Long-term effects of prior diets, dietary transition and pregnancy on adipose gene expression in dairy heifers.
Adipose tissue is highly involved in whole-body metabolism and is the main site for lipid synthesis, storage and mobilization in ruminants. Therefore, knowledge about adipose tissue responses to different diets is important, especially in growing heifers as the feeding regimes of replacement heifers affect their future success as dairy cows. However, at gene expression level such knowledge is limited. As part of a larger feed trial, adipose tissue biopsies from 24 Norwegian Red heifers were collected at 12 months of age (12MO) and at month seven of gestation (PREG) and analyzed by next-generation mRNA sequencing. Between these two sampling points, all heifers had gone through a successful conception and a feed change from four dietary treatments of high or low energy (HE/LE) and protein (HP/LP) content (treatments LPHE, HPHE, LPLE and HPLE) to a low-energy, low-protein pregnancy feed given to all animals. Gene expression differences between different feed treatments at 12MO are described in an earlier publication from our group. The main objectives of this study were to investigate the long-term effects of diets differing in protein and energy density level on gene expression in adipose tissue of growing replacement dairy heifers. To achieve this, we examined the post-treatment effects between the treatment groups at month seven of gestation; 6 months after the termination of experimental feeding, and the long-term gene expression changes occurring in the adipose tissue between 12MO and PREG. Post-treatment group comparisons showed evidence of long-term effects of dietary treatment on adipose gene expression. Differences between protein treatments were smaller than between energy treatments. Adipose gene expression changes from 12MO to PREG were much larger for the HE than the LE treatments and seemed to mostly be explained by the characteristics of the diet change. 97 genes displayed a unidirectional expression change for all groups from 12MO to PREG, and are considered to be treatment-independent, possibly caused by pregnancy or increased age. This study provides candidate genes and key regulators for further studies on pregnancy preservation (TGFB1, CFD) and metabolic regulation and efficiency (PI3K, RICTOR, MAP4K4,) in dairy cattle.


The gut microbiota regulates white adipose tissue inflammation and obesity via a family of microRNAs.
The gut microbiota is a key environmental determinant of mammalian metabolism. Regulation of white adipose tissue (WAT) by the gut microbiota is a process critical to maintaining metabolic fitness, and gut dysbiosis can contribute to the development of obesity and insulin resistance (IR). However, how the gut microbiota regulates WAT function remains largely unknown. Here, we show that tryptophan-derived metabolites produced by the gut microbiota controlled the expression of the miR-181 family in white adipocytes in mice to regulate energy expenditure and insulin sensitivity. Moreover, dysregulation of the gut microbiota-miR-181 axis was required for the development of obesity, IR, and WAT inflammation in mice. Our results indicate that regulation of miR-181 in WAT by gut microbiota-derived metabolites is a central mechanism by which host metabolism is tuned in response to dietary and environmental changes. As we also found that MIR-181 expression in WAT and the plasma abundance of tryptophan-derived metabolites were dysregulated in a cohort of obese human children, the MIR-181 family may represent a potential therapeutic target to modulate WAT function in the context of obesity.


A case report of bullous pemphigoid associated with a melanoma and review of the literature.
The association of bullous pemphigoid with melanoma remains controversial and poorly understood. Recent studies report the presence of the bullous pemphigoid antigen, BP180, in melanoma cells, yet not normal melanocytes, suggesting an underlying mechanism for cases of melanoma-associated bullous pemphigoid. We report on an 88-year-old woman who showed a temporal relationship between the development of bullous pemphigoid and melanoma. The patient did not receive programmed death ligand 1 inhibitor therapy and improved rapidly following complete excision of her melanoma, with clobetasol, doxycycline, and niacinamide. We review the literature on the relationship between bullous pemphigoid and melanoma, and propose a mechanism underlying a melanoma-associated bullous pemphigoid.


"Post or Perish"? An Early Career Researcher's Guide to Using Social Media.
Social media usage has soared in the last decade, with the majority of adults having an account on at least one platform. Sites such as LinkedIn, X, and TikTok allow users to share content using different forms, for example, written or video, long form or short form. Social media can be used by researchers to forge collaborations, rapidly disseminate new research, and demonstrate societal impact. This opinion piece aims to highlight the value of social media, in particular for early career researchers, and offer suggestions on how early career researchers can strategically use social media to build a network and an online presence. We reflect on our own experiences of social media and include some of the reasons we have been deterred from it in the past, such as fear of making a mistake, being misunderstood, or painted as being an overconfident "know it all." As the demonstration of impact and engagement becomes ever more important in grant applications and job security, social media competency is a powerful professional skill that will be important for all scientists.


Spontaneous abortions among veterinarians.
The objective of the study was to determine whether female veterinarians have an increased risk of spontaneous abortion and whether the potential risk is related to the type of work veterinarians do. The investigation was a retrospective cohort study among all the female members of the Finnish Veterinary Association (N=549). Information on pregnancies was obtained from hospital records from 1973-1990. The risk of spontaneous abortion among the veterinarians was compared with that of all other Finnish women and other upper-level employees. Odds ratios from logistic regression analyses were used as the estimates of the risk ratios. The risk of spontaneous abortion was 10.5% for the veterinarians. In the 1970s, practicing veterinarians had an increased risk of spontaneous abortion as compared with other Finnish women (adjusted odds ratio 1.8, 95% confidence interval 1.0-3.1) or other upper-level employees (adjusted odds ratio 2.0, 95% confidence interval 1.1-3.4). In the 1980s, the risk fell below that of other Finnish women. No essential differences were observed in the risk between the veterinarians employed in different occupational categories. The results suggest that the veterinarians had an increased risk of spontaneous abortion in the 1970s, but not in the 1980s. Factors which might have contributed to this decrease in risk include decreases in the prevalence and level of exposure to harmful agents, improvements in the occupational hygiene of the work environment, and an increased awareness of reproductive hazards and the use of sick leave during pregnancy.


Distributed lag non-linear models.
Environmental stressors often show effects that are delayed in time, requiring the use of statistical models that are flexible enough to describe the additional time dimension of the exposure-response relationship. Here we develop the family of distributed lag non-linear models (DLNM), a modelling framework that can simultaneously represent non-linear exposure-response dependencies and delayed effects. This methodology is based on the definition of a 'cross-basis', a bi-dimensional space of functions that describes simultaneously the shape of the relationship along both the space of the predictor and the lag dimension of its occurrence. In this way the approach provides a unified framework for a range of models that have previously been used in this setting, and new more flexible variants. This family of models is implemented in the package dlnm within the statistical environment R. To illustrate the methodology we use examples of DLNMs to represent the relationship between temperature and mortality, using data from the National Morbidity, Mortality, and Air Pollution Study (NMMAPS) for New York during the period 1987-2000.


Effect of alpha-ketoglutarate on growth and metabolism of cells cultured on three-dimensional cryogel matrix.
Alpha- ketoglutarate (α-KG) is a well-known intermediate of Kreb's cycle and thus one of the important candidates in the role of cellular metabolism. The aim was to investigate the effect of α-KG on the growth and proliferation of different cells (fibroblasts and chondrocytes). Further change in the consumption of glucose and release of ammonia in the media, upon the addition of α-KG was also examined. NIH3T3 and chondrocytes were seeded on two different macroporous cryogel matrices synthesized by poly (hydroxyethylmethaacrylate)-gelatin (HG) and alginate-gelatin (AG). Higher proliferation was observed for both the cell lines in 2-D as well as 3-D where α-KG was added to the media compared to the controls. It was evident that the chondrocytes were metabolically more active in the case of α-KG containing samples as early extracellular matrix (ECM) accumulation was observed. In comparison to the 6-8 weeks duration required by the chondrocytes for ECM accumulation in normal in-vitro culture conditions, α-KG containing samples showed an earlier accumulation within 3 weeks. In order to further validate the results, scanning electron microscopic (SEM) analysis was performed showed high ECM deposition and cells embedded in the matrix. Homogenous distribution of cells on both the synthesized matrix was reported using 4'-6-diamidino-2-phenylindole (DAPI) and propidium iodide (PI) staining. The results clearly showed reduction in ammonia concentration in α-KG containing samples thus leading to decreased ammonia toxicity that builds up during long cell culture conditions thereby enhancing the proliferation and metabolic activity. Thus α-KG can be used potentially for long batch-cultures for the production of vaccines or antibody as well as can play an important role as a bioactive molecule for in vitro neo-cartilage generation.


Prescription medicines: decision-making preferences of patients who receive different levels of public subsidy.
To compare the relative importance of medicine attributes and decision-making preferences of patients with higher or lower levels of insurance coverage in a publicly funded health care system. Cross-sectional telephone survey of randomly selected regular medicine users aged ≥18 years in the Hunter Valley, NSW, Australia. Questions about 27 medicine attributes and active involvement in decisions to start a new medicine. After adjustment, there were few differences between the 408 concession card holders (high insurance) and 410 general beneficiaries (low insurance) in their assessment of the importance of medicine attributes. For both groups, the explanation of treatment options, establishing the need for the medicine, and medicine efficacy and safety were the most important considerations. Medicine costs, the treatment burden and medicine familiarity were less important; the views of family and friends ranked lowest. There was a statistically significantly greater influence of the regular doctor for the concession card holders than general beneficiaries (93.6 vs. 84%, adjusted OR 2.80, 95% CI 1.31, 5.99). Concession card holders were more likely to favour doctors having more say in the decision-making process (crude OR 1.69, 95% CI 1.28, 2.24), and more likely to report the most recent treatment decision being made by the doctor alone, compared with general beneficiaries (61.2 vs. 40.3%). Medicine need, efficacy and safety are viewed as paramount for most patients, irrespective of insurance status. While patients report the importance of participation in treatment decisions, delegation of decision making to the doctor was common in practice.


