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Abstract Background The objective was to compare sevoflurane, a volatile sedation agent with potential bronchodilatory properties, with propofol on respiratory mechanics in critically ill patients with COPD exacerbation. Methods Prospective study in an ICU enrolling critically ill intubated patients with severe COPD exacerbation and comparing propofol and sevoflurane after 1:1 randomisation. Respiratory system mechanics (airway resistance, PEEPi, trapped volume, ventilatory ratio and respiratory system compliance), gas exchange, vitals, safety and outcome were measured at inclusion and then until H48. Total airway resistance change from baseline to H48 in both sevoflurane and propofol groups was the main endpoint. Results Sixteen patients were enrolled and were sedated for 126 h(61–228) in the propofol group and 207 h(171–216) in the sevoflurane group. At baseline, airway resistance was 21.6cmH2O/l/s(19.8–21.6) in the propofol group and 20.4cmH2O/l/s(18.6–26.4) in the sevoflurane group, (p = 0.73); trapped volume was 260 ml(176–290) in the propofol group and 73 ml(35–126) in the sevoflurane group, p = 0.02. Intrinsic PEEP was 1.5cmH2O(1–3) in both groups after external PEEP optimization. There was neither early (H4) or late (H48) significant difference in airway resistance and respiratory mechanics parameters between the two groups. Conclusions In critically ill patients intubated with COPD exacerbation, there was no significant difference in respiratory mechanics between sevoflurane and propofol from inclusion to H4 and H48.

This article elucidates the emergence of technology-empowered family practices that cross-border families develop to re-spatialize and re-temporalize their family activities and daily rhythms. Standing on the concepts of “doing family” and polymedia, we propose a dual framework of mediated doing/undoing family and explain it in an integrated WeChat environment. Specifically, the frame contains three pairs of dimensions: active versus inactive, everyday co-presence versus absent-presence and invisibility, and historical roots versus anti-traditions. Drawing on a 2-year ethnography of cross-border students communicating with their parents, we use the frame to further illuminate a set of dialectical relations between mediated doing and undoing family, and between cultural motherhood and fatherhood—culturally (un)doing gender. Findings fill gaps in the existing literature on the undoing affordances of technologies, and supplement insights on the experiences of transnational/cross-border parenthood. Our study also discusses the dual dynamics of mediated (un)doing family and presents a critical reflection on the effects of technology on gender asymmetries and gender dynamics.

Abstract Pedagogical foundations exist for incorporating technology in instruction; however, these foundations have not kept pace with technology's evolution. Through the use of Information Communication Technologies (ICTs), students now can share content directed at external audiences, i.e., audiences other than the instructor. These audiences are referred to as authentic audiences as they are public-facing and exist outside of the classroom. The existing literature offers evidence of student satisfaction with assignments directed at appealing to external audiences, however, the literature provides no comprehensive pedagogical rationale for assignments directed at authentic audiences wherein the goals are self-determined. The authors discuss the theory of heutagogy, the study of self-determined learning, as an approach for assessing assignments that utilize ICTs and are directed at authentic audiences. Finally, the authors offer an approach for the assessment of these assignments, including a rubric.

Despite decades of literature and practice with community-engaged research along with advancements in the recognition of environmental injustices, the application of equity-/justice-based and collaborative approaches between government agencies and community-based organizations has been limited. The toxic legacies of environmental racism, redlining, displacement, and segregation combined with the accelerating human-caused climate crisis warrant an increased need for consultation and collaboration between frontline communities and power brokers to markedly improve quality of life and health outcomes in environmental justice neighborhoods. This paper describes the processes and progress to date from a community-led collaboration between local community-based organizations and the Enforcement Division of the California Air Resources Board to assess and address air pollution in South Stockton, particularly from heavy-duty diesel trucks. South Stockton is one of the most polluted neighborhoods in California’s San Joaquin Valley, one of the most disparate and polluted regions in the United States. Some of the most significant components integrated into this project thus far include taking an equity-, justice-, and youth-oriented approach to community development that intentionally emphasizes a historical understanding of root causes of social and environmental injustices and provides pathways to workforce development. Including these elements has been essential in building the trust necessary to transform disparate power relations between the state and environmental justice communities, and to put multiple ways of knowing into conversation with each other to co-learn and co-power solutions to air pollution in South Stockton.

Soil connectivity envisages people's involvement in the protection and management of soil reflecting the view that improper soil management will result in soil degradation. Having realized the necessity of ensuring people's participation in managing soil degradation, in Papua New Guinea (PNG) soil use and management is of governmental interest. Soil degradation on cocoa orchards is exacerbated due to existing reliance on current soil condition. People must respond quickly, but very few soil best management practices are available. Additionally, it is speculated that inadequate soil training amongst the village extension workers (VEWs) is plummeting adoption rates. We develop a two-step impact pathway framework through soil connectivity. In the first step of this approach, a VEWs survey conducted as part of this study confirmed that their active participation in soil management remains minimal. This is a critical shortcoming in the cocoa block management. However, knowledge of soil possessed by respondents living in a location for a period is significantly developed and this connection with soil can be useful in sustainable soil use and management decisions. In the second step, a research project develops an impact pathway framework on how it sees itself planning, achieving and communicating impacts. We illustrate the development of a framework using example from a soil science project in PNG based on gaps found through the state-of-the-art knowledge. Through this exercise our aim is to highlight the links between the project communication and developmental impacts. We concluded that the framework developed is flexible to be applied across other food systems.

