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The objective was to characterize the pharmacokinetics (PK) and pharmacodynamics (PD) of glucagon after injectable or nasal administration and confirm the appropriate therapeutic dose of nasal glucagon (NG) for adult patients. Six clinical studies with PK and five clinical studies with PD (glucose) data were included in the analysis. Doses ranging from 0.5 to 6 mg NG, and 0.5 to 1 mg injectable glucagon were studied. A total of 6284 glucagon and 7130 glucose concentrations from 265 individuals (patients and healthy participants) were available. Population PK/PD modeling was performed using NONMEM. Glucagon exposure and glucose response were simulated for patients administered various doses of NG to confirm the optimal dose. Glucagon PK was well‐described with a single compartment disposition with first‐order absorption and elimination processes. Bioavailability of NG relative to injectable glucagon was 16%. Exposure–response modeling revealed that lower baseline glucose was associated with higher maximum drug effect. The carry‐over effect from prior insulin administration was incorporated into the model through a time‐dependent increase in elimination rate of glucose. Simulations showed that more than 99% of hypoglycemic adult patients would experience treatment success, defined as an increase in blood glucose to ≥70 mg/dL or an increase of ≥20 mg/dL from nadir within 30 min after administration of NG 3 mg. The population PK/PD model adequately described the PK and PD profiles of glucagon after nasal administration. Modeling and simulations confirmed that NG 3 mg is the most appropriate dose for rescue treatment during hypoglycemia emergencies. [ABSTRACT FROM AUTHOR]

The article discusses the importance of restoring peatlands for the future of both people and nature. While the authors agree with the need for restoration, they argue that the approach presented in a previous article overlooks the complex social, cultural, and political dynamics involved in peatland restoration. They emphasize the need for a more inclusive and context-specific approach that takes into account the needs and aspirations of local communities. The authors also highlight the importance of engaging with the value systems and governance issues that affect peatland restoration. [Extracted from the article]

Introduction: Opioid stewardship efforts can promote safe and effective use of opioids to optimize pain control and minimize unintended consequences. The purpose of this study is to assess the difference in post-operative opioid discharge prescribing in patients undergoing coronary artery bypass graft (CABG) surgery following implementation of a tripartite opioid stewardship intervention. Methods: This was a single-center, quality improvement study at a large, quaternary academic medical center. Adult patients undergoing CABG from July 2019 to June 2020 (pre-intervention) and November 2020 to February 2021 (post-intervention) were included. The intervention included adopting hospital-wide post-surgical opioid discharge prescribing guidelines, discharge prescriber education, and electronic medical record changes. The primary outcome was the proportion of patients receiving an opioid prescription at discharge. Secondary outcomes included total morphine milligram equivalents (MME) prescribed and non-opioid analgesics prescribed at discharge. Results: A total of 200 patients were included in the study; 100 pre- and 100 post-intervention. There was no difference in opioid discharge prescribing at discharge (74% pre-intervention vs. 72% post-intervention; P =.87). There was no difference in MMEs prescribed at discharge (145.6 ± 57 pre- vs. 162.2 ± 95 post-; P =.202). No difference was seen in non-opioid analgesic prescriptions prescribed at discharge (35% pre- vs. 40% post-; P =.56). Conclusion: A multipronged opioid stewardship intervention did not lead to a reduction in opioid prescribing at discharge. Post-intervention, there was a non-statistically significant increase in the proportion of patients who received non-opioid analgesics discharge. Future studies should assess the effect of different stewardship interventions on prescribing and patient outcomes. [ABSTRACT FROM AUTHOR]

Background: Nasal glucagon (NG) 3 mg is approved in Japan to treat hypoglycemia in pediatric patients with diabetes, but an NG clinical study has not been performed in Japanese children because of practical and ethical concerns. Objective: The aim of this study is to support the dose rationale for NG 3 mg in Japanese pediatric patients with diabetes using modeling and simulation. Methods: We used a pharmacokinetic/pharmacodynamic bridging approach to extrapolate the available clinical data to Japanese pediatric patients. Population pharmacokinetic/pharmacodynamic modeling was performed using data from seven clinical studies, including five studies in non-Japanese adults, one study in Japanese adults, and one study in non-Japanese pediatric patients. Simulation was then used to estimate glucagon exposure and glucose response after NG 3-mg administration for three age categories of Japanese pediatric patients: 4 to < 8, 8 to < 12, and 12 to < 18 years. Treatment success was defined as an increase in blood glucose to ≥ 70 or ≥ 20 mg/dL from nadir within 30 min after administration of NG 3 mg. Safety was assessed in relation to the predicted maximum glucagon concentration of NG 3 mg using NG clinical trial data and published data on intravenous and intramuscular glucagon. Results: The data showed a rapid and robust glucose response following NG 3 mg in Japanese and non-Japanese adults and non-Japanese pediatric patients, with some differences in glucagon exposure observed across studies. The pharmacokinetic/pharmacodynamic model described the observed clinical data well, and simulations indicated that > 99% of hypoglycemic Japanese pediatric patients in all three age groups would achieve treatment success. Predicted glucose responses to NG 3 mg in Japanese pediatric patients were comparable to those of intramuscular glucagon. Maximum concentration was not associated with the occurrence and severity of common adverse events (nausea, vomiting, and headache) in NG clinical studies. Furthermore, the predicted maximum concentration in Japanese pediatric patients, despite being higher than the observed maximum concentration in NG clinical studies, was substantially lower than the observed maximum concentration of 1 mg of intravenous glucagon, without serious safety issues. Conclusions: This analysis suggests NG 3 mg has robust efficacy without serious safety concerns in Japanese pediatric patients with diabetes. [ABSTRACT FROM AUTHOR]

