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Abstract Objective For treatment of medication-related osteonecrosis of the jaw, one proposed approach is the use of a topical agent to block entry of these medications in oral soft tissues. We tested the ability of phosphonoformic acid (PFA), an inhibitor of bisphosphonate entry through certain sodium-dependent phosphate contransporters (SLC20A1, 20A2, 34A1-3) as well as Dynasore, a macropinocytosis inhibitor, for their abilities to prevent zoledronate-induced (ZOL) death in human gingival fibroblasts (HGFs). Methodology MTT assay dose-response curves were performed to determine non-cytotoxic levels of both PFA and Dynasore. In the presence of 50 μM ZOL, optimized PFA and Dynasore doses were tested for their ability to restore HGF viability. To determine SLC expression in HGFs, total HGF RNA was subjected to quantitative real-time RT-PCR. Confocal fluorescence microscopy was employed to see if Dynasore inhibited macropinocytotic HGF entry of AF647-ZOL. Endosomal acidification in the presence of Dynasore was measured by live cell imaging utilizing LysoSensor Green DND-189. As a further test of Dynasore’s ability to interfere with ZOL-containing endosomal maturation, perinuclear localization of mature endosomes containing AF647-ZOL or TRITC-dextran as a control were assessed via confocal fluorescence microscopy with CellProfiler™ software analysis of the resulting photomicrographs. Results 0.5 mM PFA did not rescue HGFs from ZOL-induced viability loss at 72 hours while 10 and 30 μM geranylgeraniol did partially rescue. HGFs did not express the SLC transporters as compared to the expression in positive control tissues. 10 μM Dynasore completely prevented ZOL-induced viability loss. In the presence of Dynasore, AF647-ZOL and FITC-dextran co-localized in endosomes. Endosomal acidification was inhibited by Dynasore and perinuclear localization of both TRITC-dextran- and AF647-ZOL-containing endosomes was inhibited by 30 μM Dynasore. Conclusion Dynasore prevents ZOL-induced viability loss in HGFs by partially interfering with macropinocytosis and by inhibiting the endosomal maturation pathway thought to be needed for ZOL delivery to the cytoplasm.

Introduction Missed fractures are the most frequent diagnostic error attributed to clinicians in UK emergency departments and a significant cause of patient morbidity. Recently, advances in computer vision have led to artificial intelligence (AI)-enhanced model developments, which can support clinicians in the detection of fractures. Previous research has shown these models to have promising effects on diagnostic performance, but their impact on the diagnostic accuracy of clinicians in the National Health Service (NHS) setting has not yet been fully evaluated.Methods and analysis A dataset of 500 plain radiographs derived from Oxford University Hospitals (OUH) NHS Foundation Trust will be collated to include all bones except the skull, facial bones and cervical spine. The dataset will be split evenly between radiographs showing one or more fractures and those without. The reference ground truth for each image will be established through independent review by two senior musculoskeletal radiologists. A third senior radiologist will resolve disagreements between two primary radiologists. The dataset will be analysed by a commercially available AI tool, BoneView (Gleamer, Paris, France), and its accuracy for detecting fractures will be determined with reference to the ground truth diagnosis. We will undertake a multiple case multiple reader study in which clinicians interpret all images without AI support, then repeat the process with access to AI algorithm output following a 4-week washout. 18 clinicians will be recruited as readers from four hospitals in England, from six distinct clinical groups, each with three levels of seniority (early-stage, mid-stage and later-stage career). Changes in the accuracy, confidence and speed of reporting will be compared with and without AI support. Readers will use a secure web-based DICOM (Digital Imaging and Communications in Medicine) viewer (www.raiqc.com), allowing radiograph viewing and abnormality identification. Pooled analyses will be reported for overall reader performance as well as for subgroups including clinical role, level of seniority, pathological finding and difficulty of image.Ethics and dissemination The study has been approved by the UK Healthcare Research Authority (IRAS 310995, approved on 13 December 2022). The use of anonymised retrospective radiographs has been authorised by OUH NHS Foundation Trust. The results will be presented at relevant conferences and published in a peer-reviewed journal.Trial registration numbers This study is registered with ISRCTN (ISRCTN19562541) and ClinicalTrials.gov (NCT06130397). The paper reports the results of a substudy of STEDI2 (Simulation Training for Emergency Department Imaging Phase 2).

Objective: There is limited clinical evidence to support any specific parenchymal air leak resolution criteria when using digital pleural drainage devices following lung resection. The aim of this study is to determine an optimal air leak resolution criteria, where duration of chest tube drainage is minimized while avoiding complications from premature chest tube removal. Methods: Airflow data averaged at 10-minute intervals was collected prospectively using a digital pleural drainage device (Thopaz; Medela) in 400 patients from 2015 to 2019. All permutations of air leak resolution criteria from

ABSTRACTThe rapid evolution of SARS-CoV-2 variants presents a constant challenge to the global vaccination effort. In this study, we conducted a comprehensive investigation into two newly emerged variants, BA.2.87.1 and JN.1, focusing on their neutralization resistance, infectivity, antigenicity, cell-cell fusion, and spike processing. Neutralizing antibody (nAb) titers were assessed in diverse cohorts, including individuals who received a bivalent mRNA vaccine booster, patients infected during the BA.2.86/JN.1-wave, and hamsters vaccinated with XBB.1.5-monovalent vaccine. We found that BA.2.87.1 shows much less nAb escape from WT-BA.4/5 bivalent mRNA vaccination and JN.1-wave breakthrough infection sera compared to JN.1 and XBB.1.5. Interestingly, BA.2.87.1 is more resistant to neutralization by XBB.1.5-monovalent-vaccinated hamster sera than BA.2.86/JN.1 and XBB.1.5, but efficiently neutralized by a class III monoclonal antibody S309, which largely fails to neutralize BA.2.86/JN.1. Importantly, BA.2.87.1 exhibits higher levels of infectivity, cell-cell fusion activity, and furin cleavage efficiency than BA.2.86/JN.1. Antigenically, we found that BA.2.87.1 is closer to the ancestral BA.2 compared to other recently emerged Omicron subvariants including BA.2.86/JN.1 and XBB.1.5. Altogether, these results highlight immune escape properties as well as biology of new variants and underscore the importance of continuous surveillance and informed decision-making in the development of effective vaccines.IMPORTANCEThis study investigates the recently emerged SARS-CoV-2 variants, BA.2.87.1 and JN.1, in comparison to earlier variants and the parental D614G. Varied infectivity and cell-cell fusion activity among these variants suggest potential disparities in their ability to infect target cells and possibly pathogenesis. BA.2.87.1 exhibits lower nAb escape from bivalent mRNA vaccinee and BA.2.86/JN.1-infected sera than JN.1 but is relatively resistance to XBB.1.5-vaccinated hamster sera, revealing distinct properties in immune reason and underscoring the significance of continuing surveillance of variants and reformulation of vaccines. Antigenic differences between BA.2.87.1 and other earlier variants yield critical information not only for antibody evasion but also for viral evolution. In conclusion, this study furnishes timely insights into the spike biology and immune escape of the emerging variants BA.2.87.1 and JN.1, thus guiding effective vaccine development and informing public health interventions.

