What and how: doing good research with young people, digital intimacies, and relationships and sex education

© 2020, © 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. As part of a project funded by the Wellcome Trust, we held a one-day symposium, bringing together researchers, practitioners, and policymakers, to discuss priorities for research on relationships and sex education (RSE) in a world where young people increasingly live, experience, and augment their relationships (whether sexual or not) within digital spaces. The introduction of statutory RSE in schools in England highlights the need to focus on improving understandings of young people and digital intimacies for its own sake, and to inform the development of learning resources. We call for more research that puts young people at its centre; foregrounds inclusivity; and allows a nuanced discussion of pleasures, harms, risks, and rewards, which can be used by those working with young people and those developing policy. Generating such research is likely to be facilitated by participation, collaboration, and communication with beneficiaries, between disciplines and across sectors. Taking such an approach, academic researchers, practitioners, and policymakers agree that we need a better understanding of RSE’s place in lifelong learning, which seeks to understand the needs of particular groups, is concerned with non-sexual relationships, and does not see digital intimacies as disconnected from offline everyday ‘reality’

Maximum tumor diameter is associated with event-free survival in PET-negative patients with stage I/IIA Hodgkin lymphoma.

Introduction: the high cure rates achieved in early-stage (ES) Hodgkin lymphoma (HL) are one of the great successes of hemato-oncology, but late treatment-related toxicity undermines long-term survival. Improving overall survival and quality of life further will require maintaining disease control while potentially de-escalating chemotherapy and/or omitting radiotherapy to reduce late toxicity. Accurate stratification of patients is required to facilitate individualized treatment approaches. Response assessment using 18F-fluorodeoxyglucose positron emission tomography (PET) is a powerful predictor of outcome in HL,1,2 and has been used in multiple studies, including the United Kingdom National Cancer Research Institute Randomised Phase III Trial to Determine the Role of FDG–PET Imaging in Clinical Stages IA/IIA Hodgkin’s Disease (UK NCRI RAPID) trial, to investigate whether patients achieving complete metabolic remission (CMR) can be treated with chemotherapy alone.3-5 These PET-adapted trials have demonstrated that omitting radiotherapy results in higher relapse rates, but without compromising overall survival.3-5 For the 75% of patients who achieved CMR in RAPID, neither baseline clinical risk stratification (favorable/unfavorable) nor PET (Deauville score 1/2) predicted disease relapse; additional biomarkers are needed.1 Tumor bulk has long been recognized as prognostic in HL,1,6 but there remains uncertainty about the significance and definition of bulk in the era of PET-adapted treatment.7 We performed a subsidiary analysis of RAPID to assess the prognostic value of baseline maximum tumor dimension (MTD) in patients achieving CMR. Methods: ee have previously reported the RAPID trial design, primary results, and outcomes according to pretreatment risk stratification and PET score.1,3 Patients were aged 16 to 75 years with untreated ES-HL and without B-symptoms or mediastinal bulk (mass > 1/3 internal mediastinal diameter at T5/6).6 Metabolic response after 3 cycles of ABVD chemotherapy (doxorubicin, bleomycin, vinblastine, and dacarbazine) was centrally assessed using PET (N = 562). Patients with CMR (ie, Deauville score 1-2) were randomly assigned to receive involved field radiotherapy (IFRT; n = 208) or no further therapy (NFT; n = 211). PET-positive patients (score, 3-5; n = 143) received a fourth cycle of ABVD and IFRT. Baseline disease assessment was performed by computed tomography, and bidimensional target lesion measurements were reported by local radiologists