Background: Both pain catastrophizing and neuropathic pain have been suggested as prospective risk factors for poor postoperative pain outcomes in total joint arthroplasty (TJA). Objective: We hypothesized that pain catastrophizers, as well as patients with pain characterized as neuropathic, would exhibit higher pain scores, higher early complication rates and longer lengths of stay following primary TJA. Methods: A prospective, observational study in a single academic institution included 100 patients with end-stage hip or knee osteoarthritis scheduled for TJA. In pre-surgery, measures of health status, socio-demographics, opioid use, neuropathic pain (PainDETECT), pain catastrophizing (PCS), pain at rest and pain during activity (WOMAC pain items) were collected. The primary outcome measure was the length of stay (LOS) and secondary measures were the discharge destinations, early postoperative complications, readmissions, visual analog scale (VAS) levels and distances walked during the hospital stay. Results: The prevalence of pain catastrophizing (PCS ≥ 30) and neuropathic pain (PainDETECT ≥ 19) was 45% and 20.4%, respectively. Preoperative PCS correlated positively with PainDETECT (rs = 0.501, p = 0.001). The WOMAC positively correlated more strongly with PCS (rs = 0.512 p = 0.01) than with PainDETECT (rs = 0.329 p = 0.038). Neither PCS nor PainDETECT correlated with the LOS. Using multivariate regression analysis, a history of chronic pain medication use was found to predict early postoperative complications (OR 38.1, p = 0.47, CI 1.047–1386.1). There were no differences in the remaining secondary outcomes. Conclusions: Both PCS and PainDETECT were found to be poor predictors of postoperative pain, LOS and other immediate postoperative outcomes following TJA. [ABSTRACT FROM AUTHOR]

• Pediatric wounding patterns varied by age and intent of injury (suicide, homicide, unintentional injury). • Most pediatric suicide victims had injuries to the head and were dead on scene. • Children with homicide and unintentional deaths had more wounding pattern variation and far fewer died on scene. • Public health strategies for firearm injuries should be tailored to pediatrics based on age, intent of firearm use, and wounding pattern. Pediatric firearm injury became the leading cause of death among U.S. children in 2020. Studies evaluating wounding patterns in military and mass casualty shootings have provided insights into treatment and potential salvageability in adults, however, similar studies in the pediatric population do not exist. Hence, our study aimed to analyze wounding patterns of pediatric firearm fatalities and associated demographics and characteristics, such as place of death, to better understand pediatric firearm injuries, potential salvageability, and opportunities to reduce firearm deaths among vulnerable pediatric populations. A retrospective review of the National Violent Death Reporting System from 2005-2017 was performed on patients 18 and younger. Mortalities were stratified by patient age: <12 years and 13-18 years and by intent— homicide, suicide, and unintentional. Comparative and exploratory analyses of demographics, location of death and anatomic location of wounds were performed. Of 8,527 pediatric firearm mortalities identified, 4,728 were homicides, 3,180 were suicides and 619 were unintentional injuries. Suicide victims were most likely to be dead on scene and >90% of suicide victims suffered head/neck injuries. For victims of homicide, younger children were more likely to die on scene (61% vs 44% p < 0.001). The pattern of injury in homicides differed for younger children compared to adolescents, with younger children with more head/neck injuries and older children more thoracic, thoracoabdominal, abdominal, and junctional injuries. In both age groups, children with extremity, abdominal and thoracoabdominal injuries were more likely to die later in the emergency department or inpatient setting. Wounding patterns across pediatric firearm mortalities in the U.S. vary by age and intent. The majority of pediatric firearm deaths were due to head/neck injuries. Children with homicide and unintentional deaths had more wounding pattern variation, including more injuries to the thorax and abdomen, and a much lower rate of dead-on scene than suicide victims. Our study of wounding patterns among U.S. children killed by firearms highlights the complexity of these injuries and offers opportunities for tailored public health strategies across varying vulnerable pediatric populations. [ABSTRACT FROM AUTHOR]

Six-degree-of-freedom (pose) control is often developed on the dual-quaternions since they provide an efficient representation for implementation and a unified translational and rotational approach to control design. In this article we present a control defined on the dual 2×2 unitary groups [DU(2)] which are isomorphic to the dual-quaternions. This formulation brings us to a natural setting for the error kinematics in the form of left-invariant control systems defined on matrix Lie groups. Moreover, it is shown how this setting leads us to define geometric sliding surfaces that allow the resulting pose trajectory to be defined analytically. Furthermore, a chattering-free reaching law is used to drive the states to reach the sliding surface in finite time. It is shown that once the system states reach the geometrically defined sliding surface, the solutions of the states can be obtained as an analytic function of time, initial conditions, and the tuning parameters. This analytic form enables control in the presence of path constraints by analytically selecting an appropriate desired attitude. This approach is applied in simulation to perform a deep-space rendezvous maneuver. [ABSTRACT FROM AUTHOR]

Seram is Indonesia's 8th largest island. It is central to the historic spice islands, once a hotbed for international trade of profitable tree‐products, primarily clove and nutmeg. Recent increased rates of social and ecological change, including costly conflicts, present Seram with new challenges and opportunities for conservation and development. Using place‐based transdisciplinary research methods, we diagnose the problems emerging in Seram. Engaging with actors across multiple scales and sectors, we explore drivers of change, social‐ecological impacts, and institutional arrangements that might achieve improved inclusive and sustainable development outcomes. Traditional and formal governance arrangements require harmonizing to optimize the benefits and costs from large‐scale investments arriving in Seram. Organizations wishing to achieve positive impact can more strategically engage with the broad range of actors to harmonize divergent visions for the future and confront the reality of incoming investments and infrastructure. [ABSTRACT FROM AUTHOR]

This article addresses the coupled orbit-attitude tracking problem using low-thrust propulsion while aiming to minimize on-board spacecraft system communication. An adaptive controller is proposed by employing an event-triggered control and an extended-state-observer, where a simple strategy to tune the observer parameters is provided. Moreover, the event-triggering strategy updates and allocates the control signal to the thrusters at prescribed discrete events and is shown to significantly reduce the data-rate requirement. Finally, the performance of the controller is illustrated through numerical examples. [ABSTRACT FROM AUTHOR]