Indiscriminate regional lockdowns aim to prevent the coronavirus disease 2019 (COVID-19) infection by restricting the movement of people; however, this comes with psychological, social, and economic costs. Measures are needed that complement lockdowns and reduce adverse effects. Epidemiological studies, to date, have identified high-risk populations, but not workplaces appropriate for closure. This study was conducted to provide evidence-based measures that used exact and reliable follow-up data of the PCR-positive COVID-19 cases to complement lockdowns. The data are not subjected to selection or follow-up biases, since the Japanese government, by law, must register and follow all the PCR-positive cases until either recovery or death. Direct customer exposure may affect the quantity of viral inoculum received, which, in turn, may affect the risk of the severity of disease at infection. Therefore, the professions of the cases were grouped according to their frequency of direct customer exposure (FDCE) based on subjective observations, which resulted in five workplaces; hospital, school, food service, outdoor service, and indoor office being identified. Analyzing the follow-up data, we obtained precise estimates for the risk of severe disease, defined as intensive care unit (ICU) hospitalization or death, for the workplaces adjusted for age, sex, family status, and comorbidity. Major findings are as follows: hospital and school are the lowest risk, food and outdoor services are, despite higher FDCE, safer than indoor office. Unemployed and unclear are the highest risk, despite low FDCE. These results suggest the following workplace-specific measures complementing the lockdown: school should not be closed and indiscriminate closing of food and outdoor service industries should be avoided, since it would be more effective to reinforce their efforts to promote adherence to public health guidelines among students and customers. These actions would also reduce the adverse effects of the lockdown. This study is the first to address the causality between the workplaces and severe disease. We introduce FDCE and adherence to public health guidelines (APHGs) to associate the workplace characteristics with the risk of COVID-19 severity, which provided the basis for the measures complementing lockdowns.

This paper considers the diverse public good characteristics of COVID-19 activities along with their strategic implications. The underlying aggregator technologies, which relate individual contributions to the amount consumed, affect the prognosis for the supply of COVID-related activities. Weakest-link activities assume a particularly pivotal role in curbing the spread of COVID-19. For instance, the propagation of COVID-19 through new strains is disproportionately influenced by those countries with the smallest vaccination rates or least isolation actions. Diverse income distribution among at-risk countries raises the need to “shore up” weakest-link countries’ provision to lift global supply. Generally, shoring-up actions result in a Prisoner’s Dilemma with unfavorable collective action prospects. As the number of countries requiring shoring up increases, the less favorable is the prospect for addressing provision shortfalls. Also, as the number of capable countries to do the shoring up increases, the prospect for successful action diminishes. The paper also examines the strategic implications of other aggregators—e.g., best shot and better shot—associated with COVID-inhibiting actions. To address best-shot anti-COVID actions, countries must pool or coordinate actions to meet a threshold. A host of institutions—e.g., the World Health Organization or public-private partnerships—can facilitate shoring-up weakest-link activities or coordinating best-shot actions.

Cocoa production is impacted by major resource constraints, such as the soil's capability, and in some areas, by unreliable access to markets. A multifaceted approach that employs both biophysical and socio-economic conditions is developed here for mapping areas that are suitable for cocoa production in Papua New Guinea (PNG). This manuscript presents a case study of using multi-criteria decision making by the Analytic Hierarchy Process for mapping the fundamental criteria for cocoa suitability. The results show that temperature, precipitation and soil reveal sections within Western, Gulf and Central (along the west coast joining to National Capital District) province that have very low suitability for cocoa production. In our analysis, precipitation, soil, slope and road, were ranked as the four most important criteria. Additionally, we included stream networks because they may help irrigation and allow cocoa transport via water (e.g. Manus Island). Comparing an already existing cocoa suitability map for PNG to the one created in this study, we found some similarities. For example, the Central, Gulf, and Western (Fly) areas are either unsuitable for cocoa production or have very low potential, and exceptional areas around Rabaul and Kokopo in East New Britain, Popendetta, and Bouganiville were identified. Some new areas suitable for cocoa production in East Sepik, East New Britain, and a major stretch within West New Britain may show low to moderate suitability. The most important finding is the potential to grow cocoa in the highlands, especially, Chimbu (Simbu), Eastern Highlands, Enga, Hela, Jiwaka regions. We found that currently the majority of farmers are growing cocoa in highly suitable areas (76% in class 4, 20%in class 3 and 4% in class 5). The inclusion of slope and roads impacts the impact of flooding conditions and the amount of work and ease of access to markets as important indicators of the connection farmers make between soil suitability and their decision to grow cocoa. This is an agile step towards linking biomass production to soil capability, and connectivity, allowing cocoa suitable areas selection and the production of ‘living maps’ that continually evolve as more empirical data becomes available. This can be an essential connectivity tool for practitioners to evaluate the potential geographic range for cocoa production.