Background: In this study, we investigate indocyanine green (ICG) dye visualization of the thoracic duct (TD) and conduit perfusion during esophagectomy to reduce anastomotic leak (AL) and chylothorax adverse events (AEs). Methods: Retrospective data of adult patients who underwent esophagectomy for esophageal carcinoma between July 2019 and 2022 were included (n = 105). ICG was delivered intravenously (2 mL, 2.5 mg/mL) to assess conduit perfusion into the small bowel mesentery, inguinal lymph nodes, or foot web spaces for TD visualization using fluorescence imaging. Incidence of TD injury, chylothorax, AL, and AEs were collected. Results: A total of 23 patients received ICG (ICG for TD and perfusion (n = 12) and perfusion only (n = 11)), while 82 patients were controls. TD was visualized in 6 of 12 patients who received ICG for TD. No intraoperative TD injuries or postoperative chylothoraces occurred in these patients. Non-ICG patients had 1 (1.22%) intraoperative TD injury and 10 (12.2%) postoperative chylothoraces (grade I–IIIb). While 10 non-ICG patients (12.2%) developed AL (grade I–IVb), only 2 (8.7%) ICG patients developed AL (grade IIIa). Conclusions: This study demonstrates the utility of ICG fluorescence in intraoperative TD and conduit perfusion assessment for limiting AEs. Standard incorporation of ICG in esophagectomy may help surgeons improve the quality of care in this patient population.

Immune evasion by SARS-CoV-2 paired with immune imprinting from monovalent mRNA vaccines has resulted in attenuated neutralizing antibody responses against Omicron subvariants. In this study, we characterized two new XBB variants rising in circulation – EG.5.1 and XBB.2.3, for their neutralization and syncytia formation. We determined the neutralizing antibody titers in sera of individuals that received a bivalent mRNA vaccine booster, BA.4/5-wave infection, or XBB.1.5-wave infection. Bivalent vaccination-induced antibodies neutralized ancestral D614G efficiently, but to a much less extent, two new EG.5.1 and XBB.2.3 variants. In fact, the enhanced neutralization escape of EG.5.1 appeared to be driven by its key defining mutation XBB.1.5-F456L. Notably, infection by BA.4/5 or XBB.1.5 afforded little, if any, neutralization against EG.5.1, XBB.2.3 and previous XBB variants – especially in unvaccinated individuals, with average neutralizing antibody titers near the limit of detection. Additionally, we investigated the infectivity, fusion activity, and processing of variant spikes for EG.5.1 and XBB.2.3 in HEK293T-ACE2 and CaLu-3 cells but found no significant differences compared to earlier XBB variants. Overall, our findings highlight the continued immune evasion of new Omicron subvariants and, more importantly, the need to reformulate mRNA vaccines to include XBB spikes for better protection.

Purpose: To evaluate disease progression and associated vision changes in patients with geographic atrophy (GA) secondary to age-related macular degeneration (AMD) in 1 eye and GA or neovascular AMD (nAMD) in the fellow eye using a large dataset from routine clinical practice. Design: Retrospective analysis of clinical data over 24 months. Subjects: A total of 256 635 patients with GA from the American Academy of Ophthalmology (Academy) IRIS® Registry (Intelligent Research in Sight) Registry (January 2016 to December 2017). Methods: Patients with ≥ 24 months of follow-up were grouped by fellow-eye status: Cohort 1, GA:GA; Cohort 2, GA:nAMD, each with (subfoveal) and without subfoveal (nonsubfoveal) involvement. Eyes with history of retinal disease other than AMD were excluded. Sensitivity analysis included patients who were managed by retina specialists and had a record of imaging within 30 days of diagnosis. Main Outcome Measures: Change in visual acuity (VA), occurrence of new-onset nAMD, and GA progression from nonsubfoveal to subfoveal. Results: In total, 69 441 patients were included: 44 120 (64%) GA:GA and 25 321 (36%) GA:nAMD. Otherwise eligible patients (57 788) were excluded due to follow-up < 24 months. In both GA:GA and GA:nAMD cohorts, nonsubfoveal study eyes had better mean (standard deviation) VA at index (67 [19.3] and 66 [20.3] letters) than subfoveal eyes (59 [23.9] and 47 [26.9] letters), and 24-month mean VA changes were similar for nonsubfoveal (−7.6 and −6.2) and subfoveal (−7.9 and −6.5) subgroups. Progression to subfoveal GA occurred in 16.7% of nonsubfoveal study eyes in the GA:GA cohort and 12.5% in the GA:nAMD cohort. More new-onset study-eye nAMD was observed in the GA:nAMD (21.6%) versus GA:GA (8.2%) cohorts. Sensitivity analysis supported the robustness of the observations in the study. Conclusions: This retrospective analysis describes the natural progression of GA lesions and the decline in VA associated with the disease. Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references.

Abstract Sustainable land management encompasses a range of activity that balance land use requirements with wider conservation and ecosystem impact considerations. Perennial invasive alien plants (IAPs), such as Japanese knotweed, cause severe ecological and socio-economic impacts, and methods to control their spread also come at a cost. Synthetic herbicides are generally viewed as less sustainable and more ecologically damaging than alternative approaches. Here we used a comparative Life Cycle Assessment to evaluate the sustainability of herbicide-based management approaches and physical alternatives, using a large-scale Japanese knotweed field study as a model IAP system. Glyphosate-based methods elicited the lowest environmental impacts and economic costs during production. Geomembrane covering and integrated physiochemical methods were the costliest and imposed the greatest impacts. We discuss the costs and benefits of chemical and physical approaches for the sustainable management of invaded land and question how sustainable environmental stewardship is defined for the control of IAPs.

Background We describe a novel process using positive deviance (PD) with the Canadian Association of Thoracic Surgeons members, to identify perioperative best practice to minimise anastomotic leak (AL) and length of stay (LOS) following oesophagectomy. To our knowledge, this is the first National combination of level 1 evidence with expert opinion (ie, PD seminar) aimed at reducing AL and LOS in oesophageal surgery. Our primary hypothesis is that a multicentre National PD seminar is feasible, and could lead to the generation of best practices recommendations aimed at reducing AL and LOS in patients with oesophageal cancer.Methods Adverse events, LOS and AL incidence/severity following oesophagectomy were prospectively collected from seven Canadian thoracic institutions using Thoracic Morbidity and Mortality classification system (2017–2020). Anonymised display of centre’s data were presented, with identification of centres demonstrating PD. Surgeons from PD sites discussed principles of care, culminating in the consensus recommendations, anonymously rated by all (5-point Likert scale).Results Data from 795 esophagectomies were included, with 25 surgeons participating. Two centres were identified as having the lowest AL rates 44/395 (11.1%) (vs five centres 71/400 (17.8%) (p

Summary: The evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to challenge the efficacy of vaccination efforts against coronavirus disease 2019 (COVID-19). The Omicron XBB lineage of SARS-CoV-2 has presented dramatic evasion of neutralizing antibodies stimulated by mRNA vaccination and COVID-19 convalescence. XBB.1.16, characterized by two mutations relative to the dominating variant XBB.1.5, i.e., E180V and K478R, has been on the rise globally. In this study, we compare the immune escape of XBB.1.16 with XBB.1.5, alongside ancestral variants D614G, BA.2, and BA.4/5. We demonstrate that XBB.1.16 is strongly immune evasive, with extent comparable to XBB.1.5 in bivalent-vaccinated healthcare worker sera, 3-dose-vaccinated healthcare worker sera, and BA.4/5-wave convalescent sera. Interestingly, the XBB.1.16 spike is less fusogenic than that of XBB.1.5, and this phenotype requires both E180V and K478R mutations to manifest. Overall, our findings emphasize the importance of the continued surveillance of variants and the need for updated mRNA vaccine formulations.