Role of immunohistochemistry in the era of genetic testing in MYC-positive aggressive B-cell lymphomas: a study of 209 cases.
MYC rearrangements with or without BCL2 rearrangements have been shown to be associated with poor prognosis and inferior survival in diffuse large B-cell lymphomas (DLBCL). Most of these cases are still diagnosed by fluorescent in situ hybridisation (FISH) testing, which is expensive, requires expertise and is not routinely available in all laboratories. Immunohistochemistry (IHC) is widely available and has the potential to be used as a screening test to identify cases with increased protein expression and select cases that require confirmatory testing. We correlated the expression of MYC and BCL2 by IHC with FISH studies in an attempt to define a cut-off value, which can be used by laboratories to select cases requiring confirmatory FISH testing. The prevalence of MYC-positive DLBCL and double-hit lymphoma (DHL) has also been studied. 209 cases comprising of 15 cases of Burkitt lymphoma (BL), 13 cases of intermediate BL/DLBCL and 181 cases of DLBCL were included. IHC and FISH for MYC and BCL2 were performed and the results were correlated. The prevalence of MYC-positive DLBCL and MYC/BCL2DHL was 13.4% and 7.4%, respectively, in our study. Germinal-centre subtype was more common in MYC-positive DLBCL and DHL. MYC-positive DLBCL also showed higher median Ki-67 (>90%) and CD10 positivity as compared with MYC-negative cases. IHC can be used for screening cases, which require further confirmatory FISH testing. We recommend a cut-off value of ≥30% for MYC by IHC; however, international standardisation of these values is necessary to provide uniformity among laboratories.


An extracellular steric seeding mechanism for Eph-ephrin signaling platform assembly.
Erythropoetin-producing hepatoma (Eph) receptors are cell-surface protein tyrosine kinases mediating cell-cell communication. Upon activation, they form signaling clusters. We report crystal structures of the full ectodomain of human EphA2 (eEphA2) both alone and in complex with the receptor-binding domain of the ligand ephrinA5 (ephrinA5 RBD). Unliganded eEphA2 forms linear arrays of staggered parallel receptors involving two patches of residues conserved across A-class Ephs. eEphA2-ephrinA5 RBD forms a more elaborate assembly, whose interfaces include the same conserved regions on eEphA2, but rearranged to accommodate ephrinA5 RBD. Cell-surface expression of mutant EphA2s showed that these interfaces are critical for localization at cell-cell contacts and activation-dependent degradation. Our results suggest a 'nucleation' mechanism whereby a limited number of ligand-receptor interactions 'seed' an arrangement of receptors which can propagate into extended signaling arrays.


Tick-borne thogoto virus infection in mice is inhibited by the orthomyxovirus resistance gene product Mx1.
We show that tick-transmitted Thogoto virus is sensitive to interferon-induced nuclear Mx1 protein, which is known for its specific antiviral action against orthomyxoviruses. Influenza virus-susceptible BALB/c mice (lacking a functional Mx1 gene) developed severe disease symptoms and died within days after intracerebral or intraperitoneal infection with a lethal challenge dose of Thogoto virus. In contrast, Mx1-positive congenic, influenza virus-resistant BALB.A2G-Mx1 mice remained healthy and survived. Likewise, A2G, congenic B6.A2G-Mx1 and CBA.T9-Mx1 mice (derived from influenza virus-resistant wild mice) as well as Mx1-transgenic 979 mice proved to be resistant. Peritoneal macrophages and interferon-treated embryo cells from resistant mice exhibited the same resistance phenotype in vitro. Moreover, stable lines of transfected mouse 3T3 cells that constitutively express Mx1 protein showed increased resistance to Thogoto virus infection. We conclude that an Mx1-sensitive step has been conserved during evolution of orthomyxoviruses and suggest that the Mx1 gene in rodents may serve to combat infections by influenza virus-like arboviruses.


Naturally occurring double-stranded RNA and immune responses. Effects on plaque-forming cells and antibody formation.
A highly purified preparation of double-stranded RNA, obtained from virus-like particles in Penicillium cultures, was found to affert humoral immune responses in mice differentially depending on its time of administration in realtion to antigen. Double-stranded RNA administered with antigen, or a few hours after antigen, produced a variable degree of enhancement of plaque-forming cell numbers or agglutinating antibody levels depending on the antigen involved. Administration of double-stranded RNA 24 hours before antigen invariably produced a suppressed response. In mice which were either specifically hyporesponsive (tolerant) or non-specifically hyporesponsive (due to age or immunosuppressive drugs) double-stranded RNA administered with antigen resulted in a nearly normal immune response.


Development of a BCG challenge model for the testing of vaccine candidates against tuberculosis in cattle.
Vaccination is being considered as part of a sustainable strategy for the control of bovine tuberculosis (BTB) in the UK. The live attenuated Mycobacterium bovis bacillus Calmette-Guerin (BCG) has been used experimentally to vaccinate cattle against BTB. However, BCG confers partial protection against BTB and therefore, there is a need to develop improved vaccines. BTB vaccine efficacy experiments require the use of biosafety level 3 facilities which are expensive to maintain, generally oversubscribed and represent a bottle neck for the testing of vaccine candidates. One indicator of the induction of protective responses would be the ability of the host's immune response to control/kill mycobacteria. In this work we have evaluated an intranodal BCG challenge for the selection of vaccine candidates at biosafety level 2 which are capable of inducing mycobactericidal responses. To our knowledge, this is the first such report. Whilst BCG only confers partial protection, it is still the standard against which other vaccines are judged. Therefore we tested the BCG intranodal challenge in BCG (Danish strain) vaccinated cattle and showed that vaccinated cattle had lower BCG cfu counts than naïve cattle at 14 and 21 days after intranodal challenge with BCG (Tokyo strain). This model could help prioritize competing TB vaccine candidates and exploration of primary and secondary immune responses to mycobacteria.


Machine learning and topological data analysis identify unique features of human papillae in 3D scans.
The tongue surface houses a range of papillae that are integral to the mechanics and chemistry of taste and textural sensation. Although gustatory function of papillae is well investigated, the uniqueness of papillae within and across individuals remains elusive. Here, we present the first machine learning framework on 3D microscopic scans of human papillae ([Formula: see text]), uncovering the uniqueness of geometric and topological features of papillae. The finer differences in shapes of papillae are investigated computationally based on a number of features derived from discrete differential geometry and computational topology. Interpretable machine learning techniques show that persistent homology features of the papillae shape are the most effective in predicting the biological variables. Models trained on these features with small volumes of data samples predict the type of papillae with an accuracy of 85%. The papillae type classification models can map the spatial arrangement of filiform and fungiform papillae on a surface. Remarkably, the papillae are found to be distinctive across individuals and an individual can be identified with an accuracy of 48% among the 15 participants from a single papillae. Collectively, this is the first evidence demonstrating that tongue papillae can serve as a unique identifier, and inspires a new research direction for food preferences and oral diagnostics.


How are clinician-educators evaluated for educational excellence? A survey of promotion and tenure committee members in the United States.
Background: In recent years, educational leaders have proposed domains of educational excellence and corresponding metrics to objectively measure contributions of clinician-educators for promotion and tenure (P&T). The purpose of this study was to explore whether P&T committees in United States (US) have incorporated these recommendations into practice. Method: The authors conducted a survey of P&T leaders across institutions in US. Items included questions related to institutional tracks for P&T, domains included in promotional packets, metrics for their measurement, and use of an Educator's Portfolio (EP). Results: Respondents from 55 institutions completed the survey. The presence of a teaching academy/society was associated with the presence of a promotion track for clinician-educators (p = 0.04). Only teaching activities (91%), assessment of learners (55%), and educational scholarship (51%) were required by a majority of institutions. Few institutions used objective methods for measuring impact and less than half (47%) required an EP. Discussion: These results highlight both progress in the recognition of clinician-educators while also suggesting discordance in the perspective of educational leaders and the practice of P&T committees. The authors advocate for establishing a national community of expert medical educators who may assist P&T committees in adopting consensus-based criteria and metrics to evaluate clinician-educators' contributions.


Possible neuroprotective property of nicotinic acetylcholine receptors in association with predominant upregulation of glial cell line-derived neurotrophic factor in astrocytes.
The underlying mechanisms are still unclear for the neuroprotective properties of nicotine to date, whereas we have shown functional expression of nicotinic acetylcholine receptors (nAChRs) responsible for the influx of extracellular Ca(2+) in cultured rat cortical astrocytes. In this study, we investigated the possible involvement of astrocytic nAChRs in the neuroprotection by this agonist. Exposure to nicotine predominantly induced mRNA expression of glial cell line-derived neurotrophic factor (GDNF) among the different neurotrophic factors examined in cultured astrocytes, in a manner sensitive to nAChR antagonists, nifedipine, and aCa(2+) chelator. Nicotine significantly increased GDNF in a concentration-dependent manner in cultured astrocytes but not in neurons or neural progenitors even at the highest concentration used. In cultured astrocytes, a transient increase was seen in the expression of mRNA and corresponding protein for GDNF during sustained exposure to nicotine for 24 hr. Cytotoxicity mediated by oxidative, calcium, mitochondrial, or endoplasmic reticulum stress was invariably protected against in cortical neurons cultured with conditioned medium from astrocytes previously exposed to nicotine, and preincubation with the anti-GDNF antibody reduced the neuroprotection by conditioned medium from astrocytes exposed to nicotine. Intraperitoneal administration of nicotine transiently increased the number of cells immunoreactive for both GDNF and glial fibrillary acidic protein in rat cerebral cortex. These results suggest that astrocytic nAChRs play a role in the neuroprotection against different cytotoxins after predominant upregulation of GDNF expression through a mechanism relevant to the acceleration of extracellular Ca(2+) influx in rat brain in a particular situation.


DNA synthesis during yeast sporulation: genetic control of an early developmental event.
In yeast the mating type alleles a and a also control sporulation; heterozygous strains (a/a) sporulate while homozygous strains (a/a or a/a) do not. Net DNA synthesis, an early event preceding sporulation, occurred normally in the heterozygous strains but did not occur in the homozygous strains. Therefore, the a/a allelles also influence early development well before spore formation begins.


DNA N(6)-methyladenine: a new epigenetic mark in eukaryotes?
DNA N(6)-adenine methylation (N(6)-methyladenine; 6mA) in prokaryotes functions primarily in the host defence system. The prevalence and significance of this modification in eukaryotes had been unclear until recently. Here, we discuss recent publications documenting the presence of 6mA in Chlamydomonas reinhardtii, Drosophila melanogaster and Caenorhabditis elegans; consider possible roles for this DNA modification in regulating transcription, the activity of transposable elements and transgenerational epigenetic inheritance; and propose 6mA as a new epigenetic mark in eukaryotes.