As a waterborne pathogen of increasing concern, techniques for cost-effective and rapid characterization of Legionella are vital. This study examines the development of a Matrix Assisted Laser Desorption/Ionization-Time of Flight Mass Spectrometry (MALDI-TOF-MS) analysis methodology for this microbe. First, optimal sample preparation methods for the analysis of environmental Legionella isolates via MALDI-TOF-MS were determined. These methods were then implemented to perform strain-level characterization of environmental Legionella isolates from central Arizona. Results demonstrate that a MALDI-TOF-MS method involving BCYE agar-based culturing and protein extraction-based sample preparation yield high-quality mass spectra. Twenty-eight environmental Legionella isolates originating from two separate drinking water distribution systems were analyzed. Multiple species were detected, and strain-level characterization was achieved, with 12 unique strains distinguished. In addition, isolates of L. pneumophila, the most common species observed in the study, were correctly assigned to specific sampling sites. These results demonstrate the potential for this technique to be applied for sub-species characterization of Legionella with significant benefits over established methodologies.

OBJECTIVES:. Although patients in the ICU are closely monitored, some ICU cardiac arrest events may be preventable. In this study, we sought to reduce the rate of cardiac arrests occurring in the ICU through a quality improvement initiative. DESIGN:. Prospective, observational study. SETTING:. ICUs of a single tertiary care center. PATIENTS:. Patients hospitalized in the ICUs between August 2017 and November 2019. INTERVENTIONS:. A comprehensive trigger and response tool. MEASUREMENT AND MAIN RESULTS:. Forty-three patients experienced an ICU cardiac arrest in the preintervention epoch (6.79 arrests per 1,000 discharges), and 59 patients experienced an ICU cardiac arrest in the intervention epoch (7.91 arrests per 1,000 discharges). In the intervention epoch, the clinical trigger and response tool was activated 106 times over a 1-year period, most commonly due to unexpected new/worsening hypotension. There was no step change in arrest rate (2.24 arrests/1,000 patients; 95% CI, –1.82 to 6.28; p = 0.28) or slope change (–0.02 slope of arrest rate; 95% CI, –0.14 to 0.11; p = 0.79) comparing the preintervention and intervention time epochs. Cardiac arrests in the preintervention epoch were more likely to be “potentially preventable” than that in the intervention epoch (25.6% vs 12.3%, respectively; odds ratio, 0.58; 95% CI, 0.20–0.88; p < 0.01). CONCLUSIONS:. A novel trigger-and-response tool did not reduce the frequency of ICU cardiac arrest. Additional investigation is needed into the optimal approach for ICU cardiac arrest prevention.

Abstract Background High adrenergic tone appears to be associated with mortality in septic shock, while adrenergic antagonism may improve survival. In preparation for a randomized trial, we conducted a prospective, single-arm pilot study of esmolol infusion for patients with septic shock and tachycardia that persists after adequate volume expansion. Methods From April 2016 to March 2017, we enrolled patients admitted to an intensive care unit with sepsis who were receiving vasopressor infusion and were tachycardic despite adequate volume expansion. All patients received a continuous intravenous infusion of esmolol, targeted to heart rate 80–90/min, while receiving vasopressors. The feasibility outcomes were proportion of eligible patients consented, compliance with pre-infusion safety check, and compliance with the titration protocol. The primary clinical outcome was organ-failure-free days (OFFD) at 28 days. Results We enrolled 7 of 10 eligible patients. Mean age was 46 (± 19) years, and mean admission APACHE II was 28 (± 8). Median norepinephrine infusion rate at the initiation of esmolol infusion was 0.20 (0.14–0.23) μg/kg/min. Compliance with the safety check was 100%; compliance with components of the titration protocol was 98–100%. OFFD were 26 (24.5–26); all patients survived to day 90. Median peak esmolol infusion was 50 (25–50) μg/kg/min. Median peak norepinephrine infusion rate during esmolol infusion was 0.46 (0.13–0.50) μg/kg/min. Four patients achieved target heart rate. Protocol-defined stop events, suggesting possible intolerance to a given infusion rate, occurred in three patients, all of whom were receiving at least 50 μg/kg/min of esmolol. Conclusions In a pilot, single-arm study, we report the first published experience with esmolol infusion in tachycardic patients with septic shock in the United States. These findings support a phase 2 trial of esmolol infusion for septic shock. Lower infusion rates of esmolol infusion may be better tolerated and more feasible than higher infusion rates for such a trial. Trial registration This study was retrospectively registered at ClinicalTrials.gov (NCT02841241) on 19 July 2016.