in millimeters. The association of baseline MTD with HL-related event-free survival (EFS: progression or HL-related death) and progression-free survival (PFS) (progression or any-cause death) was assessed using Kaplan-Meier and Cox regression analyses. Non-HL deaths were either related to primary treatment toxicity or occurred in HL remission.1 United Kingdom ethical approval for the RAPID trial was via the UK Multicentre Research ethics committee. Results and discussion: baseline patient characteristics have been previously described.1 Median age was 34 years (range, 16-75 years); 184 (37.4%) of 492 patients had unfavorable risk by European Organisation for Research and Treatment of Cancer criteria, and 155 (32.3%) of 480 by German Hodgkin Study Groupcriteria. Median MTD for patients achieving CMR was 3.0 cm (interquartile range, 2.0-4.0 cm) and 3.0 cm (interquartile range, 1.8-4.5 cm) in the NFT and IFRT groups, respectively, whereas PET-positive patients had a median MTD of 3.9 cm (interquartile range, 2.8-5.1 cm). After a median follow-up of 61.6 m, 44 HL progression events occurred: 21 NFT, 9 IFRT and 14 PET-positive. No patient received salvage treatment without documented progression. Only 5 HL-related deaths occurred (1 IFRT, 4 PET-positive), and 12 non-HL deaths (4 NFT, 6 IFRT, 2 PET-positive).1 For patients with CMR (N = 419), there was a strong association between MTD and EFS (hazard ratio [HR], 1.19; 95% confidence interval [CI], 1.02-1.39; P = .02), adjusting for treatment group, with an approximate 19% increase in HL risk per centimeter increase in MTD. The association was similar in both treatment groups (NFT HR, 1.20 [95% CI, 0.99-1.44; P = .06]; IFRT HR, 1.19 [95% CI, 0.92-1.55; P = .19]). The observed effect sizes did not markedly change after adjusting for baseline clinical risk factors, and similar results were observed for PFS (supplemental Table 1). In contrast, for PET-positive patients, there was no association between MTD and EFS (HR, 0.88; 95% CI, 0.70-1.11; P = .29) or PFS (HR, 0.87; 95% CI, 0.70-1.08; P = .21). In an exploratory analysis within the NFT group, MTD was dichotomized using increasing 1-cm intervals to investigate the relationship between MTD thresholds and EFS. The largest effect size was observed with an MTD threshold of ≥5 cm (Table 1). Similar results were observed for PFS; this threshold also performed best in time-dependent receiver operating characteristic curve analyses. It was not possible to assess MTD thresholds in the IFRT group with only 9 events. Among all randomized patients, 79 (18.9%) had MTD of ≥5 cm, the majority with mediastinal (n = 43), supraclavicular (n = 17), or cervical (n = 16) locations. Five-year EFS for patients with MTD of ≥5 cm randomly assigned to NFT and IFRT was 79.3% (n = 39; 95% CI, 66.6%-92.0%) and 94.9% (n = 40; 95% CI, 88.0%-100%), respectively (P = .03; Figure 1)

A Proposed Method for Improving Residential Heating Energy Estimates Based on Billing Data

Analyses o f residential energy conservation programs frequently require reliable estimates of program effects on space-heating energy consumption. Simulation models are often used to provide such estimates. Recent, large-scale programs to collect empirical energy consumption data, however, provide a basis for alternative ways to estimate program effects that utilize the empirical data. The PRISM methodology uses relatively inexpensive billing and weather data to estimate base and temperature-sensitive (primarily space-heating) loads. We used billing data from over 300 manufactured (mobile) homes in two residential conservation projects to derive PRISM heating energy estimates. Actual heating energy data for a subset of these homes was used to develop a methodology for adjusting the initial PRISM-based heating estimates. We developed the adjustment relying on a theoretical approach and the empirical data. This approach resulted in a correction technique that reduced the average error in the initial PRISM-based space-heating estimates by about 70%. and requires primarily readily available PRISM outputs and limited housing characteristics data