Inducible expression of the cell surface heparan sulfate proteoglycan syndecan-2 (fibroglycan) on human activated macrophages can regulate fibroblast growth factor action.
Monocyte/macrophages play important roles in regulating tissue growth and angiogenesis through the controlled release of heparin-binding growth factors such as fibroblast growth factor (FGF), vascular endothelial growth factor, and heparin binding epidermal growth factor. The action of these potent growth mediators is known to be regulated by adsorption to heparan sulfate proteoglycans (HSPGs) on the surface and within the extracellular matrix of other neighboring cells, which respectively promote or restrict interactions with their signal-transducing receptors on target cells. Here we report on the nature of HSPGs inducibly expressed on the surface of macrophages that confer these cells with the capacity to regulate endogenous growth factor activity. We reveal that activated human macrophages express only a single major 48-kDa cell surface HSPG, syndecan-2 (fibroglycan) as the result of de novo RNA and protein synthesis. In addition, we demonstrate this macrophage HSPG selectively binds the macrophage-derived growth factors FGF-2, vascular endothelial growth factor and heparin binding EGF and can present FGF-2 in a form that transactivates receptor-bearing BaF32 cells. These results define a novel and unique proteoglycan profile for macrophages and imply a key role for syndecan-2 in the delivery of sequestered growth factors by inflammatory macrophages for productive binding to their appropriate target cells in vivo.


Antibiotic susceptibility of plant-derived lactic acid bacteria conferring health benefits to human.
Lactic acid bacteria (LAB) confer health benefits to human when administered orally. We have recently isolated several species of LAB strains from plant sources, such as fruits, vegetables, flowers, and medicinal plants. Since antibiotics used to treat bacterial infection diseases induce the emergence of drug-resistant bacteria in intestinal microflora, it is important to evaluate the susceptibility of LAB strains to antibiotics to ensure the safety and security of processed foods. The aim of the present study is to determine the minimum inhibitory concentration (MIC) of antibiotics against several plant-derived LAB strains. When aminoglycoside antibiotics, such as streptomycin (SM), kanamycin (KM), and gentamicin (GM), were evaluated using LAB susceptibility test medium (LSM), the MIC was higher than when using Mueller-Hinton (MH) medium. Etest, which is an antibiotic susceptibility assay method consisting of a predefined gradient of antibiotic concentrations on a plastic strip, is used to determine the MIC of antibiotics world-wide. In the present study, we demonstrated that Etest was particularly valuable while testing LAB strains. We also show that the low susceptibility of the plant-derived LAB strains against each antibiotic tested is due to intrinsic resistance and not acquired resistance. This finding is based on the whole-genome sequence information reflecting the horizontal spread of the drug-resistance genes in the LAB strains.


Keeping a Good Attitude: A Quaternion-Based Orientation Filter for IMUs and MARGs.
Orientation estimation using low cost sensors is an important task for Micro Aerial Vehicles (MAVs) in order to obtain a good feedback for the attitude controller. The challenges come from the low accuracy and noisy data of the MicroElectroMechanical System (MEMS) technology, which is the basis of modern, miniaturized inertial sensors. In this article, we describe a novel approach to obtain an estimation of the orientation in quaternion form from the observations of gravity and magnetic field. Our approach provides a quaternion estimation as the algebraic solution of a system from inertial/magnetic observations. We separate the problems of finding the "tilt" quaternion and the heading quaternion in two sub-parts of our system. This procedure is the key for avoiding the impact of the magnetic disturbances on the roll and pitch components of the orientation when the sensor is surrounded by unwanted magnetic flux. We demonstrate the validity of our method first analytically and then empirically using simulated data. We propose a novel complementary filter for MAVs that fuses together gyroscope data with accelerometer and magnetic field readings. The correction part of the filter is based on the method described above and works for both IMU (Inertial Measurement Unit) and MARG (Magnetic, Angular Rate, and Gravity) sensors. We evaluate the effectiveness of the filter and show that it significantly outperforms other common methods, using publicly available datasets with ground-truth data recorded during a real flight experiment of a micro quadrotor helicopter.


Stillbirth Associated With Infection in a Diverse U.S. Cohort.
To better characterize infection-related stillbirth in terms of pathogenesis and microbiology. We conducted a secondary analysis of 512 stillbirths in a prospective, multisite, geographically, racially and ethnically diverse, population-based study of stillbirth in the United States. Cases underwent evaluation that included maternal interview, chart abstraction, biospecimen collection, fetal autopsy, and placental pathology. Recommended evaluations included syphilis and parvovirus serology. Each case was assigned probable and possible causes of death using the INCODE Stillbirth Classification System. Cases where infection was assigned as a probable or possible cause of death were reviewed. For these cases, clinical scenario, autopsy, maternal serology, culture results, and placental pathology were evaluated. For 66 (12.9%) cases of stillbirth, infection was identified as a probable or possible cause of death. Of these, 36% (95% CI 35-38%) were categorized as a probable and 64% (95% CI 62-65%) as a possible cause of death. Infection-related stillbirth occurred earlier than non-infection-related stillbirth (median gestational age 22 vs 28 weeks, P=.001). Fetal bacterial culture results were available in 47 cases (71%), of which 35 (53%) grew identifiable organisms. The predominant species were Escherichia coli (19, 29%), group B streptococcus (GBS) (8, 12%), and enterococcus species (8, 12%). Placental pathology revealed chorioamnionitis in 50 (76%), funisitis in 27 (41%), villitis in 11 (17%), deciduitis in 35 (53%), necrosis in 27 (41%), and viral staining in seven (11%) cases. Placental pathology found inflammation or evidence of infection in 65 (99%) cases and fetal autopsy in 26 (39%) cases. In infection-related stillbirth cases, the likely causative nonbacterial organisms identified were parvovirus in two (3%) cases, syphilis in one (2%) case, cytomegalovirus (CMV) in five (8%) cases, and herpes in one (2%) case. Of infection-related stillbirth cases in a large U.S. cohort, E coli, GBS, and enterococcus species were the most common bacterial pathogens and CMV the most common viral pathogen.


Identification and Characterization of microRNAs during Retinoic Acid-Induced Regeneration of a Molluscan Central Nervous System.
Retinoic acid (RA) is the biologically active metabolite of vitamin A and has become a well-established factor that induces neurite outgrowth and regeneration in both vertebrates and invertebrates. However, the underlying regulatory mechanisms that may mediate RA-induced neurite sprouting remain unclear. In the past decade, microRNAs have emerged as important regulators of nervous system development and regeneration, and have been shown to contribute to processes such as neurite sprouting. However, few studies have demonstrated the role of miRNAs in RA-induced neurite sprouting. By miRNA sequencing analysis, we identify 482 miRNAs in the regenerating central nervous system (CNS) of the mollusc Lymnaeastagnalis, 219 of which represent potentially novel miRNAs. Of the remaining conserved miRNAs, 38 show a statistically significant up- or downregulation in regenerating CNS as a result of RA treatment. We further characterized the expression of one neuronally-enriched miRNA upregulated by RA, miR-124. We demonstrate, for the first time, that miR-124 is expressed within the cell bodies and neurites of regenerating motorneurons. Moreover, we identify miR-124 expression within the growth cones of cultured ciliary motorneurons (pedal A), whereas expression in the growth cones of another class of respiratory motorneurons (right parietal A) was absent in vitro. These findings support our hypothesis that miRNAs are important regulators of retinoic acid-induced neuronal outgrowth and regeneration in regeneration-competent species.


Large tunable fractional delay of slow light pulse and its application to fast optical correlator.
The slow light device based on photonic crystal coupled waveguide was fabricated, and a tunable delay of 72 ps was obtained for 2-ps-wide slow light pulses by local heating, which corresponds to a tunable fractional delay of 36. This value was further enhanced to 110 by compressing the output pulses through self-phase modulation and dispersion compensation in external fibers. We applied this device to optical correlator as a delay scanner, where the fractional delay determines the resolution of the delay scanning. Using this correlator, we successfully observed sub-picosecond pulses at a scan frequency up to 2 kHz, which is 100 times faster than that of mechanical scanners in conventional correlators.


On the energetic stability of solitary water waves.
We study solutions of the water-wave problem for a fluid layer of finite depth in the presence of gravity and surface tension. We use the canonical Hamiltonian formulation by Zakharov in terms of the surface elevation and the trace of the velocity potential on the surface. With a new continuity result for the Dirichlet-Neumann operator in terms of the surface as a function in H(1)(R), we show conditional energetic stability of the trivial solution in certain regions of the parameter space. In the same region we obtain stability of solitary waves under the additional assumption that the second variation of the energy has only one negative eigenvalue. The latter assumption is shown to be fulfilled for the small-amplitude solitary waves first constructed by Amick & Kirchgässner.


Prostate-derived sterile 20-like kinase 2 (PSK2) regulates apoptotic morphology via C-Jun N-terminal kinase and Rho kinase-1.
We have reported previously that human prostate-derived sterile 20-like kinase (PSK) 1 alters actin cytoskeletal organization and binds to microtubules, regulating their organization and stability. We have shown a structurally related protein kinase PSK2, which lacks a microtubule-binding site, activated c-Jun N-terminal kinase (JNK), and induced apoptotic morphological changes that include cell contraction, membrane blebbing, and apoptotic body formation. Apoptotic stimuli increased the catalytic activity of endogenous PSK2 and JNK, and dominant negative JNK or a physiological inhibitor of JNK blocked these apoptotic morphological responses to PSK2, demonstrating a requirement for JNK. PSK2 also stimulated the cleavage of Rho kinase-1 (ROCK-I), and the activity of ROCK-I was required for PSK2 to induce cell contraction and membrane blebbing. The activation of caspases was also needed for the induction of membrane blebbing by PSK2, which was itself a substrate for caspase 3. PSK2 therefore regulates apoptotic morphology associated with the execution phase of apoptosis, which involves dynamic reorganization of the actin cytoskeleton, via downstream targets that include JNK and ROCK-I. Our findings suggest that PSKs form a subgroup of sterile 20 (STE20)-like kinases that regulate different cytoskeletal processes.