Abstract Background Antibodies are critical responses to protect the host from dengue virus(DENV) infection. Antibodies target DENV by two pathologic mechanisms: virus neutralization and infection enhancement. In dengue patients, the absence of neutralizing activity in the presence of FcγR implies that infection-enhancing activity hampers the neutralizing activity of antibodies, which could potentially lead to symptomatic presentations and severe clinical outcomes. Methods A total of 100 pair serum samples from adult healthy volunteers were obtained during the dengue season in Ha Noi in 2015 for evaluation of neutralizing and infection-enhancing activity. Additionally, 20 serum samples from acute secondary DENV infection patients were also used as the patient group in this study. PRNT was performed on BHK cells and FcγR-expressing BHK cell lines for all serum samples. Results Out of 100 residents, positive neutralizing antibodies (N.A) were found in 44.23 and 76.92% for DENV-1; 38.46 and 75% for DENV-2; 19.23 and 15.38% for DENV-3; and 1.92 and 9.62% for DENV-4 for pre and post-dengue season respectively. The percentage of post-exposure residents having positive responses against single, two, or more than three DENV serotypes were 38.46, 44.23 and 15.38%, respectively. A total of 34 residents were DENV seropositive before the dengue season and these individuals demonstrated further elevation of IgG antibodies after the dengue season. At the end of the season, 18 residents were confirmed to be new asymptomatic DENV infection cases. In both groups, N.A titers determined on BHK cells were higher than that on FcγR-expressing BHK cells. In heterotypic N.A responses, N.A titers to the infecting serotype from the samples obtained from pre-exposure group were significantly higher than those of the patient group. However, fold enhancement to the infecting serotypes from the samples in the pre-exposure group was substantially lower as compared to that of the patient group. Conclusion Before and after the dengue season, serum samples from healthy volunteers demonstrated high levels of neutralizing antibodies and low or absence of infection-enhancement activity. The results suggest that while infection-enhancement activity hampers neutralizing activity of antibodies, high levels of DENV neutralizing antibodies set a critical threshold in facilitating the prevention of disease progression.

The elucidation of the molecular mechanisms of long-term synaptic plasticity has been hindered by both the compensation that can occur after chronic loss of the core plasticity molecules and by ex vivo conditions that may not reproduce in vivo plasticity. Here we describe a novel method to rapidly suppress gene expression by antisense oligodeoxynucleotides (ODNs) applied to rodent brain slices in an “Oslo-type” interface chamber. The method has three advantageous features: 1) rapid blockade of new synthesis of the targeted proteins that avoids genetic compensation, 2) efficient oxygenation of the brain slice, which is critical for reproducing in vivo conditions of long-term synaptic plasticity, and 3) a recirculation system that uses only small volumes of bath solution (< 5 ml), reducing the amount of reagents required for long-term experiments lasting many hours. The method employs a custom-made recirculation system involving piezoelectric micropumps and was first used for the acute translational blockade of protein kinase Mζ (PKMζ) synthesis during long-term potentiation (LTP) by Tsokas et al., 2016. In that study, applying antisense-ODN rapidly prevents the synthesis of PKMζ and blocks late-LTP without inducing the compensation by other protein kinase C (PKC) isoforms that occurs in PKCζ/PKMζ knockout mice. In addition, we show that in a low-oxygenation submersion-type chamber, applications of the atypical PKC inhibitor, zeta inhibitory peptide (ZIP) can result in unstable baseline synaptic transmission, but in the high-oxygenation, "Oslo-type" interface electrophysiology chamber, the drug reverses late-LTP without affecting baseline synaptic transmission. This comparison reveals that the interface chamber, but not the submersion chamber, reproduces the effects of ZIP in vivo. Therefore, the protocol combines the ability to acutely block new synthesis of specific proteins for the study of long-term synaptic plasticity, while maintaining properties of synaptic transmission that reproduce in vivo conditions relevant for long-term memory.

Ionizing radiation constitutes a health risk to imaging scientists and study animals. Both PET and CT produce ionizing radiation. CT doses in pre-clinical in vivo imaging typically range from 50 to 1,000 mGy and biological effects in mice at this dose range have been previously described. [18F]FDG body doses in mice have been estimated to be in the range of 100 mGy for [18F]FDG. Yearly, the average whole body doses due to handling of activity by PET technologists are reported to be 3–8 mSv. A preclinical PET/CT system is presented with design features which make it suitable for small animal low-dose imaging. The CT subsystem uses a X-source power that is optimized for small animal imaging. The system design incorporates a spatial beam shaper coupled with a highly sensitive flat-panel detector and very fast acquisition (

For 1990–2019, this study presents two-step GMM estimates of EU members’ demands for defense spending based on alternative spatial-weight matrices. In particular, EU spatial connectivity is tied to EU membership status, members’ contiguity, contiguity and power projection, inverse distance, and arms trade. At a Nash equilibrium, our EU demand equations are derived explicitly from a spatially based game-theoretical model of alliances. Myriad spatial linkages among EU members provide a robust free-riding finding, which differs from the spatial and non-spatial literature on EU defense spending. Even though the EU applies common trade policies and allows for unrestricted labor movement among members, members’ defense responses adhered to those of a defense alliance. Moreover, EU defense spending exhibits positive responses to GDP and transnational terrorist attacks, and a negative response to population. During the sample period, EU members did not view Russia as a military threat.