Objectives Adverse events (AEs) following thoracic surgery place considerable strain on healthcare systems. A rigorous evaluation of the economic impact of thoracic surgical AEs remains lacking and is required to understand the value of money of formal quality improvement initiatives. Our objective was to conduct a systematic review of all available literature focused on specific cost of postoperative AEs following thoracic surgery.Design Systematic review of the economic literature was performed, following recommendations from the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement.Data sources An economic search filter developed by the Canadian Agency for Drugs and Technologies in Health was applied, and MEDLINE, Embase and The Cochrane Library were searched from inception to January 2022.Eligibility criteria We included English articles involving adult patients who underwent a thoracic surgical procedure with estimated costs of postoperative complications. Eligible study designs included comparative observational studies, randomised control trials, decision analytic or cost-prediction models, cost analyses, cost or burden of illness studies, economic evaluation studies and systematic reviews and/or meta-analyses of cost analyses and cost of illness studies.Data extraction and synthesis Two reviewers independently screened titles and abstracts in the first stage and full-text articles of included studies in the second stage. Disagreements during abstract and full-text screening stages were resolved via discussion until a consensus was reached. Studies were appraised for methodological quality using the Critical Appraisal Skills Program checklist.Results 3349 studies were identified: 20 met inclusion criteria. Most were conducted in the USA (12/20), evaluating AE impact on hospital expenditures (18/20). 68 procedure-specific AE mean costs were characterised (USD$). The most commonly described were anastomotic leak (mean:range) (USD$49 278:$6 176–$133 002) and pneumonia ($12 258:$2608–$34 591) following esophagectomy, and prolonged air leak ($2556:$571–$3573), respiratory failure ($19 062:$11 841–$37 812), empyema ($30 189:$23 784–$36 595), pneumonia ($15 362:$2542–$28 183), recurrent laryngeal nerve injury ($16 420:$4224–$28 616) and arrhythmia ($6835:$5833–$8659) following lobectomy.Conclusions Hospital costs associated with AEs following thoracic surgery are substantial and varied. Quantifying costs of AEs enable future economic evaluation studies, which could help prioritising value-directed quality improvement to optimally improve outcomes and reduce costs.

Purpose . Identifying factors that influence moderate-to-vigorous intensity physical activity (MVPA) and sedentary time in metabolic and bariatric surgery (MBS) patients is necessary to inform the development of interventions. Weather/environmental factors may be especially important considering rapid climate change and the vulnerability of people with obesity to heat and pollution. Our study aimed to examine the associations of weather (maximal, average and Wet Bulb Globe Temperatures), and air pollution indices (air quality index [AQI]) with daily physical activity (PA) of both light (LPA) and MVPA and sedentary time before and after MBS. Materials and methods . Participants (n = 77) wore an accelerometer at pre- and 3, 6, and 12-months post-MBS to assess LPA/MVPA/ sedentary time (min/d). These data were combined with participants’ local (Boston, MA or Providence, RI, USA) daily weather and AQI data (extracted from federal weather and environmental websites). Results . Multilevel generalized additive models showed inverted U-shaped associations between weather indices and MVPA, with a marked reduction in MVPA for daily maximal temperatures ≥20 °C. Sensitivity analysis showed a less marked decrease of MVPA (min/d) during higher temperatures after versus before MBS. Both MVPA before and after MBS and sedentary time before MBS were negatively impacted by higher AQI levels. Conclusion . This study is the first to show that weather and air pollution indices, even in locations with good AQI and moderate temperatures, are related to variability in activity behaviors, particularly MVPA, during pre- and post-MBS. Weather/environmental conditions should be considered in MVPA prescription/strategies for adults who have undergone MBS.

Background and Aims: Although PGT-M cases can be conducted using linkage only, the inclusion of a direct test targeting the relevant genetic variants should be fundamental to best practise. We present four cases illustrating the limitations of linkage only PGT-M. Methods: Three cases used STRs for linkage analysis and the fourth Illumina Infinium Karyomapping. Direct variant detection encompassed Sanger sequencing, STRs and/or fragment PCR. Results: Case 1 Osteoporosis-pseudoglioma syndrome Sanger sequencing for LRP5c.3107G[Formula: see text]A and LRP5c.4487C[Formula: see text]A were critical for identifying a recombination in the familial control and subsequent correct assignment of STR phasing. Case 2 Osteogenesis imperfecta type I SNP-based linkage identified a recombinant embryo. Sanger sequencing for COL1A1c.2461G[Formula: see text]A resolved an unknown status to affected. Case 3 Neurofibromatosis type II Variant detection in this de novo mosaic case used two STRs within the NF2 exon2-11del to establish low- and high-risk linkage patterns. Two tumour samples with different second hit mutations exhibited reduced signal intensity for one allele. This was consistent with the presence of a weaker deleted allele due to sample contamination with non-tumour cells. Four of nine embryos contained two alleles within the minimum deletion and were first choice for transfer, resulting in an NAD prenatal confirmation and healthy liveborn. Case 4 Neurofibromatosis type I A de novo mosaic case required reverse linkage by means of a direct assay for the NF1c.1445_1446insCC variant. Affected embryos were subsequently used to phase flanking STRs and obtain linkage, resulting in one liveborn and one ongoing pregnancy. Conclusions: When a direct test is not included in PGT-M, a family may not be able to be offered a test, or misdiagnosis risk may increase. For de novo, mosaic and cases with suspected recombination in a reference sample, analysis of multiple cycles and/or the inclusion of non-clinical embryos to increase sample numbers improves accuracy of testing.

Winter Heliotrope (Petasites pyrenaicus, previously P. fragrans), is a persistent, rhizome-forming species found throughout the Mediterranean region and North Africa and is an Invasive Alien Plant (IAP) in the UK and Ireland. P. pyrenaicus excludes native flora by forming a dense, compact canopy that persists for much of the growing season, and is often found growing in rough ground, riparian areas and along communication routes, incurring significant management costs at sites of conservation interest. Our study describes the first field-based assessment of P. pyrenaicus control treatments, testing 12 physical and/or chemical treatments in replicated 1 m2 plots over four years and one chemical treatment over three years. Treatments focused on understanding phenology and resource allocation to exploit rhizome source-sink relationships in P. pyrenaicus. Multiple-stage glyphosate- and picloram-based treatments reduced leaf canopy cover to zero (%) over time, though no treatment completely eradicated P. pyrenaicus. When designing management strategies, effective P. pyrenaicus control may be achieved by a single annual soil and/or foliar application of picloram at 1.34 kg AE ha-1 in spring, or by a single annual foliar application of glyphosate in spring at 2.16 kg AE ha-1. Control is not improved by the addition of other herbicides or physical treatment methods, underlining the importance of these herbicides for perennial invasive plant management. This work confirms the importance of considering plant phenology, resource allocation and rhizome source-sink relationships, to increase treatment efficacy and reduce the environmental impacts associated with the management of P. pyrenaicus and other invasive, rhizome forming species.