We examine what can be learnt about climate sensitivity from variability in the surface air temperature record over the instrumental period, from around 1880 to the present. While many previous studies have used the trend in the time series to constrain equilibrium climate sensitivity, it has also been argued that temporal variability may also be a powerful constraint. We explore this question in the context of a simple widely used energy balance model of the climate system. We consider two recently-proposed summary measures of variability and also show how the full information content can be optimally used in this idealised scenario. We find that the constraint provided by variability is inherently skewed and its power is inversely related to the sensitivity itself, discriminating most strongly between low sensitivity values and weakening substantially for higher values. It is only when the sensitivity is very low that the variability can provide a tight constraint. Our investigations take the form of "perfect model" experiments, in which we make the optimistic assumption that the model is structurally perfect and all uncertainties (including the true parameter values and nature of internal variability noise) are correctly characterised. Therefore the results might be interpreted as a best case scenario for what we can learn from variability, rather than a realistic estimate of this. In these experiments, we find that for a moderate sensitivity of 2.5 °C, a 150 year time series of pure internal variability will typically support an estimate with a 5-95 % range of around 5 °C (e.g. 1.9-6.8 °C). Total variability including that due to the forced response, as observed in the detrended observational record, can provide a stronger constraint with an equivalent 5-95 % posterior range of around 4 °C (e.g. 1.7-5.6 °C) even when uncertainty in aerosol forcing is considered. Using a statistical summary of variability based on autocorrelation and the magnitude of residuals after detrending proves somewhat less powerful as a constraint than the full time series in both situations. Our results support the analysis of variability as a potentially useful tool in helping to constrain equilibrium climate sensitivity, but suggest caution in the interpretation of precise results. [ABSTRACT FROM AUTHOR]

Interpreting discourses among implementers of what is termed a “landscape approach” enables us to learn from their experience to improve conservation and development outcomes. We use Q-methodology to explore the perspectives of a group of experts in the landscape approach, both from academic and implementation fields, on what hinderances are in place to the realisation of achieving sustainable landscape management in Indonesia. The results show that, at a generic level, “corruption” and “lack of transparency and accountability” rank as the greatest constraints on landscape functionality. Biophysical factors, such as topography and climate change, rank as the least constraining factors. When participants considered a landscape with which they were most familiar, the results changed: the rapid change of regulations, limited local human capacity and inaccessible data on economic risks increased, while the inadequacy of democratic institutions, “overlapping laws” and “corruption” decreased. The difference indicates some fine-tuning of generic perceptions to the local context and may also reflect different views on what is achievable for landscape approach practitioners. Overall, approximately 55% of variance is accounted for by five discourse factors for each trial. Four overlapped and two discourses were discrete enough to merit different discourse labels. We labelled the discourses (1) social exclusionists, (2) state view, (3) community view, (4) integrationists, (5) democrats, and (6) neoliberals. Each discourse contains elements actionable at the landscape scale, as well as exogenous issues that originate at national and global scales. Actionable elements that could contribute to improving governance included trust building, clarified resource rights and responsibilities, and inclusive representation in management. The landscape sustainability discourses studied here suggests that landscape approach “learners” must focus on ways to remedy poor governance if they are to achieve sustainability and multi-functionality. [ABSTRACT FROM AUTHOR]

A longitudinal vaginal septum is a rare congenital anomaly that can cause dyspareunia, difficulty with tampon insertion, persistent vaginal bleeding, and dysmenorrhea. Various surgical techniques have been described. We present the case of a 14-year-old girl with obesity and diabetes mellitus with uterine didelphys and double vagina with a longitudinal vaginal septum. The patient presented with dysmenorrhea. Resection of the longitudinal vaginal septum using a GIA and EndoGIA (Medtronic, Inc, Doral Fl) stapler device was performed. We introduce a safe and effective technique for resecting a longitudinal vaginal septum using stapler technology. This technique eliminates the potential risk of thermal injury to nearby structures from currently described methods. [ABSTRACT FROM AUTHOR]

GATA1 plays a critical role in differentiation, proliferation, and apoptosis during erythropoiesis. We developed a Gata1 knock-down allele (Gata1.05) that results in GATA1 expression at 5% of endogenous level. In female mice heterozygous for both the Gata1.05 and wild-type alleles, we observed a predisposition to erythroblastic leukemia three to six months after birth. Since no male Gata1.05 progeny survive gestation, we originally maintained heterozygous females in a mixed genetic background of C57BL/6J and DBA/2 strains. Around 30% of these mice reproducibly develop leukemia, but the other subset did not develop leukemia, even though they harbor a high number of preleukemic erythroblasts. These observations prompted us to hypothesize that there may be potential influence of genetic determinants on the progression of Gata1.05-driven hematopoietic precursors to full-blown leukemia. In an initial examination of Gata1.05/X mice backcrossed into C3H/He, BALB/c, DBA/2, C57BL/6J and 129X1/SvJ strains, we discerned that the backgrounds of C57BL/6J and 129X1/SvJ significantly expedited leukemia onset in Gata1.05/X mice. Conversely, backgrounds of C3H/He, BALB/c and DBA/2 did not substantially modify the effect of the Gata1 mutation. This indicates the existence of genetic modifiers that accentuate Gata1.05 leukemogenesis. Subsequent cohort studies evaluated Gata1.05/X mice within mix backgrounds of BALB/c:129X1/SvJ and BALB/c:C57BL/6J. In these settings, Gata1.05-driven leukemia manifested in autosomal dominant patterns within the 129X1/SvJ background and in autosomal recessive patterns within C57BL/6J background. To the best of our knowledge, this study provides the inaugural evidence of genetic modifiers that can reshape the outcome based on leukemia-associated gene signatures. [ABSTRACT FROM AUTHOR]