Measuring biomaterials is usually subject to error. Measurement errors are classified into either random errors or biases. Random errors can be well controlled using appropriate statistical methods. But, biases due to unknown, unobserved, or temporary causes, may lead to biased conclusions. This study describes a verification method to examine whether measurement errors are random or not and to determine efficient statistical methods. A number of studies have dealt with associations between hair minerals and exposures such as health, dietary or environmental conditions. Most review papers, however, emphasize the necessity for validation of hair mineral measurements, since large variations can cause highly variable results. To address these issues, we answer the following questions: How can we ascertain the reliability of measurements?How can we assess and control the variability of measurements?How do we efficiently determine associations between hair minerals and exposures?How can we concisely present the reference values? Since hair minerals all have distinctive natures, it would be unproductive to examine each mineral individually to find significant and consistent answers that apply to all minerals. To surmount this difficulty, we used one simple model for all minerals to explore quantitative answers. Hair mineral measurements of six-year-old children were analyzed based on the statistical model. The analysis verified that most of the measurements were reliable, and their inter-individual variations followed two-parameter distributions. These results allow for sophisticated study designs and efficient statistical methods to examine the effects of various kinds of exposures on hair minerals.

This protocol was originally designed to examine long-term spatial memory in PKMζ knockout (i.e., PKMζ-null) mice (Tsokas et al., 2016). Our main goal was to test whether the ability of these animals to maintain previously acquired spatial information was sensitive to the type and complexity of the spatial information that needs to be remembered. Accordingly, we modified and combined into a single protocol, three novelty-preference tests, specifically the object-in-context, object-in-place and object-in-location tests, adapted from previous studies in rodents (Mumby et al., 2002; Langston and Wood, 2010; Barker and Warburton, 2011). During the training (learning) phase of the procedure, mice are repeatedly exposed to three different environments in which they learn the spatial arrangement of an environment-specific set of non-identical objects. After this learning phase is completed, each mouse receives three different memory tests configured as environment mismatches, in which the previously learned objects-in-space configurations have been modified from the original training situation. The mismatch tests differ in their cognitive demands due to the type of spatial association that is manipulated, specifically evaluating memory for object-context and object-place associations. During each memory test, the time differential spent exploring the novel (misplaced) and familiar objects is computed as an index of novelty discrimination. This index is the behavioral measure of memory recall of the previously acquired spatial associations.

We established a collection of 7,000 transgenic lines of Drosophila melanogaster. Expression of GAL4 in each line is controlled by a different, defined fragment of genomic DNA that serves as a transcriptional enhancer. We used confocal microscopy of dissected nervous systems to determine the expression patterns driven by each fragment in the adult brain and ventral nerve cord. We present image data on 6,650 lines. Using both manual and machine-assisted annotation, we describe the expression patterns in the most useful lines. We illustrate the utility of these data for identifying novel neuronal cell types, revealing brain asymmetry, and describing the nature and extent of neuronal shape stereotypy. The GAL4 lines allow expression of exogenous genes in distinct, small subsets of the adult nervous system. The set of DNA fragments, each driving a documented expression pattern, will facilitate the generation of additional constructs for manipulating neuronal function.

For more than three decades, Vinyard Software's two ITERATE (International Terrorism: Attributes of Terrorist Events) datasets have set the standard in events research for terrorism researchers. It has recently been supplemented by the DOTS (Data on Terrorist Subjects) biographies project, which covers all terrorists, supporters, and other individuals mentioned in the ITERATE project.

Current molecular methods to characterize microalgae are time-intensive and expensive. Matrix Assisted Laser Desorption/Ionization Time-of-Flight Mass Spectrometry (MALDI-TOF MS) may represent a rapid and economical alternative approach. The objectives of this study were to determine whether MALDI-TOF MS can be used to: 1) differentiate microalgae at the species and strain levels and 2) characterize simple microalgal mixtures. A common protein extraction sample preparation method was used to facilitate rapid mass spectrometry-based analysis of 31 microalgae. Each yielded spectra containing between 6 and 56 peaks in the m/z 2,000 to 20,000 range. The taxonomic resolution of this approach appeared higher than that of 18S rDNA sequence analysis. For example, two strains of Scenedesmus acutus differed only by two 18S rDNA nucleotides, but yielded distinct MALDI-TOF mass spectra. Mixtures of two and three microalgae yielded relatively complex spectra that contained peaks associated with members of each mixture. Interestingly, though, mixture-specific peaks were observed at m/z 11,048 and 11,230. Our results suggest that MALDI-TOF MS affords rapid characterization of individual microalgae and simple microalgal mixtures.