Summary: Omicron subvariants continuingly challenge current vaccination strategies. Here, we demonstrate nearly complete escape of the XBB.1.5, CH.1.1, and CA.3.1 variants from neutralizing antibodies stimulated by three doses of mRNA vaccine or by BA.4/5 wave infection, but neutralization is rescued by a BA.5-containing bivalent booster. CH.1.1 and CA.3.1 show strong immune escape from monoclonal antibody S309. Additionally, XBB.1.5, CH.1.1, and CA.3.1 spike proteins exhibit increased fusogenicity and enhanced processing compared with BA.2. Homology modeling reveals the key roles of G252V and F486P in the neutralization resistance of XBB.1.5, with F486P also enhancing receptor binding. Further, K444T/M and L452R in CH.1.1 and CA.3.1 likely drive escape from class II neutralizing antibodies, whereas R346T and G339H mutations could confer the strong neutralization resistance of these two subvariants to S309-like antibodies. Overall, our results support the need for administration of the bivalent mRNA vaccine and continued surveillance of Omicron subvariants.

Background Postoperative adverse events (AEs) following pulmonary resection enormously impact patient well-being, length of stay (LOS) and healthcare costs. Standardised AE data collection can be used to identify positive outliers demonstrating positive deviance (PD) who may be helpful to inform the best practice. Here, we describe our initial experience of a novel quality improvement process using PD to reduce LOS and AEs.Methods AE rates and LOS were collected from four centres (2014–2020) using a common dictionary. Surgeons repeatedly participated in 60 to 90 min seminars consisting of the following process: identify outcome and procedure targeted, review relevant best evidence literature, view all data anonymised by surgeon or centre (if multicentre), choose and reveal identity of best performance PD outliers, who discuss their management principles while all receive self-evaluation reports, followed by collegial discussion to generate consensus recommendations, voted by all. We assessed overall impact on AEs and LOS using aggregate data in a before/after analysis.Results A total of 131 surgeons (average 12/seminar) participated in 11 PD seminars (8 local and 3 multicentre), yielding 85 consensus recommendation (average 8/seminar). Median LOS following lobectomy decreased from 4.0 to 3.0 days (p=0.04) following local PD seminars and from 4.0 to 3.5 days (p=0.11) following multicentre seminars. Trends for reductions in multiple AE rates were also observed.Conclusion While limited by the longitudinal design, these findings provide preliminary support for this data-driven, collegial and actionable quality improvement process to help standardise and improve patient care, and merits further more rigorous investigation.

Introduction Rapid diagnostic centres (RDCs) are being implemented across the UK to accelerate the assessment of vague suspected cancer symptoms. Targeted behavioural interventions are needed to augment RDCs that serve socioeconomically deprived populations who are disproportionately affected by cancer, have lower cancer symptom awareness and are less likely to seek help for cancer symptoms. The aim of this study is to assess the feasibility and acceptability of delivering and evaluating a community-based vague cancer symptom awareness intervention in an area of high socioeconomic deprivation.Methods and analysis Intervention materials and messages were coproduced with local stakeholders in Cwm Taf Morgannwg, Wales. Cancer champions will be trained to deliver intervention messages and distribute intervention materials using broadcast media (eg, local radio), printed media (eg, branded pharmacy bags, posters, leaflets), social media (eg, Facebook) and attending local community events. A cross-sectional questionnaire will include self-reported patient interval (time between noticing symptoms to contacting the general practitioner), cancer symptom recognition, cancer beliefs and barriers to presentation, awareness of campaign messages, healthcare resource use, generic quality of life and individual and area-level deprivation indicators. Consent rates and proportion of missing data for patient questionnaires (n=189) attending RDCs will be measured. Qualitative interviews and focus groups will assess intervention acceptability and barriers/facilitators to delivery.Ethics and dissemination Ethical approval for this study was given by the London—West London & GTAC Research Ethics (21/LO/0402). This project will inform a potential future controlled study to assess intervention effectiveness in reducing the patient interval for vague cancer symptoms. The results will be critical to informing national policy and practice regarding behavioural interventions to support RDCs in highly deprived populations.

Abstract Background A variety of DNA-based methods have been applied to identify genetic markers of attention deficit hyperactivity disorder (ADHD), but the connection to RNA-based gene expression has not been fully exploited. Methods Using well defined cohorts of discordant, monozygotic twins from the Michigan State University Twin Registry, and case-controlled ADHD cases in adolescents, the present studies utilized advanced single molecule RNA sequencing to identify expressed changes in whole blood RNA in ADHD. Multiple analytical strategies were employed to narrow differentially expressed RNA targets to a small set of potential biomarkers of ADHD. Results RNA markers common to both the discordant twin study and case-controlled subjects further narrowed the putative targets, some of which had been previously associated with ADHD at the DNA level. The potential role of several differentially expressed genes, including ABCB5, RGS2, GAK, GIT1 and 3 members of the galactose metabolism pathway (GALE, GALT, GALK1) are substantiated by prior associations to ADHD and by established mechanistic connections to molecular pathways relevant to ADHD and behavioral control. Conclusions The convergence of DNA, RNA, and metabolic data suggests these may be promising targets for diagnostics and therapeutics in ADHD.

Letter To The Editor

OBJECTIVES:. To develop a physiologic grading system for the severity of acute encephalopathy manifesting as delirium or coma, based on EEG, and to investigate its association with clinical outcomes. DESIGN:. This prospective, single-center, observational cohort study was conducted from August 2015 to December 2016 and October 2018 to December 2019. SETTING:. Academic medical center, all inpatient wards. PATIENTS/SUBJECTS:. Adult inpatients undergoing a clinical EEG recording; excluded if deaf, severely aphasic, developmentally delayed, non-English speaking (if noncomatose), or if goals of care focused primarily on comfort measures. Four-hundred six subjects were assessed; two were excluded due to technical EEG difficulties. INTERVENTIONS:. None. MEASUREMENTS AND MAIN RESULTS:. A machine learning model, with visually coded EEG features as inputs, was developed to produce scores that correlate with behavioral assessments of delirium severity (Confusion Assessment Method-Severity [CAM-S] Long Form [LF] scores) or coma; evaluated using Spearman R correlation; area under the receiver operating characteristic curve (AUC); and calibration curves. Associations of Visual EEG Confusion Assessment Method Severity (VE-CAM-S) were measured for three outcomes: functional status at discharge (via Glasgow Outcome Score [GOS]), inhospital mortality, and 3-month mortality. Four-hundred four subjects were analyzed (mean [sd] age, 59.8 yr [17.6 yr]; 232 [57%] male; 320 [79%] White; 339 [84%] non-Hispanic); 132 (33%) without delirium or coma, 143 (35%) with delirium, and 129 (32%) with coma. VE-CAM-S scores correlated strongly with CAM-S scores (Spearman correlation 0.67 [0.62–0.73]; p < 0.001) and showed excellent discrimination between levels of delirium (CAM-S LF = 0 vs ≥ 4, AUC 0.85 [0.78–0.92], calibration slope of 1.04 [0.87–1.19] for CAM-S LF ≤ 4 vs ≥ 5). VE-CAM-S scores were strongly associated with important clinical outcomes including inhospital mortality (AUC 0.79 [0.72–0.84]), 3-month mortality (AUC 0.78 [0.71–0.83]), and GOS at discharge (0.76 [0.69–0.82]). CONCLUSIONS:. VE-CAM-S is a physiologic grading scale for the severity of symptoms in the setting of delirium and coma, based on visually assessed electroencephalography features. VE-CAM-S scores are strongly associated with clinical outcomes.