Agricultural usage of phosphorus (P) is largely driven by the amount of P removed from fields in harvested plant matter as offtake needs to be balanced by P fertilizer application. Reducing P concentration in grains is a way to decrease P offtake and reduce P fertilizer requirements or soil P mining where insufficient P is applied. Our objective was to assesses the genotypic variation for grain P concentration present within the rice gene pool and resolve to what extent it is affected by environment (P supply) or associated with genetic factors. About 2-fold variation in grain P concentrations were detected in two rice diversity panels, however, environmental effects were stronger than genotype effects. Genome wide association studies identified several putative loci associated with grain P concentrations. In most cases this was caused by minor haplotype associations with high grain P concentrations while associations with reduced P concentrations were identified on chromosomes 1, 6, 8, 11 and 12. Only the latter type of locus is of interest in breeding for reduced P concentrations and the most promising locus was at 20.7 Mb on chromosome 8, where a rare haplotype that was absent from all modern varieties studied reduced grain P concentration by 9.3%. This and all other loci were not consistently detected across environments or association panels, confirming that genetic effects were small compared to effects of environment. We conclude that the genetic effects detected were not sufficiently large or consistent to be of utility in plant breeding. Instead breeding efforts may have to rely on small to medium effect mutants already identified and attempt to achieve a more pronounced reduction in grain P concentration through the introgression of these mutants into a single genetic background. [ABSTRACT FROM AUTHOR]

Purpose: LY3015014 is a humanized immunoglobulin G4 (IgG4) monoclonal antibody that binds to the catalytic domain of PCSK9 and reduce low-density lipoprotein cholesterol (LDL-C) in patients with hypercholesterolemia that is poorly controlled by maximally tolerated statin therapy. The objective of this pharmacokinetic/pharmacodynamics (PK/PD) analysis was to characterize the PK and PD properties of LY3015014 and assess the effect of covariates on the LY3015014 PK-PD profiles. Methods: Single and multiple dose data from three phase1 studies in healthy subjects ( n = 133), as well as a phase 2 study in hypercholesterolemia patients ( n = 527) were combined into a single dataset for analysis. In this dataset, healthy subjects received single intravenous (IV) doses of 0.03 to 10 mg/kg, or multiple subcutaneous (SC) doses of 1.0 to 3.0 mg/kg, administered every 2 to 4 weeks, while patients received 20 to 300 mg every 4 weeks or 100 to 300 every 8 weeks. PK/PD analysis was performed using NONMEM (ICON, software version 7.0 level 3). PK and PD modeling were conducted sequentially, with PK parameters fixed during the development of the PK/PD model. PD parameters and estimated intersubject and intrasubject variability were obtained based on pharmacological drug exposure-response relationships. Age, baseline total PCSK9, body weight, diabetes diagnosis, hypercholesterolemia disease status, dose, ezetimibe administration, gender, ethnic origin, metabolic syndrome, and satin administration were evaluated as potential covariates in the PK model. Baseline total PCSK9, baseline LDL-C, diabetes diagnosis, disease status, ezetimibe administration, gender, ethnic origin, metabolic syndrome, and Statin administration were evaluated as potential covariates in the PD model. Results: LY3015014 PK profile was consistent across all the studies and between healthy subjects and hypercholesterolemia patients. The PK time course data were well described by a two compartment PK model with first order absorption, and covariates identified for PK parameters included weight on both clearance (CL) and central volume (V2), dose on CL, race on bioavailability (F), and age on V2. The PD (LDL-C) was described using an indirect response model with LY3015014 acting to stimulate the elimination of LDL-C. Covariates identified to have a statistically significant impact on PD were coadministration of statins, baseline LDL-C, metabolic syndrome status and gender. Conclusions: The population PK/PD model adequately describes the PK and PD profiles of LY3015014. Identification of clinically significant covariates will support the design and dose selection for the pivotal registration studies, ensuring that patients are dosed appropriately. [ABSTRACT FROM AUTHOR]

Aims The objectives of this article are to discuss ethical issues of informed consent in cognitively impaired patients and review considerations for capacity determination. We will also discuss how to evaluate capacity, determine competence, and obtain informed consent when a patient is deemed incompetent. This review emphasizes how to carry out informed consent procedures when capacity is questionable and discusses measures supported for use when determining cognitively impaired patients' ability to consent. Methods Information was gathered from medical and psychological codes of ethics, peer-reviewed journals, published guidelines from health-care organizations (e.g., American Medical Association), and scholarly books. Google Scholar and PsycINFO were searched for articles related to 'informed consent' and 'cognitive impairment' published in English between 1975 and 2014. Relevant sources referenced in retrieved publications were subsequently searched and reviewed. Results We selected 49 sources generated by our search. Sources were included in our review if they presented information related to at least one of our focus areas. These areas included: review of informed consent ethics and procedures, review of cognitive impairment evaluations, recommendations for measuring cognitive capacity, and alternative forms of informed consent. Conclusions Patients' cognitive impairments can hinder the ability of patients to understand treatment options. Evaluating the capacity of patients with cognitive impairment to understand treatment options is vital for valid informed consent and should be guided by best practices. Thus, proper identification of patients with questionable capacity, capacity evaluation, and determination of competence, as well as reliance upon appropriate alternative consent procedures, are paramount. [ABSTRACT FROM AUTHOR]

The article focuses on the use of education as the facilitator of change in the rural primary care consultation in Great Britain. It mentions that the developments in medical and communication technology are challenging the principles of the National Health Service of Great Britain (NHS). It offers information on the delivery of publicly funded healthcare.