Background: This is an update of a Cochrane Review first published in 2006 (McGuinness 2006), and previously updated in 2009 (McGuinness 2009). Hypertension is a risk factor for dementia. Observational studies suggest antihypertensive treatment is associated with lower incidences of cognitive impairment and dementia. There is already clear evidence to support the treatment of hypertension after stroke., Objectives: To assess whether pharmacological treatment of hypertension can prevent cognitive impairment or dementia in people who have no history of cerebrovascular disease., Search Methods: We searched the Specialised Register of the Cochrane Dementia and Cognitive Improvement Group, CENTRAL, MEDLINE, Embase, three other databases, as well as many trials registries and grey literature sources, most recently on 7 July 2020., Selection Criteria: We included randomised controlled trials (RCTs) in which pharmacological interventions to treat hypertension were given for at least 12 months. We excluded trials of pharmacological interventions to lower blood pressure in non-hypertensive participants. We also excluded trials conducted solely in people with stroke., Data Collection and Analysis: Two authors independently assessed trial quality and extracted data. We contacted study authors for additional information. We collected information regarding incidence of dementia, cognitive decline, change in blood pressure, adverse effects and quality of life. We assessed the certainty of evidence using GRADE., Main Results: We included 12 studies, totaling 30,412 participants, in this review. Eight studies compared active treatment with placebo. Of the four non-placebo-controlled studies, two compared intensive versus standard blood pressure reduction. The two final included studies compared different classes of antihypertensive drug. Study durations varied from one to five years. The combined result of four placebo-controlled trials that reported incident dementia indicated no evidence of a difference in the risk of dementia between the antihypertensive treatment group and the placebo group (236/7767 versus 259/7660, odds ratio (OR) 0.89, 95% confidence interval (CI) 0.72 to 1.09; very low certainty evidence, downgraded due to study limitations and indirectness). The combined results from five placebo-controlled trials that reported change in Mini-Mental State Examination (MMSE) may indicate a modest benefit from antihypertensive treatment (mean difference (MD) 0.20, 95% CI 0.10 to 0.29; very low certainty evidence, downgraded due to study limitations, indirectness and imprecision). The certainty of evidence for both cognitive outcomes was downgraded on the basis of study limitations and indirectness. Study durations were too short, overall, to expect a significant difference in dementia rates between groups. Dementia and cognitive decline were secondary outcomes for most studies. Additional sources of bias include: the use of antihypertensive medication by the placebo group in the placebo-controlled trials; failure to reach recruitment targets; and early termination of studies on safety grounds. Meta-analysis of the placebo-controlled trials reporting results found a mean change in systolic blood pressure of -9.25 mmHg (95% CI -9.73, -8.78) between treatment (n = 8973) and placebo (n = 8820) groups, and a mean change in diastolic blood pressure of -2.47 mmHg (95% CI -2.70, -2.24) between treatment (n = 7700) and placebo (n = 7509) groups (both low certainty evidence downgraded on the basis of study limitations and inconsistency). Three trials - SHEP 1991, LOMIR MCT IL 1996 and MRC 1996 - reported more withdrawals due to adverse events in active treatment groups than placebo groups. Participants on active treatment in Syst Eur 1998 were less likely to discontinue treatment due to side effects, and participants on active treatment in HYVET 2008 reported fewer 'serious adverse events' than in the placebo group. There was no evidence of a difference in withdrawals rates between groups in SCOPE 2003, and results were unclear for Perez Stable 2000 and Zhang 2018. Heterogeneity precluded meta-analysis. Five of the placebo-controlled trials provided quality of life (QOL) data. Heterogeneity again precluded meta-analysis. SHEP 1991, Syst Eur 1998 and HYVET 2008 reported no evidence of a difference in QOL measures between active treatment and placebo groups over time. The SCOPE 2003 sub-study (Degl'Innocenti 2004) showed a smaller drop in QOL measures in the active treatment compared to the placebo group. LOMIR MCT IL 1996 reported an improvement in a QOL measure at twelve months in one active treatment group and deterioration in another., Authors' Conclusions: High certainty randomised controlled trial evidence regarding the effect of hypertension treatment on dementia and cognitive decline does not yet exist. The studies included in this review provide low certainty evidence (downgraded primarily due to study limitations and indirectness) that pharmacological treatment of hypertension, in people without prior cerebrovascular disease, leads to less cognitive decline compared to controls. This difference is below the level considered clinically significant. The studies included in this review also provide very low certainty evidence that pharmacological treatment of hypertension, in people without prior cerebrovascular disease, prevents dementia., (Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