Left ventricular endomyocardial biopsy (EMB) is an essential tool in the management of myocarditis and is conventionally performed via transfemoral access (TFA). Transradial access EMB (TRA-EMB) is a novel alternative and the authors sought to determine its safety and feasibility by conducting a systematic review of the literature. Medline was searched in 2020, and cohort demographics, procedural details and complications were extracted from selected studies. Four observational studies with a combined total of 496 procedures were included. TRA-EMB was most frequently performed with a sheathless MP1 guide catheter via the right radial artery. The most common complication was pericardial effusion (up to 11% in one study), but pericardial drainage for tamponade was rare (one reported case). Death and mitral valve damage have not been reported. TRA-EMB was successful in obtaining samples in 99% of reported procedures. The authors concluded that TRA-EMB is a safe and feasible alternative to TFA-EMB and the most common complication is uncomplicated pericardial effusion.

Pancreatic cancer is one of the most lethal human cancers. Early detection and diagnosis of precursor lesions for pancreatic malignancy is essential to improve the morbidity and mortality associated with this diagnosis. Of the cystic precursor lesions, branch duct intraductal papillary mucinous neoplasm (IPMN) is the most frequently identified lesion and has a wide range of malignant potential. Currently, Carcinogenic embryonic antigen (CEA) levels in the cyst fluid and cytology are the two most often utilized tools to diagnose these lesions; however, their diagnostic and risk stratification capabilities are somewhat limited. Within the last decade, the use of endoscopic ultrasound-guided fine-needle aspiration has opened the door for molecular analysis of cystic fluid as an option to enhance both the diagnosis and risk stratification of these lesions. The first step is to differentiate branch duct IPMNs from other lesions. KRAS and GNAS alterations have been shown to be accurate markers for this purpose. Following cyst type identification, mutational analysis, telomere fusion, microRNAs, long non-coding RNA, and DNA methylation have been identified as potential targets for stratifying malignant potential using the cystic fluid. In this review, we will examine the various targets of cyst fluid molecular analysis and their utility in the diagnosis and risk stratification of branch duct IPMNs.

A case of pheochromocytoma producing vasoactive intestinal peptide (VIP) and left ventricular thrombus in the absence of cardiomyopathy or wall motion abnormalities on echocardiogram is presented along with a review of the relevant literature. A 30-year-old female of Afghani descent with past medical history of panic attacks presented with fever, cough, sore throat, vomiting, and was found to have an 11 cm adrenal mass consistent with primary adrenocortical adenoma versus carcinoma. Her tumor elicited catechols and vasoactive intestinal peptide. Her hospitalization was complicated by left ventricular thrombosis leading to an embolic injury to her right kidney, respiratory failure, need for transient dialysis and urinary tract infections. She developed a profuse secretory diarrhea and decision was made to treat with empiric octreotide infusion and imodium with improvement in symptoms. She underwent coil and particle embolization followed by resection. Followup PET gallium scan showed no evidence of residual disease or metastasis. VIP producing pheochromocytoma associated with intracardiac thrombosis is rare. Outcomes depend on prompt diagnosis of the pheochromocytoma and multidisciplinary approach to management.

B-cell receptor signalling inhibition by targeting Bruton tyrosine kinase (BTK) is effective in treating chronic lymphocytic leukemia (CLL). The BTK inhibitor ibrutinib may be intolerable for some patients. Acalabrutinib is a more selective BTK inhibitor that may be better tolerated by patients who are intolerant to ibrutinib. A phase 2 study of acalabrutinib was conducted in patients with relapsed/refractory CLL who were ibrutinib-intolerant and had continued disease activity. Intolerance was defined as having discontinued ibrutinib due to persistent grade 3/4 adverse events (AEs) or persistent/recurrent grade 2 AEs despite dose modification/interruption. Patients received oral acalabrutinib 100 mg twice daily until disease progression or intolerance. Sixty patients were treated. Overall response rate to acalabrutinib was 73% and three patients (5%) achieved complete remission. At median follow-up of 35 months, the median progressionfree and overall survival were not reached; 24-month estimates were 72% and 81%, respectively. The most frequent AEs with acalabrutinib were diarrhea (53%), headache (42%), contusion (40%), dizziness (33%), upper respiratory tract infection (33%), and cough (30%). Most common reasons for acalabrutinib discontinuation were progressive disease (23%) and AEs (17%). Most patients with baseline samples (49/52; 94%) and all with on-treatment samples (3/3; 100%) had no detectable BTK and/or PLCG2 mutations. Acalabrutinib is effective and tolerable in most patients with relapsed/refractory CLL who are intolerant of ibrutinib. Acalabrutinib may be useful for patients who may benefit from BTK inhibitor therapy but are ibrutinib intolerant.

En este artículo analizamos las transformaciones en los patrones de consumo de bebidas alcohólicas de personas que se encontraban transitando el aislamiento social preventivo y obligatorio (cuarentena) en el Área Metropolitana de Buenos Aires (Argentina). Desarrollamos y aplicamos una encuesta autoadministrada online a 4613 personas de 18 años o más. Un 45% declaró haber aumentado el volumen de bebidas alcohólicas consumidas en la cuarentena. Quienes han aumentado en mayor medida son las personas adultas (de 35 a 54 años). Entre las razones del aumento se destacan tener más tiempo libre, el impacto emocional de la cuarentena y la falta de rutina estable. Respecto de la frecuencia del consumo, se duplicó el número de quienes no toman bebidas alcohólicas y se triplicó la cantidad de personas que toman todos los días. Pese a estos cambios, nueve de cada 10 personas que declararon haber tomado más en la cuarentena no creen que esto afecte su salud, sus vínculos o su trabajo. Entre quienes redujeron su consumo, encontramos a los más jóvenes (18 a 24 años); y sobre los motivos, siete de cada 10 mencionaron la falta de salidas y eventos sociales.

