Stopping rules for Fisher's product criterion in terms of critical limits for the p-value in the first subsample are introduced, including early stopping in the case of missing effects. The control of qualitative treatment-stage interactions is considered. A generalization to three stages is outlined. The loss of power when using the product criterion instead of the optimal classical test on the whole sample is calculated for the test of the mean of a normal distribution, depending on increasing proportions of the first subsample in relation to the total sample size. An upper bound on the loss of power due to early stopping is derived. A general example is presented and rules for assessing the sample size in the second stage of the trial are given. The problems of interpretation and precautions to be taken for applications are discussed. Finally, the sources of bias for estimation in such designs are described.


Attention rehabilitation following stroke and traumatic brain injury. A review.
Attentional capacities, which are frequently impaired following brain injury, have also been found to be amenable to rehabilitation. This review discusses various approaches to attention rehabilitation in adult clients following stroke and traumatic brain injury. Attention process training has been accepted by many as a practice standard in postacute clients, however, its ability to generalize to new situations and to functional capacities is unclear. There is evidence for the use of psychostimulant medication, which may be most helpful when prescribed in combination with attention training. Biofeedback is a new avenue for intervention and is beginning to show some promising Rather than train underlying processes, another approach which shows promising results in a few small studies is training clients on specific functional skills, such as driving or vocational duties. Finally, modifications to the environment, implementation of strategies, provision of emotional support, and introduction of external supports/aids are important parts of a rehabilitation program, especially as the client returns to their home environment.


First report of widespread wild populations of Triatoma infestans (Reduviidae, Triatominae) in the valleys of La Paz, Bolivia.
Wild populations of Triatoma infestans, the main vector of Chagas disease in the Southern Cone countries, may be involved in reinfestation of human dwellings, limiting the success of vector-control campaigns in Bolivia. Knowledge of the distribution of these populations remains incomplete. We report here the detection of T. infestans wild populations in large areas in the department of La Paz, Bolivia. Among 18 sylvatic areas investigated, 17 were positive with T. infestans specimens. The infection rate of captured T. infestans with Trypanosoma cruzi was 85.7% in adult specimens. These results expand the geographical distribution of wild populations of T. infestans; it may be distributed throughout the Inter-Andean Dry Forest eco-region of Bolivia. The current information allows us to propose the hypothesis that a sylvatic origin of the reinfestation is located in the valleys of La Paz.


The study protocol of a blinded randomised-controlled cross-over trial of lavender oil as a treatment of behavioural symptoms in dementia.
The agitated behaviours that accompany dementia (e.g. pacing, aggression, calling out) are stressful to both nursing home residents and their carers and are difficult to treat. Increasingly more attention is being paid to alternative interventions that are associated with fewer risks than pharmacology. Lavandula angustifolia (lavender) has been thought, for centuries, to have soothing properties, but the existing evidence is limited and shows mixed results. The aim of the current study is to test the effectiveness of topically applied pure lavender oil in reducing actual counts of challenging behaviours in nursing home residents. We will use a blinded repeated measures design with random cross-over between lavender oil and placebo oil. Persons with moderate to severe dementia and associated behavioural problems living in aged care facilities will be included in the study. Consented, willing participants will be assigned in random order to lavender or placebo blocks for one week then switched to the other condition for the following week. In each week the oils will be applied on three days with at least a two-day wash out period between conditions. Trained observers will note presence of target behaviours and predominant type of affect displayed during the 30 minutes before and the 60 minutes after application of the oil. Nursing staff will apply 1 ml of 30% high strength essential lavender oil to reduce the risk of missing a true effect through under-dosing. The placebo will comprise of jojoba oil only. The oils will be identical in appearance and texture, but can easily be identified by smell. For blinding purposes, all staff involved in applying the oil or observing the resident will apply a masking cream containing a mixture of lavender and other essential oils to their upper lip. In addition, nursing staff will wear a nose clip during the few minutes it takes to massage the oil to the resident's forearms. If our results show that the use of lavender oil is effective in reducing challenging behaviours in individuals with dementia, it will potentially provide a safer intervention rather than reliance on pharmacology alone. The study's findings will translate easily to other countries and cultures. Australian New Zealand Clinical Trials Registry - ACTRN 12609000569202.