In systemic lupus erythematosus (SLE), perturbed immunoregulation underpins a pathogenic imbalance between regulatory and effector CD4 + T-cell activity. However, to date, the characterization of the CD4 + regulatory T cell (Treg) compartment in SLE has yielded conflicting results. Here we show that patients have an increased frequency of CD4 + FOXP3 + cells in circulation owing to a specific expansion of thymically-derived FOXP3 + HELIOS + Tregs with a demethylated FOXP3 Treg-specific demethylated region. We found that the Treg expansion was strongly associated with markers of recent immune activation, including PD-1, plasma concentrations of IL-2 and the type I interferon biomarker soluble SIGLEC-1. Since the expression of the negative T-cell signaling molecule PTPN22 is increased and a marker of poor prognosis in SLE, we tested the influence of its missense risk allele Trp 620 (rs2476601C>T) on Treg frequency. Trp 620 was reproducibly associated with increased frequencies of thymically-derived Tregs in blood, and increased PD-1 expression on both Tregs and effector T cells (Teffs). Our results support the hypothesis that FOXP3 + Tregs are increased in SLE patients as a consequence of a compensatory mechanism in an attempt to regulate pathogenic autoreactive Teff activity. We suggest that restoration of IL-2-mediated homeostatic regulation of FOXP3 + Tregs by IL-2 administration could prevent disease flares rather than treating at the height of a disease flare. Moreover, stimulation of PD-1 with specific agonists, perhaps in combination with low-dose IL-2, could be an effective therapeutic strategy in autoimmune disease and in other immune disorders., (Copyright © 2019 Ferreira, Castro Dopico, Oliveira, Rainbow, Yang, Trzupek, Todd, McNeill, Steri, Orrù, Fiorillo, Crouch, Pekalski, Cucca, Tree, Vyse, Wicker and Todd.)

Factors that influence response to drug treatment are of increasing importance. We report an analysis of genetic factors affecting response to cholinesterase inhibitor therapy in 165 subjects with Alzheimer's disease (AD). The presence of apolipoprotein E ε4 (APOE ε4) allele was associated with early and late cognitive response to cholinesterase inhibitor treatment in mild AD (Mini-Mental State Examination (MMSE) ≥21) (P<0.01). In moderate-to-severe AD (MMSE ≤15), presence of the BCHE-K variant was associated with late response to cholinesterase inhibitor treatment (P=0.02). Testing for APOE and BCHE genotypes may be useful in therapeutic decision making.

Several lines of evidence indicate that the Abeta peptide is involved at some level in the pathological process that results in the clinical symptoms of AD (Alzheimer's disease). The N-terminus of Abeta is generated by cleavage of the Met-Asp bond at position 671-672 of APP (amyloid precursor protein), catalysed by a proteolytic activity called beta-secretase. Two 'beta-secretase' proteases have been identified: BACE (beta-site APP-cleaving enzyme) and BACE2. The cause of sporadic AD is currently unknown, but some studies have reported elevated BACE/beta-secretase activity in brain regions affected by the disease. We have demonstrated that robust beta-secretase activity is also detectable in platelets that contain APP and release Abeta. This review considers the current evidence for alterations in beta-secretase activity, and/or alterations in BACE expression, in post-mortem brain tissue and platelets from individuals with AD.

The aims of this study were to investigate whether the preferred facial relationship chosen by professionals and the general public is Class I and to ascertain whether viewing two-dimensional (2D) or three-dimensional (3D) images had any effect on the ranking of facial attractiveness. Orthodontists (n = 47), maxillofacial surgeons (n = 25) and members of the general public (n = 78) assessed 2D and 3D facial scans of two males and two females that had been morphed to produce five images reflecting different skeletal patterns: Class I, mild and moderate Class II, and mild and moderate Class III. Each assessor placed the images in rank order of preference, after viewing alternate 2D and 3D image formats for each face. The data were analysed using logistic regression. In 2D, professionals (orthodontists and maxillofacial surgeons) chose Class I as the preferred facial image more frequently than the general public for only one of the four faces. However, in 3D format they chose Class I as the preferred facial image for some subject faces more, and others less, frequently when compared with the general public. The gender of the assessor was not significant when assessing the preferred facial relationship for Class I images in either 2D or 3D formats. The oldest assessors (56+ years) were significantly less likely than the younger age groups to select Class I as the preferred facial relationship in both 2D and 3D. In summary, there was too great a degree of variation to say that a difference between 2D and 3D facial images was evident.