Air Exchange Rates in New Energy-Efficient Manufactured Housing

During the 1989-1990 heating season, Pacific Northwest Laboratory, for the Bonneville Power Administration, measured the ventilation characteristics of 139 newly constructed energy-efficient manufactured homes and a control sample of 35 newer manufactured homes. A standard door fan pressurization technique was used to estimate shell leakiness, and a passive perfluorocarbon tracer technique was used to estimate overall air exchange rates. A measurement of the designated whole-house exhaust system flow rate was taken as well as an occupant and structure survey. The energy-efficient manufactured homes have very low air exchange rates, significantly lower than either existing manufactured homes or site-built homes. The standard deviation of the effective leakage area for this sample of homes is small (25% to 30% of the mean), indicating that the leakiness of manufactured housing stock can be confidently characterized by the mean value. There is some indication of increased ventilation due to the energy-efficient whole-house ventilation specification, but not directly related to the operation of the wholehouse system. The mechanical systems as installed and operated do not provide the intended ventilation; consequently indoor air quality could possibly be adversely impacted and moisture/condensation in the living space is a potential problem

Positron Emission Tomography Score Has Greater Prognostic Significance Than Pretreatment Risk Stratification in Early-Stage Hodgkin Lymphoma in the UK RAPID Study.

PURPOSE: Accurate stratification of patients is an important goal in Hodgkin lymphoma (HL), but the role of pretreatment clinical risk stratification in the context of positron emission tomography (PET) -adapted treatment is unclear. We performed a subsidiary analysis of the RAPID trial to assess the prognostic value of pretreatment risk factors and PET score in determining outcomes. PATIENTS AND METHODS: Patients with stage IA to IIA HL and no mediastinal bulk underwent PET assessment after three cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine; 143 PET-positive patients (PET score, 3 to 5) received a fourth doxorubicin, bleomycin, vinblastine, and dacarbazine cycle and involved-field radiotherapy, and 419 patients in complete metabolic remission were randomly assigned to receive involved-field radiotherapy (n = 208) or no additional treatment (n = 211). Cox regression was used to investigate the association between PET score and pretreatment risk factors with HL-specific event-free survival (EFS). RESULTS: High PET score was associated with inferior EFS, before (P .4). CONCLUSION: In RAPID, a positive PET scan did not carry uniform prognostic weight; only a PET score of 5 was associated with inferior outcomes. This suggests that in future trials involving patients without B symptoms or mediastinal bulk, a score of 5 rather than a positive PET result should be used to guide treatment escalation in early-stage HL

CD103 Expression Is Required for Destruction of Pancreatic Islet Allografts by CD8+ T Cells

The mechanisms by which CD8 effector populations interact with epithelial layers is a poorly defined aspect of adaptive immunity. Recognition that CD8 effectors have the capacity to express CD103, an integrin directed to the epithelial cell-specific ligand E-cadherin, potentially provides insight into such interactions. To assess the role of CD103 in promoting CD8-mediated destruction of epithelial layers, we herein examined the capacity of mice with targeted disruption of CD103 to reject pancreatic islet allografts. Wild-type hosts uniformly rejected islet allografts, concomitant with the appearance of CD8+CD103+ effectors at the graft site. In contrast, the majority of islet allografts transplanted into CD103−/− hosts survived indefinitely. Transfer of wild-type CD8 cells into CD103−/− hosts elicited prompt rejection of long-surviving islet allografts, whereas CD103−/− CD8 cells were completely ineffectual, demonstrating that the defect resides at the level of the CD8 cell. CD8 cells in CD103−/− hosts exhibited normal effector responses to donor alloantigens in vitro and trafficked normally to the graft site, but strikingly failed to infiltrate the islet allograft itself. These data establish a causal relationship between CD8+CD103+ effectors and destruction of graft epithelial elements and suggest that CD103 critically functions to promote intragraft migration of CD8 effectors into epithelial compartments