BackgroundPregnancy is a teachable moment for behaviour change. Multiple guidelines target pregnant women for behavioural intervention. This systematic review of systematic reviews reports the effectiveness of interventions delivered during pregnancy on changing women's behaviour across multiple behavioural domains.MethodsFourteen databases were searched for systematic reviews published from 2008, reporting interventions delivered during pregnancy targeting smoking, alcohol, diet or physical activity as outcomes. Data on behaviour change related to these behaviours are reported here. Quality was assessed using the JBI critical appraisal tool for umbrella reviews. Consistency in intervention effectiveness and gaps in the evidence-base are described.ResultsSearches identified 24,388 results; 109 were systematic reviews of behaviour change interventions delivered in pregnancy, and 36 reported behavioural outcomes. All smoking and alcohol reviews identified reported maternal behaviours as outcomes (n = 16 and 4 respectively), whereas only 16 out of 89 diet and/or physical activity reviews reported these behaviours. Most reviews were high quality (67%) and interventions were predominantly set in high-income countries. Overall, there was consistent evidence for improving healthy diet behaviours related to increasing fruit and vegetable consumption and decreasing carbohydrate intake, and fairly consistent evidence for increase in some measures of physical activity (METs and VO2 max) and for reductions in fat intake and smoking during pregnancy. There was a lack of consistent evidence across reviews reporting energy, protein, fibre, or micronutrient intakes; smoking cessation, abstinence or relapse; any alcohol behaviours.ConclusionsThe most consistent review evidence is for interventions improving dietary behaviours during pregnancy compared with other behaviours, although the majority of diet reviews prioritised reporting health-related outcomes over behavioural outcomes. Heterogeneity between reported behaviour outcomes limits ability to pool data in meta-analysis and more consistent reporting is needed. Limited data are available for alcohol interventions in pregnancy or interventions in low- or middle-income-countries, which are priority areas for future research.

Fractional flow reserve is the gold standard for assessing the haemodynamic significance of intermediate coronary artery stenoses. Cumulative evidence has shown that FFR-guided revascularisation reduces stent implantations and improves patient outcomes. However, despite the wealth of evidence and guideline recommendations, its use in clinical practice remains minimal. Patient and technical limitations of FFR as well as the need for intracoronary instrumentation, use of adenosine, and increased costs have limited FFR’s applicability in clinical practice. Over the last decade, several angiography-derived FFR software packages have been developed which do not require intracoronary pressure assessment with a guidewire or need for administration of hyperaemic agents. At present, there are 3 commercially available software packages and several other non-commercial technologies that have been described in the literature. These technologies have been validated against invasive FFR showing good accuracy and correlation. However, the methodology behind these solutions is different—some algorithms are based on solving the governing equations of fluid dynamics such as the Navier–Stokes equation while others have opted for a more simplified mathematical formula approach. The aim of this review is to critically appraise the methodology behind all the known angiography-derived FFR technologies highlighting the key differences and limitations.

As a test of the time symmetry of forbidden-line emission processes, we measured the [OIII]λλ4959 and 5007 emission lines of more than 12,000 galaxies from the Sloan Digital Sky Survey DR8 to examine the [OIII]λλ4959,5007 flux ratio as a function of redshift z. Using two different approaches, we fitted each line with a Gaussian curve and rejected any spectrum not conforming to requirements of line symmetry, S/N levels, and continuum fit. We found the variance in the ratio of flux to be between 4.7 and −3.3% for 0

Abstract Background Prostate cancer is the most common cancer in men in the UK. NICE guidelines on recognition and referral of suspected cancer, recommend performing digital rectal examination (DRE) on patients with urinary symptoms and urgently referring if the prostate feels malignant. However, this is based on the results of one case control study, so it is not known if DRE performed in primary care is an accurate method of detecting prostate cancer. Methods The aim of this review is to ascertain the sensitivity, specificity, positive and negative predictive value of DRE for the detection of prostate cancer in symptomatic patients in primary care. CENTRAL, MEDLINE, EMBASE and CINAHL databases were searched in august 2015 for studies in which a DRE was performed in primary care on symptomatic patients and compared against a reference diagnostic procedure. Results Four studies were included with a total of 3225 patients. The sensitivity and specificity for DRE as a predictor of prostate cancer in symptomatic patients was 28.6 and 90.7%, respectively. The positive and negative predictive values were 42.3 and 84.2%, respectively. Conclusion This review found that DRE performed in general practice is accurate, and supports the UK NICE guidelines that patients with a malignant prostate on examination are referred urgently for suspected prostate cancer. Abnormal DRE carried a 42.3% chance of malignancy, above the 3% risk threshold which NICE guidance suggests warrants an urgent referral. However this review questions the benefit of performing a DRE in primary care in the first instance, suggesting that a patient’s risk of prostate cancer based on symptoms alone would warrant urgent referral even if the DRE feels normal.

The natural extension to the SU(5) Georgi-Glashow grand unification model is to enlarge the gauge symmetry group. In this work, the SU(7) symmetry group is examined. The Cartan subalgebra is determined along with their commutation relations. The associated roots and weights of the SU(7) algebra are derived and discussed. The raising and lowering operators are explicitly constructed and presented. Higher dimensional representations are developed by graphical as well as tensorial methods. Applications of the SU(7) Lie group to supersymmetric grand unification as well as applications are discussed.

Abstract Background Deep vein thrombosis (DVT) is a common complication of peripherally inserted central catheters (PICCs). PICCs are increasingly utilised in the management of cancer patients, a group which carries both additional risks for vascular thromboembolism as well as for complex morbidity. We analysed a cohort of cancer patients subjected to PICC insertion in a single cancer centre for the incidence of all-type vascular thromboembolism (VTE) and investigated relative risk factors. Methods In this clinical audit, the records of patients referred for PICC insertion in our centre in the period between 1/1/2011 and 1/4/2014 were retrospectively reviewed. The primary outcomes investigated were a) PICC-related deep vein thrombosis (PRDVT) and b) distant VTE (lower limb DVT and pulmonary embolism). 4Fr single lumen PICCs were placed in all patients. The Kaplan Meier method was used to study time from PICC insertion to PRDVT/VTE. Survival curves were compared using the log rank method. Logistic and Cox regression analyses were used to assess local, distant and combined endpoints. Results Four hundred ninety patients were included in the analysis of which 27 (5.5%) developed a PRDVT. Statistically significant risk factors for developing PRDVT in multivariate analysis included more than one attempt for insertion (OR 2.61, 95%CI: 1.12–6.05) and the use of fluoropyrimidine containing chemotherapy (OR 4.27, 95%CI 1.3–14.07). Twenty-six patients developed a distant VTE. Male gender was the only significant risk factor for distant VTE. When all-type VTE were considered together fluoropyrimidine containing chemotherapy (OR 4.54, 95% CI 1.63–12.61), male gender (OR 2.03, 95% CI 1.04–3.93) and white cell count (OR 1.12, 95% CI 1.00–1.26) were statistically significant as risk factors in this analysis. Conclusions This is a large study of VTE following PICC insertion in cancer patients which also looks at the rate of distant VTE. The observed PRDVT incidence is comparable with available literature. Fluoropyrimidine containing chemotherapy and more than one attempt for PICC insertion were independent predictors of PICC-associated VTE whilst the former remained an independent predictor of all-type VTE. Anticoagulation did not prevent thrombotic events in this cohort.