Divorce by parliament in the 18th and early 19th centuries was long considered to be the preserve of the wealthy and the upper ranks of society. But while social standing has guided historians' analysis of those who obtained divorce, the standing of those who failed to obtain divorce has been largely overlooked. If rank or status is to serve true analytical purpose, the successful must be set against the failed. Juxtaposing the successes and failures by group across the period reveals that the upper echelons of society were by no means preferred. Even distinctive cases - for instance of multiple failure - were not decided on rank. Status is ultimately shown to be of limited significance. Although the sources are not at all explicit, from the analysis of certain specific cases, it would appear that moral and legal judgments (for example, on collusion) far outweighed any social prejudices. [ABSTRACT FROM AUTHOR]

Purpose - The assessment of a deteriorating masonry structure should lead to an objective evaluation of condition. This process is, however, inevitably subjective owing to human interpretation. The condition of the substrate and the required repairs cannot be guaranteed and may vary from building inspector to inspector. For conservation works the determination of repairs is a function of condition but also directly relates to the underpinning framework of building conservation philosophy. These are also fundamentally subjective. The combination of both condition survey subjectivity and building conservation philosophy's nebulous nature creates the potential for project aesthetic and technical divergence. This paper aims to examine this issue. Design/methodology/approach - The paper presents a literature review and hypothetical case studies. Findings - It has been shown by various researchers that a visual survey is subjective and is therefore prone to differences in reporting. In addition, the application of building conservation philosophy is seen through the perspective of the professional specifying the repairs. The combination of these two factors leads to the potential for significant project outcomes. Originality/value - Subjectivity of evaluation of condition for traditional masonry structures has been little studied by academics and practitioners alike, and it is generally assumed that these yield objective, rational data. This is not necessarily the case. The application of building conservation philosophy to determine repair strategies is also a subjective process. The combination of both may lead to significant project divergence. These combined factors have never previously been discussed. [ABSTRACT FROM AUTHOR]

Point-quarter, random-pairs, 0.004-ha-arm-length-rectangle, and 0.04-ha-circle methods for sampling density, diameters, and size categories were used in an oak-hickory (Quercus-Carya) woodlot. Results from three trials for each method were compared to actual density of trees determined from a total count of trees in the woodlot. With respect to accuracy per time spent, the 0.04-ha circle was the best method and the point-quarter method was the worst. These findings improve on previous studies because, for the first time, repeated trials in the field were employed. [ABSTRACT FROM AUTHOR]

Anecdotal evidence suggests the endangered Great Hornbill (Buceros bicornis) needs mature, large old- growth trees for nesting. We tested this hypothesis by measuring vegetation characteristics al 24 nest sties in southern India and compared these data with that obtained from equal numbers of unused forest sites. Characteristics significantly different from surrounding forest at hornbill nesting sites were several properties related to size of trees. The nesting habitat characteristics of the species stress the importance of mature forests with emergent trees for nests of the Great Hornbill. Trees used by Great Hornbills for nests, compared to unused trees, averaged 18.5 in taller, 0.85 m greater in diameter, and emerged more above the forest canopy by 12.7 m. Canopy height, canopy cover, and number of large trees >75 cm DBH were greater at nest sites than at unused sites by 5.79 m, 3.15%, and 1.63 trees, respectively. [ABSTRACT FROM AUTHOR]

Although it is well established that coronary heart disease (CHD) patients with depression exhibit increased mortality compared with equally ill cardiac patients without depression, the mechanisms mediating this effect remain obscure. Depression is characterized by vulnerability to stress and heightened stress responsiveness, and stress can theoretically act through several biological pathways to contribute to excess mortality from CHD. Mechanisms connecting stress, depression and cardiovascular mortality have not been previously explored in detail. The purpose of this study was to assess the effects of stress and depression on myocardial perfusion and plasma cortisol concentrations in CHD patients. Patients with CHD with and without depression (n = 28) underwent single photon emission computed tomography imaging of myocardial perfusion at rest and during a stressful cognitive challenge. Severity of ischaemia was measured by summing perfusion defect scores across myocardial segments and subtracting out rest from stress scores. Plasma cortisol concentrations were measured at baseline and in response to the stressful challenge. There were no differences in stress-induced myocardial ischaemia or plasma cortisol response to stress between CHD patients with and without depression. Depressed CHD patients with a history of psychological trauma (n = 5) had an increase in stress-induced ischaemia scores [7; standard deviation (SD) = 5] compared with CHD patients with depression without a history of psychological trauma (2 SD = 2) and CHD patients without depression or psychological trauma (1; SD = 2) (F = 8.51; degree of freedom = 2,23; p = 0.007). Eighty per cent of CHD/depression trauma-exposed subjects had stress-induced ischaemia as opposed to 38 per cent of CHD/depression subjects without trauma exposure and 23 per cent of subjects with CHD without depression or trauma. Self-reported nervousness during the cognitive stressor was correlated with stress-induced ischaemia. These preliminary findings suggest that depression with a history of prior exposure to traumatic stress is associated with increased risk for stress-induced cardiovascular ischaemia. Copyright © 2008 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

GATA1 is a prototypical lineage-restricted transcription factor that is central to the correct differentiation, proliferation and apoptosis of erythroid and megakaryocytic cells. Mutations in GATA1 can generate a truncated protein, which contributes to the genesis of transient myeloproliferative disorder (TMD) and acute megakaryoblastic leukaemia (AMKL) in infants with Down syndrome. Similarly, Gata1 knockdown to 5% of its wild-type level causes high incidence of erythroid leukaemia in mice. The GATA1-related leukaemias in both human and mouse could provide important insights into the mechanism of multi-step leukaemogenesis. Efforts are afoot to produce mouse models that are reflective of TMD and AMKL. [ABSTRACT FROM AUTHOR]

The literature pertaining to nesting of the Great Hornbill (Buceros bicornis) is ambiguous regarding whether the birds use mud as plaster material to seal their nest cavity entrances. We studied the breeding biology of the species in southern India and detected no evidence of mud delivery or usage in 183 hrs of nest observations. Chemical analysis of plaster material showed that it was composed exclusively of fecal material and not mud. [ABSTRACT FROM AUTHOR]

Summary: We reviewed published studies reporting the direct medical costs of treating HIV-infected people in countries using highly active antiretroviral therapy (HAART). Of 543 potentially relevant studies, only nine provided adequate data to make a meaningful statement about costs. Within studies, people with more advanced disease incurred higher total costs. Valid comparisons of total direct medical costs between studies were not possible because of differences in the specific components included, the heterogeneous nature of study populations in terms of disease stage, the sources and methods used to estimate unit costs, and the level of aggregation at which results were reported. The advent of HAART has major implications for the cost of treating HIV-infected individuals. Although this information is important for planning purposes, only a small number of published studies provide useful estimates of the direct cost. A useful method of estimating resource use and costs is computer simulation. [Copyright &y& Elsevier]