Soil respiration in a northeastern US temperate forest: a 22‐year synthesis

To better understand how forest management, phenology, vegetation type, and actual and simulated climatic change affect seasonal and inter‐annual variations in soil respiration (Rs), we analyzed more than 100,000 individual measurements of soil respiration from 23 studies conducted over 22 years at the Harvard Forest in Petersham, Massachusetts, USA. We also used 24 site‐years of eddy‐covariance measurements from two Harvard Forest sites to examine the relationship between soil and ecosystem respiration (Re). Rs was highly variable at all spatial (respiration collar to forest stand) and temporal (minutes to years) scales of measurement. The response of Rs to experimental manipulations mimicking aspects of global change or aimed at partitioning Rs into component fluxes ranged from −70% to +52%. The response appears to arise from variations in substrate availability induced by changes in the size of soil C pools and of belowground C fluxes or in environmental conditions. In some cases (e.g., logging, warming), the effect of experimental manipulations on Rs was transient, but in other cases the time series were not long enough to rule out long‐term changes in respiration rates. Inter‐annual variations in weather and phenology induced variation among annual Rs estimates of a magnitude similar to that of other drivers of global change (i.e., invasive insects, forest management practices, N deposition). At both eddy‐covariance sites, aboveground respiration dominated Re early in the growing season, whereas belowground respiration dominated later. Unusual aboveground respiration patterns—high apparent rates of respiration during winter and very low rates in mid‐to‐late summer—at the Environmental Measurement Site suggest either bias in Rs and Re estimates caused by differences in the spatial scale of processes influencing fluxes, or that additional research on the hard‐to‐measure fluxes (e.g., wintertime Rs, unaccounted losses of CO2 from eddy covariance sites), daytime and nighttime canopy respiration and its impacts on estimates of Re, and independent measurements of flux partitioning (e.g., aboveground plant respiration, isotopic partitioning) may yield insight into the unusually high and low fluxes. Overall, however, this data‐rich analysis identifies important seasonal and experimental variations in Rs and Re and in the partitioning of Re above‐ vs. belowground

Soil respiration in a northeastern US temperate forest: a 22‐year synthesis

To better understand how forest management, phenology, vegetation type, and actual and simulated climatic change affect seasonal and inter‐annual variations in soil respiration (Rs), we analyzed more than 100,000 individual measurements of soil respiration from 23 studies conducted over 22 years at the Harvard Forest in Petersham, Massachusetts, USA. We also used 24 site‐years of eddy‐covariance measurements from two Harvard Forest sites to examine the relationship between soil and ecosystem respiration (Re). Rs was highly variable at all spatial (respiration collar to forest stand) and temporal (minutes to years) scales of measurement. The response of Rs to experimental manipulations mimicking aspects of global change or aimed at partitioning Rs into component fluxes ranged from −70% to +52%. The response appears to arise from variations in substrate availability induced by changes in the size of soil C pools and of belowground C fluxes or in environmental conditions. In some cases (e.g., logging, warming), the effect of experimental manipulations on Rs was transient, but in other cases the time series were not long enough to rule out long‐term changes in respiration rates. Inter‐annual variations in weather and phenology induced variation among annual Rs estimates of a magnitude similar to that of other drivers of global change (i.e., invasive insects, forest management practices, N deposition). At both eddy‐covariance sites, aboveground respiration dominated Re early in the growing season, whereas belowground respiration dominated later. Unusual aboveground respiration patterns—high apparent rates of respiration during winter and very low rates in mid‐to‐late summer—at the Environmental Measurement Site suggest either bias in Rs and Re estimates caused by differences in the spatial scale of processes influencing fluxes, or that additional research on the hard‐to‐measure fluxes (e.g., wintertime Rs, unaccounted losses of CO2 from eddy covariance sites), daytime and nighttime canopy respiration and its impacts on estimates of Re, and independent measurements of flux partitioning (e.g., aboveground plant respiration, isotopic partitioning) may yield insight into the unusually high and low fluxes. Overall, however, this data‐rich analysis identifies important seasonal and experimental variations in Rs and Re and in the partitioning of Re above‐ vs. belowground