Colouring cryo-cooled crystals: online microspectrophotometry.
X-rays can produce a high concentration of radicals within cryo-cooled macromolecular crystals. Some radicals have large extinction coefficients in the visible (VIS) range of the electromagnetic spectrum, and can be observed optically and spectrally. An online microspectrophotometer with high temporal resolution has been constructed that is capable of measuring UV/VIS absorption spectra (200-1100 nm) during X-ray data collection. The typical X-ray-induced blue colour that is characteristic of a wide range of cryo-conditions has been identified as trapped solvated electrons. Disulphide-containing proteins are shown to form disulphide radicals at millimolar concentrations, with absorption maxima around 400 nm. The solvated electrons and the disulphide radicals seem to have a lifetime in the range of seconds up to minutes at 100 K. The temperature dependence of the kinetics of X-ray-induced radical formation is different for the solvated electrons compared with the disulphide radicals. The online microspectrophotometer provides a technique complementary to X-ray diffraction for analysing and characterizing intermediates and redox states of proteins and enzymes.


The challenges of detecting subtle population structure and its importance for the conservation of emperor penguins.
Understanding the boundaries of breeding populations is of great importance for conservation efforts and estimates of extinction risk for threatened species. However, determining these boundaries can be difficult when population structure is subtle. Emperor penguins are highly reliant on sea ice, and some populations may be in jeopardy as climate change alters sea-ice extent and quality. An understanding of emperor penguin population structure is therefore urgently needed. Two previous studies have differed in their conclusions, particularly whether the Ross Sea, a major stronghold for the species, is isolated or not. We assessed emperor penguin population structure using 4,596 genome-wide single nucleotide polymorphisms (SNPs), characterized in 110 individuals (10-16 per colony) from eight colonies around Antarctica. In contrast to a previous conclusion that emperor penguins are panmictic around the entire continent, we find that emperor penguins comprise at least four metapopulations, and that the Ross Sea is clearly a distinct metapopulation. Using larger sample sizes and a thorough assessment of the limitations of different analytical methods, we have shown that population structure within emperor penguins does exist and argue that its recognition is vital for the effective conservation of the species. We discuss the many difficulties that molecular ecologists and managers face in the detection and interpretation of subtle population structure using large SNP data sets, and argue that subtle structure should be taken into account when determining management strategies for threatened species, until accurate estimates of demographic connectivity among populations can be made.


Development of a novel IGRA assay to test T cell responsiveness to HBV antigens in whole blood of chronic Hepatitis B patients.
Interferon gamma release assays (IGRA) have been developed to support easy and fast diagnosis of diseases like tuberculosis, and CMV in transplant patients. IGRAs focus on cellular immunity especially memory T cells and thus also allow rapid screening prior to complex flow cytometric testing. Here, we describe a novel, sensitive whole blood based cytokine release assay capable of assessing T cell responsiveness to HBV antigens in Hepatitis B patients and assessing hepatitis B vaccination status in healthy individuals. Seventy two chronic Hepatitis B patients (CHB), 8 acute hepatitis B patients (AHB) and 80 healthy controls (HC) were tested by ELISA for IFNγ- and IL2-secretion in whole blood after challenge with synthetic peptide libraries of hepatitis B core antigen (HBcAg) or hepatitis B surface antigen (HBsAg). The developed IGRA test reliably differentiated between Hepatitis B patients, vaccinees and unvaccinated healthy controls. Treatment naïve and treated CHB patients showed a weaker IFNγ response to HBcAg (16 ± 5 and 35 ± 28 pg/ml, respectively) compared to the AHB group (82 ± 39 pg/ml), whereas HC remained unresponsive (6 ± 1 pg/ml). IL2 levels after HBcAg challenge were also higher in the AHB group compared to naive and treated CHB as well as HC (47 ± 21 vs. 12 ± 3, 15 ± 10 and 12 ± 9 pg/ml, respectively). HBsAg stimulation led to increased IFNγ and IL2 levels in the AHB group (33 ± 12 and 22 ± 12 pg/ml) and even higher levels in HC due to a high hepatitis B vaccination rate (41 ± 10 and 167 ± 58 pg/ml). Naive and treated CHB patients developed no or only weaker IFNγ or IL2 responses to HBsAg (5 ± 2 and 12 ± 7 pg/ml, for naive CHB, 12 ± 10 and 18 ± 15 pg/ml, for treated CHB). For HC, IL2 release after HBsAg stimulation depicted hepatitis B vaccination status with a diagnostic sensitivity and specificity of 85 % and 90 %. Our novel whole blood based cytokine release assay constitutes an easy and robust tool for screening HBV specific cellular immunity as alternative to flow cytometry or ELISPOT assays.


Ecology and conservation: contributions to One Health.
Although One Health is widely promoted as a more effective approach towards human, animal and ecosystem health, the momentum is still driven largely by health professionals, predominantly from the veterinary sector. While few can doubt the merits of interdisciplinary One Health approaches to tackle complex health problems, operating across the disciplines still presents many challenges. This paper focuses on the contributions of partners from ecology and conservation to One Health approaches, and identifies four broad areas which could act as a focus for practical engagement and bring ecological and conservation objectives more to the forefront of the One Health agenda: i) developing initiatives with shared conservation and health objectives, particularly in and around protected areas and including programmes addressing human reproductive health and mental health; ii) broadening concepts of health to extend beyond indicators of disease to include the assessment of ecological impacts; iii) the integration of ecological and epidemiological monitoring systems within protected areas to support conservation management and wildlife disease surveillance; iv) building partnerships to bring conservation, health, development and animal welfare agencies together to combat threats to global biodiversity and health from the international trade in wildlife and wildlife products.


Defining and quantifying the resilience of responses to disturbance: a conceptual and modelling approach from soil science.
There are several conceptual definitions of resilience pertaining to environmental systems and, even if resilience is clearly defined in a particular context, it is challenging to quantify. We identify four characteristics of the response of a system function to disturbance that relate to "resilience": (1) degree of return of the function to a reference level; (2) time taken to reach a new quasi-stable state; (3) rate (i.e. gradient) at which the function reaches the new state; (4) cumulative magnitude of the function (i.e. area under the curve) before a new state is reached. We develop metrics to quantify these characteristics based on an analogy with a mechanical spring and damper system. Using the example of the response of a soil function (respiration) to disturbance, we demonstrate that these metrics effectively discriminate key features of the dynamic response. Although any one of these characteristics could define resilience, each may lead to different insights and conclusions. The salient properties of a resilient response must thus be identified for different contexts. Because the temporal resolution of data affects the accurate determination of these metrics, we recommend that at least twelve measurements are made over the temporal range for which the response is expected.


Functional Organization of the Ventral Auditory Pathway.
The fundamental problem in audition is determining the mechanisms required by the brain to transform an unlabelled mixture of auditory stimuli into coherent perceptual representations. This process is called auditory-scene analysis. The perceptual representations that result from auditory-scene analysis are formed through a complex interaction of perceptual grouping, attention, categorization and decision-making. Despite a great deal of scientific energy devoted to understanding these aspects of hearing, we still do not understand (1) how sound perception arises from neural activity and (2) the causal relationship between neural activity and sound perception. Here, we review the role of the "ventral" auditory pathway in sound perception. We hypothesize that, in the early parts of the auditory cortex, neural activity reflects the auditory properties of a stimulus. However, in latter parts of the auditory cortex, neurons encode the sensory evidence that forms an auditory decision and are causally involved in the decision process. Finally, in the prefrontal cortex, which receives input from the auditory cortex, neural activity reflects the actual perceptual decision. Together, these studies indicate that the ventral pathway contains hierarchical circuits that are specialized for auditory perception and scene analysis.


Impact of subclinical mastitis on greenhouse gas emissions intensity and profitability of dairy cows in Norway.
Impaired animal health causes both productivity and profitability losses on dairy farms, resulting in inefficient use of inputs and increase in greenhouse gas (GHG) emissions produced per unit of product (i.e. emissions intensity). Here, we used subclinical mastitis as an exemplar to benchmark alternative scenarios against an economic optimum and adjusted herd structure to estimate the GHG emissions intensity associated with varying levels of disease. Five levels of somatic cell count (SCC) classes were considered namely 50,000 (i.e. SCC50), 200,000, 400,000, 600,000 and 800,000cells/mL (milliliter) of milk. The effects of varying levels of SCC on milk yield reduction and consequential milk price penalties were used in a dynamic programming (DP) model that maximizes the profit per cow, represented as expected net present value, by choosing optimal animal replacement rates. The GHG emissions intensities associated with different levels of SCC were then computed using a farm-scale model (HolosNor). The total culling rates of both primiparous (PP) and multiparous (MP) cows for the five levels of SCC scenarios estimated by the model varied from a minimum of 30.9% to a maximum of 43.7%. The expected profit was the highest for cows with SCC200 due to declining margin over feed, which influenced the DP model to cull and replace more animals and generate higher profit under this scenario compared to SCC50. The GHG emission intensities for the PP and MP cows with SCC50 were 1.01kg (kilogram) and 0.95kg carbon dioxide equivalents (CO2e) per kg fat and protein corrected milk (FPCM), respectively, with the lowest emissions being achieved in SCC50. Our results show that there is a potential to reduce the farm GHG emissions intensity by 3.7% if the milk production was improved through reducing the level of SCC to 50,000cells/mL in relation to SCC level 800,000cells/mL. It was concluded that preventing and/or controlling subclinical mastitis consequently reduces the GHG emissions per unit of product on farm that results in improved profits for the farmers through reductions in milk losses, optimum culling rate and reduced feed and other variable costs. We suggest that further studies exploring the impact of a combination of diseases on emissions intensity are warranted.


Comorbidities in osteoarthritis (ComOA): a combined cross-sectional, case-control and cohort study using large electronic health records in four European countries.
Osteoarthritis (OA) is one of the leading chronic conditions in the older population. People with OA are more likely to have one or more other chronic conditions than those without. However, the temporal associations, clusters of the comorbidities, role of analgesics and the causality and variation between populations are yet to be investigated. This paper describes the protocol of a multinational study in four European countries (UK, Netherlands, Sweden and Spain) exploring comorbidities in people with OA. This multinational study will investigate (1) the temporal associations of 61 identified comorbidities with OA, (2) the clusters and trajectories of comorbidities in people with OA, (3) the role of analgesics on incidence of comorbidities in people with OA, (4) the potential biomarkers and causality between OA and the comorbidities, and (5) variations between countries.A combined case-control and cohort study will be conducted to find the temporal association of OA with the comorbidities using the national or regional health databases. Latent class analysis will be performed to identify the clusters at baseline and joint latent class analysis will be used to examine trajectories during the follow-up. A cohort study will be undertaken to evaluate the role of non-steroidal anti-inflammatory drugs (NSAIDs), opioids and paracetamol on the incidence of comorbidities. Mendelian randomisation will be performed to investigate the potential biomarkers for causality between OA and the comorbidities using the UK Biobank and the Rotterdam Study databases. Finally, a meta-analyses will be used to examine the variations and pool the results from different countries. Research ethics was obtained according to each database requirement. Results will be disseminated through the FOREUM website, scientific meetings, publications and in partnership with patient organisations.