To facilitate collaborative research efforts between multi-investigator teams using DNA microarrays, we identified sources of error and data variability between laboratories and across microarray platforms, and methods to accommodate this variability. RNA expression data were generated in seven laboratories, which compared two standard RNA samples using 12 microarray platforms. At least two standard microarray types (one spotted, one commercial) were used by all laboratories. Reproducibility for most platforms within any laboratory was typically good, but reproducibility between platforms and across laboratories was generally poor. Reproducibility between laboratories increased markedly when standardized protocols were implemented for RNA labeling, hybridization, microarray processing, data acquisition and data normalization. Reproducibility was highest when analysis was based on biological themes defined by enriched Gene Ontology (GO) categories. These findings indicate that microarray results can be comparable across multiple laboratories, especially when a common platform and set of procedures are used.

Purine analogs are effective in the treatment of several chronic lymphoproliferative disorders (CLPD) including hairy cell leukemia (HCL). To date, little evidence exists that these drugs are oncogenic. We report a case of HCL in a 66-year-old male treated with 2-deoxycoformycin. Just over 1 year following completion of his treatment, falling platelet and white cell counts were associated with the development of dysplastic features in his bone marrow and a rising blast cell count, culminating in the development of acute myeloid leukemia (AML). To the best of our knowledge only two previous cases of AML have been linked to treatment of HCL with purine analogs, both with 2-chlorodeoxyadenosine. We emphasize the need for long term follow up of patients treated with purine analogs and suggest that even those who are apparently cured be monitored periodically.

Drug development involves the chemical identification and characterization of a compound to determine stability and define the drug's preliminary actions. Preclinical research follows in animals to develop a pharmacokinetic profile to determine dose range, biotransformation, elimination, and toxicology. The 4 phases of clinical research, phase 1 to phase 4, encompass a progressive investigation of healthy subjects, otherwise healthy patients, to patients with a target disease to obtain US Food and Drug Administration (FDA) approval. Clinical studies include open-label noncomparative studies during phases 1 and 2, and double-blind, comparative, and placebo-controlled studies during phases 2 and 3. Approval from the FDA follows the successful evaluation of the drug. After drug marketing, phase 4 clinical trials continue to collect safety and efficacy information. Many drugs that undergo this drug development process succeed in obtaining FDA approval and are marketed for clinical use. There are several circumstances, however, that preclude the successful completion of drug development, FDA approval, and marketing. This study describes a clinical trial of a new benzodiazepine, Ro 48-6791. Ro 48-6791 was being developed as an ultra-short-acting benzodiazepine with clinical effects of shorter duration than midazolam. The purpose of this study was to define a safe dose range for the induction and maintenance of conscious sedation of patients in an outpatient gastroenterology laboratory. Efficacy criteria to be evaluated included time to onset of action, duration of action, and psychomotor fitness upon recovery. Patients were assessed by using the Observer's Assessment of Alertness/Sedation score (OAA/S) and a 5-m heel-toe-line-walk test (HTLW). The patients were divided into 2 groups. Group 1 patients received Ro 48-6791. Group 2 patients were premedicated with meperidine before administration of Ro 48-6791. Ro 48-6791 was titrated over 30 seconds, and patients were observed for 90 seconds before the next dose was given. The OAA/S score, oxygen saturation, and vital signs were charted every minute through induction and every 5 minutes during the procedure. Patients received Ro 48-6791 until they reached on OAA/S score of 3, corresponding to slowed patient response to name calling. Group 1 (Ro 48-6791 alone) required greater induction doses and increased time to induction. Maintenance doses were the same for both groups. The duration of action of Ro 48-6791 as measured by the OAA/S score and HTLW test did not differ between groups. Ro 48-6791 seemed to be a safe and effective agent to achieve conscious sedation in outpatients undergoing short invasive procedures. However, clinical drug development of Ro 48-6791 was stopped because it did not meet the efficacy criteria of an ultra-short-acting benzodiazepine.

Three different two-dimensional (2-D) gel electrophoretic techniques have been modified to provide high resolution of human erythrocyte membrane proteins. The resulting gels were referenced to the established one-dimensional (1-D) sodium dodecylsulfate (SDS) gel electrophoretic profile, and the effects of endogenous proteolysis and cytosolic contamination were studied. It is concluded that in vitro proteolysis and cytosolic contamination do not contribute significantly to the patterns observed on the 2-D gels, under the conditions used for erythrocyte ghost preparation. The procedures require only small quantities of blood; as many as twenty 2-D gel profiles can be obtained from 5 ml of blood. The combination of nonequilibrium isoelectric focusing (IEF) in the first dimension, SDS electrophoresis in the second dimension, and very sensitive silver staining techniques resolves more than 250 individual protein spots. This appears to be the most useful single procedure for the analysis of red cell membrane proteins. Membrane protein profiles from patients with Duchenne muscular dystrophy, Wernicke-Korsakoff syndrome, and acanthocytosis with degeneration of the basal ganglia were compared with normal controls. The patterns for Duchenne muscular dystrophy and Wernicke-Korsakoff syndrome were not different from normal patterns. The pattern for the patient with acanthocytosis and degeneration of the basal ganglia consistently showed a high level for one protein in the 100,000 mol. wt. range.