This paper presents an algorithmic method for solving the two-plant simultaneous bounded domain stabilization problem for SISO LTI systems. This problem has no closed form solution. The solution provides robust performance in the presence of sensor or actuator failure, or other major parameter changes. Vidyasagar (1987) studied a similar problem involving partially bounded stability domains. However, stability with respect to partially bounded domains only partially bound performance characteristics, such as control energy and transient response. The current investigation gives necessary conditions for simultaneous bounded domain stability and demonstrates a geometry-based solution algorithm which can be automated. The possible solutions to the problem and the admissible solutions are represented as sets of points in Euclidean space. The solution to the problem is found by using computational geometric techniques to detect points in the intersection of these two sets, if there is one, and deducing the simultaneous stabilizing compensator design from the points found in the intersection. [ABSTRACT FROM AUTHOR]

Evaluates the stage of evolution in the study of in vivo functions of the locus control region (LCR) of the beta-globin gene. Two studies indicating surprising lack of influence of the LCR on overall chromatin sensitivity; Failure of earlier globin transgenes to express at high levels because they lacked the LCR.

This work describes a stroboscopic optical boxcar technique for the determination of fluorescence lifetimes which achieves performance comparable to techniques such as time-correlated single photon counting or phase modulation. The stroboscopic technique is based on the use of a traveling wave injected into a delay line connecting the dynodes of a photomultiplier tube. The transient potential difference created between two adjacent dynodes results simultaneously in significant amplification and the generation of a ‘‘gate’’ for the amplification process. Accurate control of the timing between the flashing of the gated lamp and the computer controlled delayable triggering of the photomultiplier tube pulser allows the gate to be placed at any time position within the range of the digital delay generator. The intensity of the fluorescence emission can thus be measured as a function of time relative to the excitation flash yielding data which is very similar to that from time-correlated single photon counting. Data analysis is done by iterative reconvolution in a procedure very similar to the analysis of time-correlated single photon counting data. Fluorescence lifetimes from a few hundred picoseconds to hundreds of nanoseconds can be determined to an accuracy and precision of better than ±2%. [ABSTRACT FROM AUTHOR]

Presents information on a study which looked at the home range size and foraging habitat for red-cockaded woodpeckers in Arkansas. Details on the study area; Insight on the methodology used to conduct the study; Discussion based on the results of the study.

Studies the long-term effects of cavity-entrance restrictors on red-cockaded woodpecker and addresses concerns over possible damage to the bills of birds as a result of pecking on the metal restrictors. Ways in increasing the suitability of cavities for red-cockaded woodpeckers; Amount of damage to bill wear of red-cockaded woodpeckers from exposure to entrance restrictors.

The article deals with the categorization of acute-cerebro-vascular injured and normals. In a study conducted in this regard, the experimental subjects were diagnosed by hospital physicians as acute cerebro-vascular injured (CVA). It was hypothesized that acute cerebro-vascular accident patients with widely diffuse cerebral damage would adapt their categorizing behavior to meet the demands imposed by payoff matrices less efficiently than normals. The predicted interaction between degree of brain damage and ability to adapt categorizing behavior to meet the demands set by payoff matrices was observed.

Background: Vagal Nerve Stimulation (VNS) has been shown to be efficacious for the treatment of depression, but to date, VNS devices have required surgical implantation, which has limited widespread implementation. Methods: New noninvasive VNS (nVNS) devices have been developed which allow external stimulation of the vagus nerve, and their effects on physiology in patients with stress-related psychiatric disorders can be measured with brain imaging, blood biomarkers, and wearable sensing devices. Advantages in terms of cost and convenience may lead to more widespread implementation in psychiatry, as well as facilitate research of the physiology of the vagus nerve in humans. nVNS has effects on autonomic tone, cardiovascular function, inflammatory responses, and central brain areas involved in modulation of emotion, all of which make it particularly applicable to patients with stress-related psychiatric disorders, including posttraumatic stress disorder (PTSD) and depression, since dysregulation of these circuits and systems underlies the symptomatology of these disorders. Results: This paper reviewed the physiology of the vagus nerve and its relevance to modulating the stress response in the context of application of nVNS to stress-related psychiatric disorders. Conclusions: nVNS has a favorable effect on stress physiology that is measurable using brain imaging, blood biomarkers of inflammation, and wearable sensing devices, and shows promise in the prevention and treatment of stress-related psychiatric disorders. [ABSTRACT FROM AUTHOR]

High tumbling rates of uncooperative target pose strong technical challenges and collision risks that can prevent removal of the debris using contact, such as with robotic arms or capture nets. Electrostatic touchless detumbling is a promising technology that can be used to decrease the rotational velocity of an uncooperative object in geosynchronous orbit, from a safe distance. This paper demonstrates the advantages of applying a Lyapunov optimal control in conjunction with a surface multisphere model. This approach allows for the analysis of general shapes, eliminating the need for analytical approximations on debris shape and expected torque, employed by previous work. Moreover, using this model, the robustness of the system to uncertainties to the debris center of mass position is tested. This analysis uncovers an unstable phenomenon that was previously not captured using simpler models. An active disturbance rejection control ensures robustness of the system in the cases analyzed, also granting an increase in its effectiveness. It is shown in simulation that the system can exploit deviations in the center of mass to achieve a higher level of controllability and completely detumble all components of angular velocity. [ABSTRACT FROM AUTHOR]