We analyzed chromatin dynamics and transcriptional activity of human embryonic stem cell (hESC)-derived cardiac progenitor cells (CPCs) and KDR+/CD34+ endothelial cells generated from different mesodermal origins. Using an unbiased algorithm to hierarchically rank genes modulated at the level of chromatin and transcription, we identified candidate regulators of mesodermal lineage determination. HOPX, a non-DNA-binding homeodomain protein, was identified as a candidate regulator of blood-forming endothelial cells. Using HOPX reporter and knockout hESCs, we show that HOPX regulates blood formation. Loss of HOPX does not impact endothelial fate specification but markedly reduces primitive hematopoiesis, acting at least in part through failure to suppress Wnt/β-catenin signaling. Thus, chromatin state analysis permits identification of regulators of mesodermal specification, including a conserved role for HOPX in governing primitive hematopoiesis.

Prolonged total treatment times (TTTs) beyond 56 days are associated with worse outcomes for cervical cancer treated with radiation therapy. We reviewed treatment times in a cohort of 24 consecutive patients treated with definitive chemoradiation (CRT) at our institution and found that only 14 patients (58.3%) completed treatment in less than or equal to 56 days. The primary objectives of this institutional quality improvement initiative were to identify sources for delays in treatment completion and to implement effective measures in an effort to minimise prolonged TTT. Pareto plot and process mapping were used to identify and resolve root causes of prolonged treatment. The Plan-Do-Study-Act method was then implemented to reduce treatment duration. Post-intervention treatment times were prospectively evaluated in 81 subsequent patients treated with definitive CRT. Process mapping identified inefficiencies with scheduling, staggered treatments and inadequate patient and staff education. Institutional changes were implemented, heavily utilising oncology nurses’ skill set in staff re-education and care coordination. Our workflow was redesigned to reduce/eliminate treatment delays. These interventions led to a significant improvement in the percentage of patients meeting the goal TTT compared with the pre-intervention cohort (85.2% vs 58.3%, p

This article presents the results of a dialogue between decision-makers and experts in Latin America and the Caribbean on priority-setting for interventions and studies on Aedes aegypti control. The article is part of a project that included a systematic review of mosquito control strategies and a qualitative study with key informants from the region. Using a collective deliberative process assisted by the results of the above-mentioned projects, a list of priorities was developed by consensus for the implementation of vector control strategies and the development of key regional research lines. It was agreed that the best strategy is integrated vector management, divided into: (a) chemical control; (b) biological control; (c) environmental management; (d) community participation; and (e) integrated surveillance. The workshop highlighted the crucial role of government leadership and inter-sector coordination between government agencies and civil society stakeholders. The proposed priorities for research lines were: Ae. aegypti vector competence and associated factors; community components of interventions; incorporation of technology into vector control and monitoring; most efficient modalities of integrated surveillance; entomological indicators with the best predictive capacity; and resistance to insecticides. The policy dialogue methodology allowed validating and enriching the results of other levels of research, besides establishing priorities for regional research and control strategies.

Gene expression in all organisms is controlled by cooperative interactions between DNA-bound transcription factors (TFs), but quantitatively measuring TF-DNA and TF-TF interactions remains difficult. Here we introduce a strategy for precisely measuring the Gibbs free energy of such interactions in living cells. This strategy centers on the measurement and modeling of ‘allelic manifolds’, a multidimensional generalization of the classical genetics concept of allelic series. Allelic manifolds are measured using reporter assays performed on strategically designed cis-regulatory sequences. Quantitative biophysical models are then fit to the resulting data. We used this strategy to study regulation by two Escherichia coli TFs, CRP and [Formula: see text] RNA polymerase. Doing so, we consistently obtained energetic measurements precise to [Formula: see text] kcal/mol. We also obtained multiple results that deviate from the prior literature. Our strategy is compatible with massively parallel reporter assays in both prokaryotes and eukaryotes, and should therefore be highly scalable and broadly applicable.Editorial note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that minor issues remain unresolved (see decision letter).

KMT2A partial tandem duplication occurs in approximately 5–10% of patients with acute myeloid leukemia and is associated with adverse prognosis. KMT2A wild type is epigenetically silenced in KMT2A partial tandem duplication; re-expression can be induced with DNA methyltransferase and/or histone deacetylase inhibitors in vitro, sensitizing myeloid blasts to chemotherapy. We hypothesized that epigenetic silencing of KMT2A wildtype contributes to KMT2A partial tandem duplication-associated leukemogenesis and pharmacologic re-expression activates apoptotic mechanisms important for chemoresponse. We developed a regimen for this unique molecular subset, but due to relatively low frequency of KMT2A partial tandem duplication, this dose finding study was conducted in relapsed/refractory disease regardless of molecular subtype. Seventeen adults (< age 60) with relapsed/refractory acute myeloid leukemia were treated on study. Patients received decitabine 20 milligrams/meter2 daily on days 1–10 and vorinostat 400 milligrams daily on days 5–10. Cytarabine was dose-escalated from 1.5 grams/meter2 every 12 hours to 3 grams/meter2 every 12 hours on days 12, 14 and 16. Two patients experienced dose limiting toxicities at dose level 1 due to prolonged myelosuppression. However, as both patients achieved complete remission after Day 42, the protocol was amended to adjust the definition of hematologic dose limiting toxicity. No further dose limiting toxicities were found. Six of 17 patients achieved complete remission including 2 of 4 patients with KMT2A partial tandem duplication. Combination therapy with decitabine, vorinostat and cytarabine was tolerated in younger relapsed/refractory acute myeloid leukemia and should be explored further focusing on the KMT2A partial tandem duplication subset. (clinicaltrials.gov identifier 01130506).

Opened in the summer of 2013, the Searchlight Archive at the University of Northampton offers researchers one of the largest collections of material on the far right and anti-fascist movements in Europe. The University of Northampton is very grateful to Gerry Gable, Editor of Searchlight Magazine, for allowing us to house this material, and place it in the public domain. Consisting of hundreds of boxes of unique material, with around 350 presently on our catalogue, the archive has already welcomed dozens of researchers (from undergraduate dissertation students to professional academics), and has contributed to numerous articles and papers too. This resource has a wide range of applicability into on-going research into the history and contemporary dynamics of radicalism. So far, researchers have only scratched the surface of its relevance for emergent debates into themes such as networking and transnational forms of extremism, gender and far right activity, and the roles played by civil society in counteracting the impact of ultra-nationalism.

The article analyzes the intersections between religion and politics by observing the debate about same-sex marriage in Argentina in 2010. It begins by critically examining some principles of the secularization theory about the role of religious beliefs, particularly how these beliefs are articulated in contemporary sexual policy. The article focuses on three main phenomena to show how religion was mobilized in favor of the expansion of rights: the activist LGBT strategy of allying itself with religious actors; the support of evangelical churches and Catholic priests in favor of recognition of egalitarian marriage; and the use of religious discourse by legislators to justify their support for the legal reform.