Automated 3D mapping of hippocampal atrophy and its clinical correlates in 400 subjects with Alzheimer's disease, mild cognitive impairment, and elderly controls.
We used a new method we developed for automated hippocampal segmentation, called the auto context model, to analyze brain MRI scans of 400 subjects from the Alzheimer's disease neuroimaging initiative. After training the classifier on 21 hand-labeled expert segmentations, we created binary maps of the hippocampus for three age- and sex-matched groups: 100 subjects with Alzheimer's disease (AD), 200 with mild cognitive impairment (MCI) and 100 elderly controls (mean age: 75.84; SD: 6.64). Hippocampal traces were converted to parametric surface meshes and a radial atrophy mapping technique was used to compute average surface models and local statistics of atrophy. Surface-based statistical maps visualized links between regional atrophy and diagnosis (MCI versus controls: P = 0.008; MCI versus AD: P = 0.001), mini-mental state exam (MMSE) scores, and global and sum-of-boxes clinical dementia rating scores (CDR; all P < 0.0001, corrected). Right but not left hippocampal atrophy was associated with geriatric depression scores (P = 0.004, corrected); hippocampal atrophy was not associated with subsequent decline in MMSE and CDR scores, educational level, ApoE genotype, systolic or diastolic blood pressure measures, or homocysteine. We gradually reduced sample sizes and used false discovery rate curves to examine the method's power to detect associations with diagnosis and cognition in smaller samples. Forty subjects were sufficient to discriminate AD from normal and correlate atrophy with CDR scores; 104, 200, and 304 subjects, respectively, were required to correlate MMSE with atrophy, to distinguish MCI from normal, and MCI from AD.


Sickle cell disease: an international survey of results of HLA-identical sibling hematopoietic stem cell transplantation.
Despite advances in supportive therapy to prevent complications of sickle cell disease (SCD), access to care is not universal. Hematopoietic cell transplantation is, to date, the only curative therapy for SCD, but its application is limited by availability of a suitable HLA-matched donor and lack of awareness of the benefits of transplant. Included in this study are 1000 recipients of HLA-identical sibling transplants performed between 1986 and 2013 and reported to the European Society for Blood and Marrow Transplantation, Eurocord, and the Center for International Blood and Marrow Transplant Research. The primary endpoint was event-free survival, defined as being alive without graft failure; risk factors were studied using a Cox regression models. The median age at transplantation was 9 years, and the median follow-up was longer than 5 years. Most patients received a myeloablative conditioning regimen (n = 873; 87%); the remainder received reduced-intensity conditioning regimens (n = 125; 13%). Bone marrow was the predominant stem cell source (n = 839; 84%); peripheral blood and cord blood progenitors were used in 73 (7%) and 88 (9%) patients, respectively. The 5-year event-free survival and overall survival were 91.4% (95% confidence interval, 89.6%-93.3%) and 92.9% (95% confidence interval, 91.1%-94.6%), respectively. Event-free survival was lower with increasing age at transplantation (hazard ratio [HR], 1.09; P < .001) and higher for transplantations performed after 2006 (HR, 0.95; P = .013). Twenty-three patients experienced graft failure, and 70 patients (7%) died, with the most common cause of death being infection. The excellent outcome of a cohort transplanted over the course of 3 decades confirms the role of HLA-identical sibling transplantation for children and adults with SCD.


Extracting Plant Phenology Metrics in a Great Basin Watershed: Methods and Considerations for Quantifying Phenophases in a Cold Desert.
Plant phenology is recognized as important for ecological dynamics. There has been a recent advent of phenology and camera networks worldwide. The established PhenoCam Network has sites in the United States, including the western states. However, there is a paucity of published research from semi-arid regions. In this study, we demonstrate the utility of camera-based repeat digital imagery and use of R statistical phenopix package to quantify plant phenology and phenophases in four plant communities in the semi-arid cold desert region of the Great Basin. We developed an automated variable snow/night filter for removing ephemeral snow events, which allowed fitting of phenophases with a double logistic algorithm. We were able to detect low amplitude seasonal variation in pinyon and juniper canopies and sagebrush steppe, and characterize wet and mesic meadows in area-averaged analyses. We used individual pixel-based spatial analyses to separate sagebrush shrub canopy pixels from interspace by determining differences in phenophases of sagebrush relative to interspace. The ability to monitor plant phenology with camera-based images fills spatial and temporal gaps in remotely sensed data and field based surveys, allowing species level relationships between environmental variables and phenology to be developed on a fine time scale thus providing powerful new tools for land management.