Transcription factor GATA1 controls the delicate balance between proliferation, differentiation and apoptosis in both the erythroid and megakaryocytic lineages. In addition to full-length GATA1, there is an GATA1 isoform, GATA1s, that lacks the amino-terminal transactivation domain. Somatic GATA1 mutations that lead to the exclusive production of GATA1s appear to be necessary and sufficient for the development of a preleukemic condition called transient myeloproliferative disorder (TMD) in Down syndrome newborns. Subsequent clonal evolution among latent TMD blasts leads to the development of acute megakaryoblastic leukemia (AMKL). We originally established transgenic mice that express only GATA1s, which exhibit hyperproliferation of immature megakaryocytes, thus mimicking human TMD; however, these mice never developed AMKL. Here, we report that transgenic mice expressing moderate levels of GATA1s, i.e., roughly comparable levels to endogenous GATA1, were prone to develop AMKL in young adults. However, when GATA1s is expressed at levels significantly exceeding that of endogenous GATA1, the development of leukemia was restrained in a dose dependent manner. If the transgenic increase of GATA1s in progenitors remains small, GATA1s supports the terminal maturation of megakaryocyte progenitors insufficiently, and consequently the progenitors persisted, leading to an increased probability for acquisition of additional genetic modifications. In contrast, more abundant GATA1s expression compensates for this maturation block, enabling megakaryocytic progenitors to fully differentiate. This study provides evidence for the clinical observation that the abundance of GATA1s correlates well with the progression to AMKL in Down syndrome. Key points: 1. The abundance of GATA1s is a strong prognostic factor of TMD for leukemia by mediating differentiation of megakaryocytes. 2. Persistent TMD blasts not undergoing differentiation are prone to leukemic transformation. [ABSTRACT FROM AUTHOR]

Catecholamine synthesized in the sympathoadrenal system, including sympathetic neurons and adrenal chromaffin cells, is vital for cardiovascular homeostasis. It has been reported that GATA2, a zinc finger transcription factor, is expressed in murine sympathoadrenal progenitor cells. However, a physiological role for GATA2 in adrenal chromaffin cells has not been established. In this study, we demonstrate that GATA2 is specifically expressed in adrenal chromaffin cells. We examined the consequences of Gata2 loss‐of‐function mutations, exploiting a Gata2 conditional knockout allele crossed to neural crest‐specific Wnt1‐Cre transgenic mice (Gata2 NC‐CKO). The vast majority of Gata2 NC‐CKO embryos died by embryonic day 14.5 (e14.5) and exhibited a decrease in catecholamine‐producing adrenal chromaffin cells, implying that a potential catecholamine defect might lead to the observed embryonic lethality. When intercrossed pregnant dams were fed with synthetic adrenaline analogs, the lethality of the Gata2 NC‐CKO embryos was partially rescued, indicating that placental transfer of the adrenaline analogs complements the lethal catecholamine deficiency in the Gata2 NC‐CKO embryos. These results demonstrate that GATA2 participates in the development of neuroendocrine adrenaline biosynthesis, which is essential for fetal survival. [ABSTRACT FROM AUTHOR]

Forestry is becoming more complex as a result of diverging societal demands. Indigenous Peoples' reconciliation and the challenges of climate change call for research that embraces transdisciplinarity, reciprocity, and problem-focused learning at the landscape scale. Both globally and in Canada, forestry and forest research are struggling to keep pace with this growing complexity. Place-based collaborative research and learning initiatives, described here as "learning landscapes," offer an under-explored approach to meeting diversifying goals for forest landscapes. We describe recent progress in Quesnel, British Columbia, where researchers and local institutions are engaging to strengthen resilience and innovation in the forest sector. We first define the concept of learning landscape in the context of transdisciplinary sustainability science, and then illustrate this approach using the case study of Quesnel. We describe a process of systems diagnosis, including asset mapping and analysis of potential forestry pathways through a "best bets" framework. We propose a Theory of Change as a way forward, outlining opportunities for government, industry, and communities in developing regional capacity for integrated management and high-value forest products. We reflect on the contributions of learning landscapes to knowledge generation, experiential learning, and institutional development, and discuss implications for steering decision-making in locally driven sustainability transitions. [ABSTRACT FROM AUTHOR]

Abstract Jargon aphasia is an acquired language disorder characterised by high proportions of nonword error production, rendering spoken language incomprehensible. There exist two major hypotheses relating to the source of nonword error; one implicates disruption to phonological processing and the other suggests both phonological and lexical contributions. The lexical sources are described as failure in lexical retrieval followed by surrogate phonological construction, or a lexical selection error further compounded by phonological breakdown. The current study analysed nonword error patterns of ten individuals with fluent neologistic Jargon aphasia in word repetition, reading and picture naming to gain insights into the contributions of these different sources. It was predicted that, if lexical retrieval deficits contribute to nonword production, naming would produce a greater proportion and severity of nonword errors in comparison to repetition and reading, where phonology is present and additional nonlexical processing can support production. Both group and case series analyses were implemented to determine whether quantity and quality of nonwords differed across the three production tasks. Nonword phoneme inventories were compared against the normative phoneme distribution to explore whether phonological production takes place within a typically organised, lexically constrained system. Results demonstrated fewer nonword errors in naming and a tendency for nonwords in naming to be characterised by lower phonological accuracy. However, nonwords were, for the most part, constructed with reference to target phonological information and, generally, nonword phonological production patterns adhered to the statistical properties of the learned phonological system. While a subset of the current group demonstrated very limited lexical processing capacity which manifested as nonword errors in naming being most disrupted, overall the results suggest that nonwords are largely underpinned by some degree of successful lexical retrieval and implicate phonological sources, which manifest more severely when production is accomplished via nonlexical processing routes. Highlights • Picture naming elicited fewer nonwords than reading or repetition. • Nonwords in picture naming tended to have lower phonological accuracy than those from reading or repetition. • Nonwords were constructed with reference to target lexico-phonological information, suggesting a phonological source. • Tasks which increased focus on lexico-semantic processing reduced the likelihood of nonword production. • Greater focus on phonological information increased the likelihood of observing a nonword. [ABSTRACT FROM AUTHOR]