El artículo explora las relaciones de las organizaciones de la sociedad civil (OSC) identificadas con un credo religioso que se dedican al tratamiento de los consumos de drogas, con el Estado, otras OSC y otros actores no estatales. El objetivo es describir y analizar los vínculos entre dichas organizaciones, el Estado (en sus distintos niveles, organismos y poderes) y otras organizaciones no estatales (iglesias, federaciones de Organizaciones No Gubernamentales, redes trasnacionales, partidos políticos), en el proceso de implementación de políticas públicas de drogas en partidos del Gran Buenos Aires (PGBA), territorio conocido popularmente como el “conurbano”. Analizamos tres dimensiones de los vínculos entre estas OSC religiosas y el Estado: las relaciones económicas; la articulación en los tratamientos propiamente dichos; y los argumentos de sus referentes para explicar la falta de apoyo y/o articulación. Además, describimos el tipo de relaciones de estas instituciones con otras OSC y otros actores no estatales que dan origen, colaboran en el funcionamiento y permiten el sustento económico de estos dispositivos. El artículo se basa en observaciones y entrevistas a referentes instituciones evangélicas y católicas orientadas a la atención de usuarios con consumos de drogas en la Ciudad de Buenos Aires y los partidos del GBA.

Los actores religiosos participan crecientemente de los debates públicos contemporáneos. En América Latina al activismo de la Iglesia católica se ha sumado el de los grupos evangélicos. Este artículo compara dos procesos en los que participaron políticamente las Iglesias protestantes históricas en Argentina: la defensa de los derechos humanos frente a las violaciones de la dictadura militar (1976-1983) y el apoyo a la ley de Matrimonio Igualitario (2010) para parejas del mismo sexo. Nuestra conjetura es que la actuación de estas Iglesias en ambos contextos comparte rasgos significativos para explicar las modalidades de participación política (no partidaria).

El autor se cuestiona ¿Cómo nace y evoluciona la industria del video doméstico? Los datos demuestran el impacto de este sobre el cine y la televisión. Después del auge de la video-piratería las transnacionales anglosajonas del video recapturan casi todo el mercado español. Aunque no hay datos parecería que América Latina sucede un proceso análogo de expansión y concentración. Trata además sobre la producción de videos de sexo y violencia, los conflictos entre las industrias audiovisuales, los imperios (industria cinematográfica) contraatacan, Videoindustria y Estado, Japón, USA, UK.

El artículo explora los orígenes y dinámicas contemporáneas de la sexología en Argentina, con el objetivo de analizar dos cuestiones relevantes: 1) ¿cómo perciben sexólogas y sexólogos la creciente medicalización de la sexualidad?; y 2) ¿han incorporado estos profesionales, de alguna manera, una perspectiva de género en sus intervenciones? Ambos fenómenos se vinculan, ya que la medicalización contribuiría a la reproducción de asimetrías y estereotipos tradicionales de género, tanto en la organización del campo sexológico como en las concepciones de sexualidad utilizadas. El artículo se basa en una investigación empírica a partir de fuentes secundarias (programas decursos y congresos sexológicos, reglamentos de afiliación y acreditación de asociaciones sexológicas, curriculum vitae de profesionales) y entrevistas a referentes del campo sexológico y a profesionales que abordan cuestiones de sexualidad e interactúan frecuentemente con sexólogos, pero que no se reconocen como tales.

Japanese Knotweed s.l. taxa are amongst the most aggressive vascular plant Invasive Alien Species (IAS) in the world. These taxa form dense, suppressive monocultures and are persistent, pervasive invaders throughout the more economically developed countries (MEDCs) of the world. The current paper utilises the Object-Based Image Analysis (OBIA) approach of Definiens Imaging Developer software, in combination with very high spatial resolution (VHSR) colour infra-red (CIR) and visible‑band (RGB) aerial photography in order to detect Japanese Knotweed s.l. taxa in Wales (UK). An algorithm was created using Definiens in order to detect these taxa, using variables found to effectively distinguish them from landscape and vegetation features. The results of the detection algorithm were accurate, as confirmed by field validation and desk‑based studies. Further, these results may be incorporated into Geographical Information Systems (GIS) research as they are readily transferable as vector polygons (shapefiles). The successful detection results developed within the Definiens software should enable greater management and control efficacy. Further to this, the basic principles of the detection process could enable detection of these taxa worldwide, given the (relatively) limited technical requirements necessary to conduct further analyses.

El artículo analiza las expectativas y experiencias relativas a la primera relación sexual de adolescentes. Es un acontecimiento enmarcado en un proceso de aprendizaje erótico, corporal y práctico que la excede temporalmente. El análisis se basa en entrevistas individuales con 22 varones y 22 mujeres, de 15 a 19 años, de estratos socioeconómicos medios y residentes en Trelew, ciudad de 100 mil habitantes en la Patagonia argentina. Los papeles esperados para varones y mujeres en su primera relación sexual son opuestos y complementarios, apareciendo en los relatos dos escenas típicas de iniciación sexual, una gradualista y la otra espontánea.The present article analyses expectations and experiences related to the first sexual relation, considering it as an event framed within a process of erotic, corporeal and practical learning that temporally exceeds its boundaries. The article is based on individual interviews with 44 teenagers (22 male and 22 female) from 15 to 19 years of age, who are members of the middle class and live in Trelew, a city of one hundred thousand inhabitants in the Argentinean Patagonia. Expected roles for girls and boys regarding their first sexual relation are both opposed and complementary and two typical scenes of sexual initiation are revealed by our informants' stories, one gradualistic and one spontaneous.

The DAF-16/FoxO transcription factor controls growth, metabolism and aging in Caenorhabditis elegans. The large number of genes that it regulates has been an obstacle to understanding its function. However, recent analysis of transcript and chromatin profiling implies that DAF-16 regulates relatively few genes directly, and that many of these encode other regulatory proteins. We have investigated the regulation by DAF-16 of genes encoding the AMP-activated protein kinase (AMPK), which has α, β and γ subunits. C. elegans has 5 genes encoding putative AMP-binding regulatory γ subunits, aakg-1-5. aakg-4 and aakg-5 are closely related, atypical isoforms, with orthologs throughout the Chromadorea class of nematodes. We report that ∼75% of total γ subunit mRNA encodes these 2 divergent isoforms, which lack consensus AMP-binding residues, suggesting AMP-independent kinase activity. DAF-16 directly activates expression of aakg-4, reduction of which suppresses longevity in daf-2 insulin/IGF-1 receptor mutants. This implies that an increase in the activity of AMPK containing the AAKG-4 γ subunit caused by direct activation by DAF-16 slows aging in daf-2 mutants. Knock down of aakg-4 expression caused a transient decrease in activation of expression in multiple DAF-16 target genes. This, taken together with previous evidence that AMPK promotes DAF-16 activity, implies the action of these two metabolic regulators in a positive feedback loop that accelerates the induction of DAF-16 target gene expression. The AMPK β subunit, aakb-1, also proved to be up-regulated by DAF-16, but had no effect on lifespan. These findings reveal key features of the architecture of the gene-regulatory network centered on DAF-16, and raise the possibility that activation of AMP-independent AMPK in nutritionally replete daf-2 mutant adults slows aging in C. elegans. Evidence of activation of AMPK subunits in mammals suggests that such FoxO-AMPK interactions may be evolutionarily conserved.