Prevalence of use of erectile dysfunction medication by Dutch military personnel between 2003 and 2012.
Use of ED medication can be seen as a marker for ED. ED is associated with increasing age, exposure to traumatic events and physical injuries in military veterans. The objective of this study was to assess the prevalence of use of ED medication in Dutch military personnel in the period 2003-2012 and to assess its association with age and psychotropic medication use. Data on dispensing of ED medication, age and co-medication with psychotropic medication of all Dutch military personnel between 2003 and 2012 were collected. The prevalence of ED medication use in each year was estimated, stratified for age and use of psychotropic medication. The number of ED medication users increased a hundredfold from 0.09 to 9.29 per 1000 per year between 2003 and 2012. ED medication was more often used by men over 40 than under 40 (prevalence in 2012: 2.4% vs 0.2%, OR (2003-2012, adjusted for calendar year) 15.6, 95% CI 13.5-17.9) and by men using psychotropic medication (prevalence in 2012: 3.8% vs 0.9%, OR (2003-2012, adjusted for calendar year) 3.13, 95% CI 2.66-3.67). This study shows a strong increase between 2003 and 2012 in a number of ED medication users in male Dutch military personnel. ED medication use increases with age and with psychotropic medication use.


Deciphering colorectal cancer genetics through multi-omic analysis of 100,204 cases and 154,587 controls of European and east Asian ancestries.
Colorectal cancer (CRC) is a leading cause of mortality worldwide. We conducted a genome-wide association study meta-analysis of 100,204 CRC cases and 154,587 controls of European and east Asian ancestry, identifying 205 independent risk associations, of which 50 were unreported. We performed integrative genomic, transcriptomic and methylomic analyses across large bowel mucosa and other tissues. Transcriptome- and methylome-wide association studies revealed an additional 53 risk associations. We identified 155 high-confidence effector genes functionally linked to CRC risk, many of which had no previously established role in CRC. These have multiple different functions and specifically indicate that variation in normal colorectal homeostasis, proliferation, cell adhesion, migration, immunity and microbial interactions determines CRC risk. Crosstissue analyses indicated that over a third of effector genes most probably act outside the colonic mucosa. Our findings provide insights into colorectal oncogenesis and highlight potential targets across tissues for new CRC treatment and chemoprevention strategies.


Computational solutions to large-scale data management and analysis.
Today we can generate hundreds of gigabases of DNA and RNA sequencing data in a week for less than US$5,000. The astonishing rate of data generation by these low-cost, high-throughput technologies in genomics is being matched by that of other technologies, such as real-time imaging and mass spectrometry-based flow cytometry. Success in the life sciences will depend on our ability to properly interpret the large-scale, high-dimensional data sets that are generated by these technologies, which in turn requires us to adopt advances in informatics. Here we discuss how we can master the different types of computational environments that exist - such as cloud and heterogeneous computing - to successfully tackle our big data problems.


Modelling sugar diffusion across plant leaf cuticles: the effect of free water on substrate availability to phyllosphere bacteria.
We present a continuous model for the diffusion of sugars across intact plant leaf cuticles. It is based on the flow of sugars from a source, representing the leaf apoplast, to a sink, in the shape of a hemispherical drop of water on the outside of the cuticle. Flow is a function of the difference between sugar concentrations C(Source) and C(Sink) , permeability P of the cuticle, volume V(Sink) of the water drop, as well as its contact angle α with the cuticle surface. Using a bacterial bioreporter for fructose, and a two-compartment experimental set-up consisting of isolated cuticles of walnut (Juglans regia) carrying water droplets while floating on solutions with increasing concentrations of fructose, we determined a value of 1 × 10⁻⁶ m h⁻¹ for P. Using this value, we explored different scenarios for the leaching of sugars across plant leaf cuticles to reveal in quantitative terms how diffusion takes longer when V(Sink) increases, P decreases or α increases. Bacterial growth was modelled as a function of changes in P, α and V(Sink) and was consistent with observations or suggestions from the literature in relation to the availability of free water on leaves. These results are discussed in the light of bacteria as ecosystem engineers, i.e. with the ability to modify the plant leaf surface environment in favour of their own survival, e.g. by increasing cuticle leakage or leaf wetness. Our model represents a first step towards a more comprehensive model which will enhance our quantitative understanding of the factors that play a role in nutrient availability to bacterial colonizers of the phyllosphere, or plant leaf surface.