Essential Emergency and Critical Care: a consensus among global clinical experts.
Globally, critical illness results in millions of deaths every year. Although many of these deaths are potentially preventable, the basic, life-saving care of critically ill patients are often overlooked in health systems. Essential Emergency and Critical Care (EECC) has been devised as the care that should be provided to all critically ill patients in all hospitals in the world. EECC includes the effective care of low cost and low complexity for the identification and treatment of critically ill patients across all medical specialties. This study aimed to specify the content of EECC and additionally, given the surge of critical illness in the ongoing pandemic, the essential diagnosis-specific care for critically ill patients with COVID-19. In a Delphi process, consensus (>90% agreement) was sought from a diverse panel of global clinical experts. The panel iteratively rated proposed treatments and actions based on previous guidelines and the WHO/ICRC's Basic Emergency Care. The output from the Delphi was adapted iteratively with specialist reviewers into a coherent and feasible package of clinical processes plus a list of hospital readiness requirements. The 269 experts in the Delphi panel had clinical experience in different acute medical specialties from 59 countries and from all resource settings. The agreed EECC package contains 40 clinical processes and 67 requirements, plus additions specific for COVID-19. The study has specified the content of care that should be provided to all critically ill patients. Implementing EECC could be an effective strategy for policy makers to reduce preventable deaths worldwide.


Melatonin as a potential therapy for sepsis: a phase I dose escalation study and an ex vivo whole blood model under conditions of sepsis.
Sepsis is a massive inflammatory response mediated by infection, characterized by oxidative stress, release of cytokines, and mitochondrial dysfunction. Melatonin accumulates in mitochondria, and both it and its metabolites have potent antioxidant and anti-inflammatory activities and may be useful in sepsis. We undertook a phase I dose escalation study in healthy volunteers to assess the tolerability and pharmacokinetics of 20, 30, 50, and 100 mg oral doses of melatonin. In addition, we developed an ex vivo whole blood model under conditions mimicking sepsis to determine the bioactivity of melatonin and the major metabolite 6-hydroxymelatonin at relevant concentrations. For the phase I trial, oral melatonin was given to five subjects in each dose cohort (n = 20). Blood and urine were collected for measurement of melatonin and 6-hydroxymelatonin, and symptoms and physiological measures were assessed. Validated sleep scales were completed. No adverse effects after oral melatonin, other than mild transient drowsiness with no effects on sleeping patterns, were seen, and no symptoms were reported. Melatonin was rapidly cleared at all doses with a median [range] elimination half-life of 51.7 [29.5-63.2] min across all doses. There was considerable variability in maximum melatonin levels within each dose cohort, but 6-hydoxymelatonin sulfate levels were less variable and remained stable for several hours. For the ex vivo study, blood from 20 volunteers was treated with lipopolysaccharide and peptidoglycan plus a range of concentrations of melatonin/6-hydroxymelatonin. Both melatonin and 6-hydroxymelatonin had beneficial effects on sepsis-induced mitochondrial dysfunction, oxidative stress, and cytokine responses at concentrations similar to those achieved in vivo.


Multi-wavelength Transmission-Reflection Analysis for fiber monitoring.
We propose and implement a novel approach based on multi-wavelength Transmission-Reflection Analysis (MW-TRA) technique for monitoring lossy events (e.g. disconnected connectors, fiber breaks and fiber bendings) along an optical fiber link. By launching un-modulated continuous-wave lights carried by different wavelengths into the fiber and measuring their transmitted and reflected/backscattered optical powers, our proposed MW-TRA scheme is able to localize any lossy event (including both reflective and non-reflective) and to quantify the corresponding insertion and return losses with high accuracy.


A chemical toolbox for the study of bromodomains and epigenetic signaling.
Bromodomains (BRDs) are conserved protein interaction modules which recognize (read) acetyl-lysine modifications, however their role(s) in regulating cellular states and their potential as targets for the development of targeted treatment strategies is poorly understood. Here we present a set of 25 chemical probes, selective small molecule inhibitors, covering 29 human bromodomain targets. We comprehensively evaluate the selectivity of this probe-set using BROMOscan and demonstrate the utility of the set identifying roles of BRDs in cellular processes and potential translational applications. For instance, we discovered crosstalk between histone acetylation and the glycolytic pathway resulting in a vulnerability of breast cancer cell lines under conditions of glucose deprivation or GLUT1 inhibition to inhibition of BRPF2/3 BRDs. This chemical probe-set will serve as a resource for future applications in the discovery of new physiological roles of bromodomain proteins in normal and disease states, and as a toolset for bromodomain target validation.


Diagnosis and management of Waldenström macroglobulinemia: Mayo stratification of macroglobulinemia and risk-adapted therapy (mSMART) guidelines.
Waldenström macroglobulinemia is a B-cell malignancy with lymphoplasmacytic infiltration in the bone marrow or lymphatic tissue and a monoclonal immunoglobulin M protein (IgM) in the serum. It is incurable with current therapy, and the decision to treat patients as well as the choice of treatment can be complex. Using a risk-adapted approach, we provide recommendations on timing and choice of therapy. Patients with smoldering or asymptomatic Waldenström macroglobulinemia and preserved hematologic function should be observed without therapy. Symptomatic patients with modest hematologic compromise, IgM-related neuropathy that requires therapy, or hemolytic anemia unresponsive to corticosteroids should receive standard doses of rituximab alone without maintenance therapy. Patients who have severe constitutional symptoms, profound hematologic compromise, symptomatic bulky disease, or hyperviscosity should be treated with the DRC (dexamethasone, rituximab, cyclophosphamide) regimen. Any patient with symptoms of hyperviscosity should first be treated with plasmapheresis. For patients who experience relapse after a response to initial therapy of more than 2 years' duration, the original therapy should be repeated. For patients who had an inadequate response to initial therapy or a response of less than 2 years' duration, an alternative agent or combination should be used. Autologous stem cell transplant should be considered in all eligible patients with relapsed disease.


An easy-to-prepare mini-scaffold for DNA origami.
The DNA origami strategy for assembling designed supramolecular complexes requires ssDNA as a scaffold strand. A system is described that was designed approximately one third the length of the M13 bacteriophage genome for ease of ssDNA production. Folding of the 2404-base ssDNA scaffold into a variety of origami shapes with high assembly yields is demonstrated.


Unexpected role of interferon-γ in regulating neuronal connectivity and social behaviour.
Immune dysfunction is commonly associated with several neurological and mental disorders. Although the mechanisms by which peripheral immunity may influence neuronal function are largely unknown, recent findings implicate meningeal immunity influencing behaviour, such as spatial learning and memory. Here we show that meningeal immunity is also critical for social behaviour; mice deficient in adaptive immunity exhibit social deficits and hyper-connectivity of fronto-cortical brain regions. Associations between rodent transcriptomes from brain and cellular transcriptomes in response to T-cell-derived cytokines suggest a strong interaction between social behaviour and interferon-γ (IFN-γ)-driven responses. Concordantly, we demonstrate that inhibitory neurons respond to IFN-γ and increase GABAergic (γ-aminobutyric-acid) currents in projection neurons, suggesting that IFN-γ is a molecular link between meningeal immunity and neural circuits recruited for social behaviour. Meta-analysis of the transcriptomes of a range of organisms reveals that rodents, fish, and flies elevate IFN-γ/JAK-STAT-dependent gene signatures in a social context, suggesting that the IFN-γ signalling pathway could mediate a co-evolutionary link between social/aggregation behaviour and an efficient anti-pathogen response. This study implicates adaptive immune dysfunction, in particular IFN-γ, in disorders characterized by social dysfunction and suggests a co-evolutionary link between social behaviour and an anti-pathogen immune response driven by IFN-γ signalling.


Identifying Risk and Resilience Factors Associated With the Likelihood of Seeking Mental Health Care Among U.S. Army Soldiers-in-Training.
The Department of Defense aims to maintain mission readiness of its service members. Therefore, it is important to understand factors associated with treatment seeking in order to identify areas of prevention and intervention early in a soldier's career that can promote positive functioning and increase their likelihood of seeking mental health care when necessary. Using a theory of planned behavior lens, this study identified potential barriers (risk) and facilitators (resilience) to treatment seeking among 24,717 soldiers-in-training who participated in the New Soldiers Study component of the "Army Study to Assess Risk and Resilience in Servicemembers" (Army STARRS). Approval for this study was granted by the University of Iowa IRB # 201706739. Hierarchal linear regression modeling and independent samples t-tests were used to examine associations between demographics and study variables, intersections of risk and resilience, and to explore differences in the likelihood of seeking help based on mental health diagnoses. A four-stage hierarchical linear regression was conducted, using likelihood of help-seeking as the dependent variable, to identify the most salient factors related to help-seeking. "Step one" of the analysis revealed soldiers-in-training who identified as female, Hispanic or Other ethnicity, and married, divorced, or separated reported a greater likelihood of seeking help. "Step two" of the analysis indicated soldiers-in-training with a history of sexual trauma, experience of impaired parenting, and clinical levels of mental health symptomatology (anxiety, depression, PTSD) reported a greater likelihood of seeking help. Inversely, soldiers-in-training with a history of emotional trauma and parental absence/separation reported a lower likelihood of seeking help. "Step three" of the analysis demonstrated soldiers-in-training with a prior history of seeking help and larger social networks had a greater likelihood of seeking help. "Step four" of the analysis revealed several interactive effects between risk and resilience factors. Specifically, soldiers-in-training who reported greater depressive symptomatology in combination with prior history of treatment seeking reported a greater likelihood of help seeking, whereas soldiers-in-training who reported prior sexual trauma and PTSD in combination with large social networks reported a lower likelihood of seeking help. Finally, a greater percentage of soldiers-in-training with clinical levels of anxiety, depression, and PTSD indicated they would likely seek help in comparison to soldiers-in-training without clinical symptoms. Findings suggest few soldiers-in-training are likely to seek help when experiencing a problem. General efforts to encourage help-seeking when needed are warranted with particular focus on subsets of soldiers-in-training (eg, men, those with a history of some adverse childhood experiences). Strengths of this study include the examination of a large sample of soldiers-in-training to identify possible leverage points for early intervention or prevention prior to entering stressful military operating environments. Limitations of this study include the examination of only one military branch and exclusion of soldiers not "in-training." Future studies could consider replicating the current study using a sample of military personnel longitudinally to track behavioral trends as well as looking at military populations outside of basic combat training.