Motivation Biological function in protein complexes emerges from more than just the sum of their parts: molecules interact in a range of different sub-complexes and transfer signals/information around internal pathways. Modern proteomic techniques are excellent at producing a parts-list for such complexes, but more detailed analysis demands a network approach linking the molecules together and analysing the emergent architectural properties. Methods developed for the analysis of networks in social sciences have proven very useful for splitting biological networks into communities leading to the discovery of sub-complexes enriched with molecules associated with specific diseases or molecular functions that are not apparent from the constituent components alone. Results Here, we present the Bioconductor package BioNAR, which supports step-by-step analysis of biological/biomedical networks with the aim of quantifying and ranking each of the network's vertices based on network topology and clustering. Examples demonstrate that while BioNAR is not restricted to proteomic networks, it can predict a protein's impact within multiple complexes, and enables estimation of the co-occurrence of metadata, i.e. diseases and functions across the network, identifying the clusters whose components are likely to share common function and mechanisms. Availability and implementation The package is available from Bioconductor release 3.17: https://bioconductor.org/packages/release/bioc/html/BioNAR.html. [ABSTRACT FROM AUTHOR]

Magnetic resonance imaging (MRI), angiography (MRA) and venography (MRV) display venous and neurovascular obstruction in patients with thoracic outlet syndrome (TOS) and migraine (Clin. Anat. 1995; 8:1-16; JNMA. 2003; 95:298-306). Costoclavicular compression of the bicuspid valves within the internal jugular vein and the veins of the neck and supraclavicular fossae results in venous congestion of cerebral dural sinuses secondary to increased intracranial, intrathoracic and intraabdominal pressures. Patients complain of upper extremity pain, numbness, tingling and edema; facial, back and lower extremity pain; visual blurring and "floaters", and syncope. Cerebral venous hemodynamics plays a role in the pain of migraine headache. Headache is prominent in TOS patients with venous obstruction. The great vein of Galen drains into the straight sinus, with drainage into the longitudinal, transverse and sigmoid sinuses into the internal jugular vein. Multiplanar imaging of the dural sinuses in suspected TOS patients was conducted on the 1.5 Tesla (GE Signa LX), 4.0 mm thickness, 512 x 256 matrix and saline water bags to enhance signal to noise ratio. Blood flow was displayed as changes in proton density without contrast. Dilatation of the vein of Galen secondary to costoclavicular compression of the bicuspid valves within the draining veins of the neck and supraclavicular fossae is displayed in this presentation. [ABSTRACT FROM AUTHOR]

The transcription factor GATA3 is essential for the genesis and maturation of the T cell lineage, and GATA3 dysregulation has pathological consequences. Previous studies have shown that GATA3 function in T cell development is regulated by multiple signaling pathways and that the Notch nuclear effector, RBP-J, binds specifically to the Gata3 promoter. We previously identified a T cell-specific Gata3 enhancer (Tce1) lying 280 kb downstream from the structural gene and demonstrated in transgenic mice that Tce1 promoted T lymphocyte-specific transcription of reporter genes throughout T cell development; however, it was not clear if Tce1 is required for Gata3 transcription in vivo. Here, we determined that the canonical Gata3 promoter is insufficient for Gata3 transcriptional activation in T cells in vivo, precluding the possibility that promoter binding by a host of previously implicated transcription factors alone is responsible for Gata3 expression in T cells. Instead, we demonstrated that multiple lineage-affiliated transcription factors bind to Tce1 and that this enhancer confers T lymphocyte-specific Gata3 activation in vivo, as targeted deletion of Tce1 in a mouse model abrogated critical functions of this T cell-regulatory element. Together, our data show that Tce1 is both necessary and sufficient for critical aspects of Gata3 T cell-specific transcriptional activity. [ABSTRACT FROM AUTHOR]

Introduction: Prior studies have shown inconsistent findings of an association between depression and epigenetic aging. DNA methylation (DNAm) age acceleration can measure biological aging. We adopted a robust co‐twin control study design to examine whether depression is associated with DNAm age acceleration after accounting for the potential confounding influences of genetics and family environment. Methods: We analyzed data on a sub‐cohort of the Vietnam Era Twin Registry. A total of 291 twins participated at baseline and 177 at follow‐up visit after a mean of 11.7 years, with 111 participants having DNA samples for both time points. Depression was measured using the Beck Depression Inventory II (BDI‐II). Six measures of DNAm age acceleration were computed at each time point, including Horvath's DNAm age acceleration (HorvathAA), intrinsic epigenetic age acceleration (IEAA), Hannum's DNAm age acceleration (HannumAA), extrinsic epigenetic age acceleration (EEAA), GrimAge acceleration (GrimAA), and PhenoAge acceleration (PhenoAA). Mixed‐effects modeling was used to assess the within‐pair association between depression and DNAm age acceleration. Results: At baseline, a 10‐unit higher BDI‐II total score was associated with HannumAA (0.73 years, 95% confidence interval [CI] 0.13–1.33, p =.019) and EEAA (0.94 years, 95% CI 0.22–1.66, p =.012). At follow‐up, 10‐unit higher BDI‐II score was associated with PhenoAA (1.32 years, 95% CI 0.18–2.47, p =.027). Conclusion: We identified that depression is associated with higher levels of DNAm age acceleration. Further investigation is warranted to better understand the underlying mechanisms for the potential causal relationship between depression and accelerated aging. [ABSTRACT FROM AUTHOR]

Interleukin-33 antibody failed to demonstrate benefit in a phase II, double-blind, randomized, placebo-controlled study in adult patients with moderate-to-severe atopic dermatitis Dear Editor, therapeutic intervention for atopic dermatitis (AD) focuses on neutralizing effector cytokines such as interleukin (IL)-4 and IL-13-1,2 IL-33 is a driver of T helper (Th)2-mediated inflammation and is upstream of IL-4 and IL-13. SP b sp Other race data: placebo [American Indian Alaska Native: I N i (%) 1 (3), missing: 2], 50 mg LY3375880 [Black or African American: 1 (3), missing: 2], 150 mg LY3375880 [Black or African American: 2 (6), missing: 1] and 600 mg LY3375880 [Black or African American: 3 (9)]. [Extracted from the article]