The α1D-adrenergic receptor is expressed intracellularly and coupled to increases in intracellular calcium and reactive oxygen species in human aortic smooth muscle cells

Background: The cellular localization of the α1D-adrenergic receptor (α1D-AR) is controversial. Studies in heterologous cell systems have shown that this receptor is expressed in intracellular compartments. Other studies show that dimerization with other ARs promotes the cell surface expression of the α1D-AR. To assess the cellular localization in vascular smooth muscle cells, we developed an adenoviral vector for the efficient expression of a GFP labeled α1D-AR. We also measured cellular localization with immunocytochemistry. Intracellular calcium levels, measurement of reactive oxygen species and contraction of the rat aorta were used as measures of functional activity. Results: The adenovirally expressed α1D-AR was expressed in intracellular compartments in human aortic smooth muscle cells. The intracellular localization of the α1D-AR was also demonstrated with immunocytochemistry using an α1D-AR specific antibody. RT-PCR analysis detected mRNA transcripts corresponding to the α1A-α1B- and α1D-ARs in these aortic smooth muscle cells. Therefore, the presence of the other α1-ARs, and the potential for dimerization with these receptors, does not alter the intracellular expression of the α1D-AR. Despite the predominant intracellular localization in vascular smooth muscle cells, the α1D-AR remained signaling competent and mediated the phenylephrine-induced increases in intracellular calcium. The α1D-AR also was coupled to the generation of reactive oxygen species in smooth muscle cells. There is evidence from heterologous systems that the α1D-AR heterodimerizes with the β2-AR and that desensitization of the β2-AR results in α1D-AR desensitization. In the rat aorta, desensitization of the β2-AR had no effect on contractile responses mediated by the α1D-AR. Conclusion: Our results suggest that the dimerization of the α1D-AR with other ARs does not alter the cellular expression or functional response characteristics of the α1D-AR

The α\u3csub\u3e1D\u3c/sub\u3e-Adrenergic Receptor Is Expressed Intracellularly and Coupled to Increases in Intracellular Calcium and Reactive Oxygen Species in Human Aortic Smooth Muscle Cells

Background: The cellular localization of the α1D-adrenergic receptor (α1D-AR) is controversial. Studies in heterologous cell systems have shown that this receptor is expressed in intracellular compartments. Other studies show that dimerization with other ARs promotes the cell surface expression of the α1D-AR. To assess the cellular localization in vascular smooth muscle cells, we developed an adenoviral vector for the efficient expression of a GFP labeled α1D-AR. We also measured cellular localization with immunocytochemistry. Intracellular calcium levels, measurement of reactive oxygen species and contraction of the rat aorta were used as measures of functional activity. Results: The adenovirally expressed α1D-AR was expressed in intracellular compartments in human aortic smooth muscle cells. The intracellular localization of the α1D-AR was also demonstrated with immunocytochemistry using an α1D-AR specific antibody. RT-PCR analysis detected mRNA transcripts corresponding to the α1A-α1B- and α1D-ARs in these aortic smooth muscle cells. Therefore, the presence of the other α1-ARs, and the potential for dimerization with these receptors, does not alter the intracellular expression of the α1D-AR. Despite the predominant intracellular localization in vascular smooth muscle cells, the α1D-AR remained signaling competent and mediated the phenylephrine-induced increases in intracellular calcium. The α1D-AR also was coupled to the generation of reactive oxygen species in smooth muscle cells. There is evidence from heterologous systems that the α1D-AR heterodimerizes with the β2-AR and that desensitization of the β2-AR results in α1D-AR desensitization. In the rat aorta, desensitization of the β2-AR had no effect on contractile responses mediated by the α1D-AR. Conclusion: Our results suggest that the dimerization of the α1D-AR with other ARs does not alter the cellular expression or functional response characteristics of the α1D-AR