Co-use of alcohol, tobacco, and licit and illicit controlled substances among pregnant and non-pregnant women in the United States: Findings from 2006 to 2014 National Survey on Drug Use and Health (NSDUH) data.
The use, misuse and co-use of alcohol, cannabis, tobacco, and other licit and illicit controlled substances has increased in past decades leading to higher rates of morbidity, overdose, and mortality in women of reproductive age. Co-use compounds the adverse health effects of substance use compared to single-use of similar substances. Little is known about the full range of substance combinations used by pregnant and non-pregnant women. We sought to describe patterns of co-use of alcohol, tobacco, and controlled substances, and examine correlates of co-use in a nationally-representative sample of women. Cross-sectional study using self-reported survey data from 2006 to 2014 for women ages 18-49 years (N = 160,371) in National Survey on Drug Use and Health data. We use weighted proportions and 95% confidence intervals (CI) to report differences in substance use patterns in pregnant and non-pregnant women. Multivariate logistic regression models assessed association between characteristics and type of substance use pattern. Prevalence of substance co-use among pregnant women is 5.1% and among non-pregnant women is 23.6%. Nearly all of the most frequent co-use patterns included alcohol, cannabis, or tobacco. Determinants of co-use among pregnant women included: younger age (18-25 years) compared to ≥ 26 years [AOR (95% CI): 1.81 (1.18, 2.80)]; and past year history of substance use [AOR 5.42 (3.59, 8.20)]. Co-use of several substances, including and especially of tobacco, alcohol and cannabis, persists among pregnant women in the United States. Efforts that aim to improve maternal and child health should address the complexity of substance use during pregnancy, including and beyond opioids.


Providing Unique Support for Health Study Among Young Black and Latinx Men Who Have Sex With Men and Young Black and Latinx Transgender Women Living in 3 Urban Cities in the United States: Protocol for a Coach-Based Mobile-Enhanced Randomized Control Trial.
The US National HIV/AIDS Strategy 2020 calls for increasing access to care, improving outcomes of people living with HIV, and targeting biomedical prevention efforts, including access to pre-exposure prophylaxis (PrEP) in communities where HIV is most heavily concentrated. The cities of Baltimore, Maryland (MD); Washington, DC; and Philadelphia, Pennsylvania (PA) are disproportionately burdened by high rates of new cases of HIV infection, with high prevalence among young Black and Latinx men who have sex with men (YBLMSM) and young Black and Latinx transgender women (YBLTW) aged 15-24 years. This study aims (1) to identify and recruit YBLMSM and YBLTW who are at risk or living with HIV in Baltimore, MD; Philadelphia, PA; and Washington, DC, using respondent-driven sampling (RDS) with targeted seed selection, and (2) to assess the efficacy of a coach-based mobile-enhanced intervention (MEI) compared with standard of care (SOC) to increase successful engagement and retention into HIV, PrEP, and substance use treatment care across the HIV care and prevention continua in 3 Mid-Atlantic cities. This paper describes the protocol and progress as of October 20, 2019. This study uses a multiphase mixed methods design. The first phase is a formative, qualitative research with focus group discussions and key informant interviews. The second phase consists of evaluating the ability of RDS with targeted seed selection. The third phase includes 2 embedded randomized controlled trials (RCTs), where participants complete a baseline sociobehavioral survey, rapid HIV testing, and eligible youth enroll in parallel status-dependent RCTs that randomize the participant to 1 of 2 study arms: MEI with coach or SOC. Participants are asked to complete a web-based survey and provide biologic specimens-HIV-1 RNA (viral load) or HIV-1 antibody test and urine drug screen-at baseline and at 3, 6, and 12 months, and an exit interview at 18 months. A formative qualitative research was conducted in February 2017 and May 2018, and this led to further refinement of recruitment and study methods. Aim 1 recruitment began in September 2017 with subsequent enrollment into the RCTs. Recruitment is ongoing with 520 participants screened and 402 (77.3%) enrolled in aim 1 by October 2020. Of these, 159 are enrolled in the 2 randomized trials: 36 (22.6%) HIV-positive not virally suppressed (aim 2) and 123 (77.4%) high-risk HIV-negative (aim 3). This study has the potential to significantly impact the medical and substance use services provided to YBLMSM and YBLTW in the United States by providing rigorous scientific evidence outlining approaches and strategies that improve the uptake and engagement of YBLMSM and YBLTW in the HIV treatment and prevention continuum. ClinicalTrials.gov NCT03194477; https://clinicaltrials.gov/ct2/show/NCT03194477. DERR1-10.2196/17269.


Screening for Down's syndrome: effects, safety, and cost effectiveness of first and second trimester strategies.
To compare the effects, safety, and cost effectiveness of antenatal screening strategies for Down's syndrome. Analysis of incremental cost effectiveness. United Kingdom. Number of liveborn babies with Down's syndrome, miscarriages due to chorionic villus sampling or amniocentesis, health care costs of screening programme, and additional costs and additional miscarriages per additional affected live birth prevented by adopting a more effective strategy. Compared with no screening, the additional cost per additional liveborn baby with Down's syndrome prevented was 22 000 pound sterling for measurement of nuchal translucency. The cost of the integrated test was 51 000 pound sterling compared with measurement of nuchal translucency. All other strategies were more costly and less effective, or cost more per additional affected baby prevented. Depending on the cost of the screening test, the first trimester combined test and the quadruple test would also be cost effective options. The choice of screening strategy should be between the integrated test, first trimester combined test, quadruple test, or nuchal translucency measurement depending on how much service providers are willing to pay, the total budget available, and values on safety. Screening based on maternal age, the second trimester double test, and the first trimester serum test was less effective, less safe, and more costly than these four options.


LifeLines: using visualization to enhance navigation and analysis of patient records.
LifeLines provide a general visualization environment for personal histories. We explore its use for clinical patient records. A Java user interface is described, which presents a one-screen overview of a computerized patient record using timelines. Problems, diagnoses, test results or medications can be represented as dots or horizontal lines. Zooming provides more details; line color and thickness illustrate relationships or significance. The visual display acts as a giant menu, giving direct access to the data.


The HEALing (Helping to End Addiction Long-term SM) Communities Study: Protocol for a cluster randomized trial at the community level to reduce opioid overdose deaths through implementation of an integrated set of evidence-based practices.
Opioid overdose deaths remain high in the U.S. Despite having effective interventions to prevent overdose deaths, there are numerous barriers that impede their adoption. The primary aim of the HEALing Communities Study (HCS) is to determine the impact of an intervention consisting of community-engaged, data-driven selection, and implementation of an integrated set of evidence-based practices (EBPs) on reducing opioid overdose deaths. The HCS is a four year multi-site, parallel-group, cluster randomized wait-list controlled trial. Communities (n = 67) in Kentucky, Massachusetts, New York and Ohio are randomized to active intervention (Wave 1), which starts the intervention in Year 1 or the wait-list control (Wave 2), which starts the intervention in Year 3. The HCS will test a conceptually driven framework to assist communities in selecting and adopting EBPs with three components: 1) a community engagement strategy with local coalitions to guide and implement the intervention; 2) a compendium of EBPs coupled with technical assistance; and 3) a series of communication campaigns to increase awareness and demand for EBPs and reduce stigma. An implementation science framework guides the intervention and allows for examination of the multilevel contexts that promote or impede adoption and expansion of EBPs. The primary outcome, number of opioid overdose deaths, will be compared between Wave 1 and Wave 2 communities during Year 2 of the intervention for Wave 1. Numerous secondary outcomes will be examined. The HCS is the largest community-based implementation study in the field of addiction with an ambitious goal of significantly reducing fatal opioid overdoses.


Selection of obese patients undergoing ambulatory surgery: a systematic review of the literature.
The incidence of obesity has increased over the past 2 decades. In recent years, several studies have assessed perioperative outcomes in obese patients undergoing ambulatory surgery. However, this evidence has not been reviewed and evaluated systematically. We conducted a systematic review of studies published between 1948 and May 2012, assessing perioperative outcome in adult obese patients undergoing ambulatory surgery. All studies were eligible for inclusion if they reported perioperative complications including unplanned hospital admission and readmission. A literature search revealed 23 studies (13 prospective and 10 retrospective), and 1 systematic review assessing laparoscopic bariatric surgery. A total of 106,119 patients were included in the analysis with 62,476 patients included in the prospective trials and 43,643 patients included in the retrospective trials (not including the systematic review of laparoscopic bariatric surgery). Of these, 39,548 patients underwent bariatric surgery. The super obese (body mass index [BMI] >50 kg/m) appear to be at higher risk of complications. Patients undergoing nonbariatric surgery had a lower degree of obesity (BMI approximately 30 kg/m). Patients undergoing bariatric surgery were morbidly obese (BMI >40 kg/m), which is associated with a higher comorbidity burden. However, the lack of increase in unanticipated admission rate in this patient population may be related to thorough preoperative assessment and avoidance of patients with comorbid conditions. The literature lacks adequate information to make strong recommendations regarding appropriate selection of the obese patients scheduled for ambulatory surgery. The literature does indicate that the super obese (BMI >50 kg/ m) do present an increased risk for perioperative complications, while patient with lower BMIs do not seem to present any increased risk as long as any comorbidities are minimal or optimized before surgery. This review also identifies knowledge gaps and recommends future research required to guide optimal selection of obese patients scheduled for ambulatory surgery.


The Yin and Yang of synaptic active zone assembly.
Mechanisms of synapse assembly are relevant for our understanding of neuronal development, as well as the processes of learning and memory. The presynaptic active zone membrane is covered by a protein-rich matrix, which is thought to be important for fast vesicle fusion, as well as potentially contributing to synapse stability. By genetic analysis, matrix proteins of active zones from various families have been shown to promote synapse assembly. New evidence shows that the evolutionarily conserved protein RSY-1 (regulator of synaptogenesis 1) locally inhibits active zone assembly to restrict synapse formation to the correct positions during Caenorhabditis elegans development. Thus, the protein interactions that assemble the architecture of the active zone appear to locally integrate not only positive but also negative signals.


The Community Adaptive Planning Assessment: a clinical tool for documenting future planning with clients.
The objectives of this article are to (a) identify features needed in a clinical tool in order to organize collaborative planning for the future between therapist and client; (b) describe the structure and procedures for use of the Community Adaptive Planning Assessment (CAPA), which was developed to meet these needs; (c) summarize research on the usability, trustworthiness, and clinical effectiveness of the CAPA; and (d) consider future work to further evaluate qualitative tools like the CAPA for clinical and research purposes. Initial and revised versions of the CAPA were evaluated through several studies. Usability was examined through questionnaires completed by therapists who used the CAPA in acute care, rehabilitation, home health, and community programs with a total of 105 clients who had a variety of acute and chronic disabilities. Trustworthiness was evaluated through comparison of information gathered from 21 clients with that from their family members. Clinical effectiveness was evaluated for discharge planning through content analysis of community outcomes of goals and plans established before discharge. Initial studies indicate that the CAPA has sound usability, trustworthiness, and clinical effectiveness for a variety of service delivery systems and with a variety of clients when used by experienced therapists. Findings support use of these three criteria for evaluation of tools designed to document qualitative consultation-based practice. Results are related to broader issues in the profession, including a need for further study of collaborative planning for the future between clients and therapists, ways in which qualitative aspects of practice can be documented efficiently, ways in which outcomes of consultation-based practice can be evaluated, and establishment of criteria for evaluation of emerging qualitative assessments and intervention tools.


A systematic review on the development of asthma and allergic diseases in relation to international immigration: the leading role of the environment confirmed.
The prevalence of asthma and allergic diseases is rising worldwide. Evidence on potential causal pathways of asthma and allergies is growing, but findings have been contradictory, particularly on the interplay between allergic diseases and understudied social determinants of health like migration status. This review aimed at providing evidence for the association between migration status and asthma and allergies, and to explore the mechanisms between migration status and the development of asthma and allergies. Systematic review on asthma and allergies and immigration status in accordance with the guidelines set by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. The pooled odds ratio (OR) of the prevalence of asthma in immigrants compared to the host population was 0.60 (95% CI 0.45-0.84), and the pooled OR for allergies was 1.01 (95% CI 0.62-1.69). The pooled OR for the prevalence of asthma in first generation versus second generation immigrants was 0.37 (95% CI 0.25-0.58). Comparisons between populations in their countries of origin and those that emigrated vary depending on their level of development; more developed countries show higher rates of asthma and allergies. Our findings suggest a strong influence of the environment on the development of asthma and allergic diseases throughout the life course. The prevalence of asthma is generally higher in second generation than first generation immigrants. With length of residence in the host country the prevalence of asthma and allergic diseases increases steadily. These findings are consistent across study populations, host countries, and children as well as adults. Differences have been found to be significant when tested in a linear model, as well as when comparing between early and later age of migration, and between shorter and longer time of residence.


Genetic variability and geographic differentiation among three species of Triatomine bugs (Hemiptera-Reduviidae).
Three species of triatomine bugs, Triatoma sordida, T. guasayana, and T. patagonica, were examined by cytogenetic (C-banded karyotypes and male meiotic process) and isoenzymatic studies. These three species, with different importance as Chagas' disease vectors, were found to be closely related according to their known ethologic, ecologic, and morphologic traits. Although they have the same diploid chromosome number (2n = 22 constituted by 20 autosomes and an XY male/XX female sex mechanism), each species has a distinct chromosomal behavior during male meiosis and a specific amount and localization of C-heterochromatic blocks. Moreover, these chromosome characteristics allowed us to differentiate two T. sordida populations. Isoenzymatic data confirmed the taxonomic status of the three species and together with our cytogenetic results questioned the species homogeneity of T. sordida.


Application of Bayesian network including Microcystis morphospecies for microcystin risk assessment in three cyanobacterial bloom-plagued lakes, China.
Microcystis spp., which occur as colonies of different sizes under natural conditions, have expanded in temperate and tropical freshwater ecosystems and caused seriously environmental and ecological problems. In the current study, a Bayesian network (BN) framework was developed to access the probability of microcystins (MCs) risk in large shallow eutrophic lakes in China, namely, Taihu Lake, Chaohu Lake, and Dianchi Lake. By means of a knowledge-supported way, physicochemical factors, Microcystis morphospecies, and MCs were integrated into different network structures. The sensitive analysis illustrated that Microcystis aeruginosa biomass was overall the best predictor of MCs risk, and its high biomass relied on the combined condition that water temperature exceeded 24 °C and total phosphorus was above 0.2 mg/L. Simulated scenarios suggested that the probability of hazardous MCs (≥1.0 μg/L) was higher under interactive effect of temperature increase and nutrients (nitrogen and phosphorus) imbalance than that of warming alone. Likewise, data-driven model development using a naïve Bayes classifier and equal frequency discretization resulted in a substantial technical performance (CCI = 0.83, K = 0.60), but the performance significantly decreased when model excluded species-specific biomasses from input variables (CCI = 0.76, K = 0.40). The BN framework provided a useful screening tool to evaluate cyanotoxin in three studied lakes in China, and it can also be used in other lakes suffering from cyanobacterial blooms dominated by Microcystis.


Prevalence, location, and size of maxillary sinus septa: panoramic radiograph versus computed tomography scan.
To determine the prevalence, location, and size of maxillary sinus septa, and to compare the results of panoramic radiographs and computed tomography (CT) scans. This study included 30 patients, 17 women and 13 men, with a mean age of 50.9 years (range, 28-73 years), undergoing treatment planning for implant-supported restorations in the maxilla. Three observers analyzed the panoramic radiographs, the conventional CT scans in acetate, and the Implametric 3-dimensional CT (3Dent, Valencia, Spain). The maxillary sinus septa of each patient and the type of septa, as well as its location and size, were recorded. In 60 maxillary sinuses, panoramic radiographs showed 32 septa (53.3%); CT in acetate showed 42 septa (70%); and Implametric 3-dimensional CT showed 40 septa (66.7%). Most septa (60%) were located in the middle region of the maxillary sinus, 22.5% in the posterior region, and 17.5% in the anterior region. The mean height of the septa was 4.78 ± 1.76 mm. Panoramic radiographs led to an erroneous diagnosis in 46.5% of the cases. Maxillary sinus septa are a frequent anatomic variation. They can be found in any of the maxillary sinus regions independently of patient edentulism. The panoramic radiograph can lead to false-positive and false-negative findings in the visualization of septa in almost half of cases. Therefore, whenever a maxillary sinus lift is planned, a thorough study of the affected sinus should be made using CT.


Exploring Spatiotemporal Trends in Commercial Fishing Effort of an Abalone Fishing Zone: A GIS-Based Hotspot Model.
Assessing patterns of fisheries activity at a scale related to resource exploitation has received particular attention in recent times. However, acquiring data about the distribution and spatiotemporal allocation of catch and fishing effort in small scale benthic fisheries remains challenging. Here, we used GIS-based spatio-statistical models to investigate the footprint of commercial diving events on blacklip abalone (Haliotis rubra) stocks along the south-west coast of Victoria, Australia from 2008 to 2011. Using abalone catch data matched with GPS location we found catch per unit of fishing effort (CPUE) was not uniformly spatially and temporally distributed across the study area. Spatial autocorrelation and hotspot analysis revealed significant spatiotemporal clusters of CPUE (with distance thresholds of 100's of meters) among years, indicating the presence of CPUE hotspots focused on specific reefs. Cumulative hotspot maps indicated that certain reef complexes were consistently targeted across years but with varying intensity, however often a relatively small proportion of the full reef extent was targeted. Integrating CPUE with remotely-sensed light detection and ranging (LiDAR) derived bathymetry data using generalized additive mixed model corroborated that fishing pressure primarily coincided with shallow, rugose and complex components of reef structures. This study demonstrates that a geospatial approach is efficient in detecting patterns and trends in commercial fishing effort and its association with seafloor characteristics.


Comparative economic evaluation of data from the ACRIN National CT Colonography Trial with three cancer intervention and surveillance modeling network microsimulations.
To estimate the cost-effectiveness of computed tomographic (CT) colonography for colorectal cancer (CRC) screening in average-risk asymptomatic subjects in the United States aged 50 years. Enrollees in the American College of Radiology Imaging Network National CT Colonography Trial provided informed consent, and approval was obtained from the institutional review board at each site. CT colonography performance estimates from the trial were incorporated into three Cancer Intervention and Surveillance Modeling Network CRC microsimulations. Simulated survival and lifetime costs for screening 50-year-old subjects in the United States with CT colonography every 5 or 10 years were compared with those for guideline-concordant screening with colonoscopy, flexible sigmoidoscopy plus either sensitive unrehydrated fecal occult blood testing (FOBT) or fecal immunochemical testing (FIT), and no screening. Perfect and reduced screening adherence scenarios were considered. Incremental cost-effectiveness and net health benefits were estimated from the U.S. health care sector perspective, assuming a 3% discount rate. CT colonography at 5- and 10-year screening intervals was more costly and less effective than FOBT plus flexible sigmoidoscopy in all three models in both 100% and 50% adherence scenarios. Colonoscopy also was more costly and less effective than FOBT plus flexible sigmoidoscopy, except in the CRC-SPIN model assuming 100% adherence (incremental cost-effectiveness ratio: $26,300 per life-year gained). CT colonography at 5- and 10-year screening intervals and colonoscopy were net beneficial compared with no screening in all model scenarios. The 5-year screening interval was net beneficial over the 10-year interval except in the MISCAN model when assuming 100% adherence and willingness to pay $50,000 per life-year gained. All three models predict CT colonography to be more costly and less effective than non-CT colonographic screening but net beneficial compared with no screening given model assumptions.


Metformin in women with type 2 diabetes in pregnancy (MiTy): a multicentre, international, randomised, placebo-controlled trial.
Although metformin is increasingly being used in women with type 2 diabetes during pregnancy, little data exist on the benefits and harms of metformin use on pregnancy outcomes in these women. We aimed to investigate the effects of the addition of metformin to a standard regimen of insulin on neonatal morbidity and mortality in pregnant women with type 2 diabetes. In this prospective, multicentre, international, randomised, parallel, double-masked, placebo-controlled trial, women with type 2 diabetes during pregnancy were randomly assigned from 25 centres in Canada and four in Australia to receive either metformin 1000 mg twice daily or placebo, added to insulin. Randomisation was done via a web-based computerised randomisation service and stratified by centre and pre-pregnancy BMI (<30 kg/m2 or ≥30 kg/m2) in a ratio of 1:1 using random block sizes of 4 and 6. Women were eligible if they had type 2 diabetes, were on insulin, had a singleton viable pregnancy, and were between 6 and 22 weeks plus 6 days' gestation. Participants were asked to check their fasting blood glucose level before the first meal of the day, before the last meal of the day, and 2 h after each meal. Insulin doses were adjusted aiming for identical glucose targets (fasting glucose <5·3 mmol/L [95 mg/dL], 2-h postprandial glucose <6·7 mmol/L [120 mg/dL]). Study visits were done monthly and patients were seen every 1-4 weeks as was needed for standard clinical care. At study visits blood pressure and bodyweight were measured; patients were asked about tolerance to their pills, any hospitalisations, insulin doses, and severe hypoglycaemia events; and glucometer readings were downloaded to the central coordinating centre. Participants, caregivers, and outcome assessors were masked to the intervention. The primary outcome was a composite of fetal and neonatal outcomes, for which we calculated the relative risk and 95% CI between groups, stratifying by site and BMI using a log-binomial regression model with an intention-to-treat analysis. Secondary outcomes included several relevant maternal and neonatal outcomes. The trial was registered with ClinicalTrials.gov, NCT01353391. Between May 25, 2011, and Oct 11, 2018, we randomly assigned 502 women, 253 (50%) to metformin and 249 (50%) to placebo. Complete data were available for 233 (92%) participants in the metformin group and 240 (96%) in the placebo group for the primary outcome. We found no significant difference in the primary composite neonatal outcome between the two groups (40% vs 40%; p=0·86; relative risk [RR] 1·02 [0·83 to 1·26]). Compared with women in the placebo group, metformin-treated women achieved better glycaemic control (HbA1c at 34 weeks' gestation 41·0 mmol/mol [SD 8·5] vs 43·2 mmol/mol [-10]; 5·90% vs 6·10%; p=0·015; mean glucose 6·05 [0·93] vs 6·27 [0·90]; difference -0·2 [-0·4 to 0·0]), required less insulin (1·1 units per kg per day vs 1·5 units per kg per day; difference -0·4 [95% CI -0·5 to -0·2]; p<0·0001), gained less weight (7·2 kg vs 9·0 kg; difference -1·8 [-2·7 to -0·9]; p<0·0001) and had fewer caesarean births (125 [53%] of 234 in the metformin group vs 148 [63%] of 236 in the placebo group; relative risk [RR] 0·85 [95% CI 0·73 to 0·99]; p=0·031). We found no significant difference between the groups in hypertensive disorders (55 [23%] in the metformin group vs 56 [23%] in the placebo group; p=0·93; RR 0·99 [0·72 to 1·35]). Compared with those in the placebo group, metformin-exposed infants weighed less (mean birthweight 3156 g [SD 742] vs 3375 g [742]; difference -218 [-353 to -82]; p=0·002), fewer were above the 97th centile for birthweight (20 [9%] in the metformin group vs 34 [15%] in the placebo group; RR 0·58 [0·34 to 0·97]; p=0·041), fewer weighed 4000 g or more at birth (28 [12%] in the metformin group vs 44 [19%] in the placebo group; RR 0·65 [0·43 to 0·99]; p=0·046), and metformin-exposed infants had reduced adiposity measures (mean sum of skinfolds 16·0 mm [SD 5·0] vs 17·4 [6·2] mm; difference -1·41 [-2·6 to -0·2]; p=0·024; mean neonatal fat mass 13·2 [SD 6·2] vs 14·6 [5·0]; p=0·017). 30 (13%) infants in the metformin group and 15 (7%) in the placebo group were small for gestational age (RR 1·96 [1·10 to 3·64]; p=0·026). We found no significant difference in the cord c-peptide between groups (673 pmol/L [435] in the metformin group vs 758 pmol/L [595] in the placebo group; p=0·10; ratio of means 0·88 [0·72 to 1·02]). The most common adverse event reported was gastrointestinal (38 events in the metformin group and 38 events in the placebo group). We found several maternal glycaemic and neonatal adiposity benefits in the metformin group. Along with reduced maternal weight gain and insulin dosage and improved glycaemic control, the lower adiposity and infant size measurements resulted in fewer large infants but a higher proportion of small-for-gestational-age infants. Understanding the implications of these effects on infants will be important to properly advise patients who are contemplating the use of metformin during pregnancy. Canadian Institutes of Health Research, Lunenfeld-Tanenbaum Research Institute, University of Toronto.


Perceived Masculinity Predicts U.S. Supreme Court Outcomes.
Previous studies suggest a significant role of language in the court room, yet none has identified a definitive correlation between vocal characteristics and court outcomes. This paper demonstrates that voice-based snap judgments based solely on the introductory sentence of lawyers arguing in front of the Supreme Court of the United States predict outcomes in the Court. In this study, participants rated the opening statement of male advocates arguing before the Supreme Court between 1998 and 2012 in terms of masculinity, attractiveness, confidence, intelligence, trustworthiness, and aggressiveness. We found significant correlation between vocal characteristics and court outcomes and the correlation is specific to perceived masculinity even when judgment of masculinity is based only on less than three seconds of exposure to a lawyer's speech sample. Specifically, male advocates are more likely to win when they are perceived as less masculine. No other personality dimension predicts court outcomes. While this study does not aim to establish any causal connections, our findings suggest that vocal characteristics may be relevant in even as solemn a setting as the Supreme Court of the United States.


Landscape genetics indicate recently increased habitat fragmentation in African forest-associated chafers.
Today, indigenous forests cover less than 0.6% of South Africa's land surface and are highly fragmented. Most forest relicts are very small and typically occur in fire-protected gorges along the eastern Great Escarpment. Yet, they hold a unique and valuable fauna with high endemism and ancient phylogenetic lineages, fostered by long-term climatic stability and complex microclimates. Despite numerous studies on southern African vegetation cover, the current state of knowledge about the natural extension of indigenous forests is rather fragmentary. We use an integrated approach of population-level phylogeography and climatic niche modeling of forest-associated chafer species to assess connectivity and extent of forest habitats since the last glacial maximum. Current and past species distribution models ascertained potential fluctuations of forest distribution and supported a much wider potential current extension of forests based on climatic data. Considerable genetic admixture of mitochondrial and nuclear DNA among many populations and an increase in mean population mutation rate in Extended Bayesian Skyline Plots of all species indicated more extended or better connected forests in the recent past (<5 kya). Genetic isolation of certain populations, as revealed by population differentiation statistics (GST'), as well as landscape connectivity statistics and habitat succession scenarios suggests considerable loss of habitat connectivity. As major anthropogenic influence is likely, conservational actions need to be considered.


Molecular analysis of the pothos latent virus genome.
Pothos latent virus (PoLV) is an isometric virus with a positive-sense, single-stranded RNA genome of 4415 nt. The genome contains five open reading frames (ORF), coding for five proteins with approximate molecular masses of 25, 84, 40, 27 and 14 kDa, respectively. In vitro synthesized PoLV RNA was infectious to Nicotiana benthamiana plants and protoplasts, but could not support replication of the defective interfering (DI) and satellite RNAs associated with Cymbidium ringspot tombusvirus. No DI RNA related to PoLV was generated after repeated passaging with infected sap. Mutagenesis studies defined the role of the ORF 4 product (27 kDa) as a movement protein, and the ORF 5 product (14 kDa) as being responsible for symptom severity. Moreover, it was shown that the coat protein (CP) is important in regulating synthesis of the 14 kDa protein, excess production of which is lethal to infected plants. CP mutants defective in capsid formation infected plants systemically and induced severe necrotic symptoms. Conversely, CP mutants able to form apparently normal virus particles induced symptoms indistinguishable from those elicited by wild-type virus.


A Prognostic Nomogram for Disease-Specific Survival in Patients with Pancreatic Ductal Adenocarcinoma of the Head of the Pancreas Following Pancreaticoduodenectomy.
BACKGROUND This study developed and validated a nomogram to predict patient prognosis for pancreatic ductal adenocarcinoma (PDAC) of the head of the pancreas following pancreaticoduodenectomy. MATERIAL AND METHODS Retrospective data were obtained from 4,383 patients with PDAC of the head of the pancreas who underwent pancreaticoduodenectomy between 2004-2013 from 11 Registries Research Data of the Surveillance, Epidemiology,and End Results (SEER) database. Cox proportional hazards model was used to identify independent risk factors. The predictive accuracy of the nomogram was determined by the concordance index (C-index) and calibration curve. The results were externally validated by comparison with data from 1,743 patients from 7 other Registries Research Data. RESULTS Of the 4,383 patients in the training dataset, median disease-specific survival (DSS) was 17.0 months (range, 1.0-131 months), and postoperative 1-year, 3-year, and 5-year DSS rates were 70.3%, 26.1%, and 16.8%, respectively. Multivariate analysis showed that patient sex, age, tumor grade, regional lymph nodes examined, positive regional lymph nodes, tumor size, extent of local invasion, and tumor metastases were independent risk factors for DSS. The C-index of the internal validation dataset for prediction of DSS was 0.64 (95% CI, 0.63-0.65), which was superior to the American Joint Committee on Cancer (AJCC) staging, 0.57 (95% CI, 0.56-0.58) (P<0.001). The 5-year DSS rates and median DSS time for patients in the low-risk group were significantly greater compared with high-risk group (P<0.001). CONCLUSIONS A validated prognostic disease-specific nomogram for patient survival in PDAC of the head of the pancreas following pancreaticoduodenectomy was developed.