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Objective: Temporary abstinence from alcohol may convey physiological benefits and enhance well-being. The aim of this study was to address a lack of information about: (1) correlates of successful completion of a planned period of abstinence, and (2) how success or failure in planned abstinence affects subsequent alcohol consumption. Methods: 857 British adults (249 men, 608 women) participating in the “Dry January” alcohol abstinence challenge completed a baseline questionnaire, a one-month follow-up questionnaire, and a 6-month follow-up questionnaire. Key variables assessed at baseline included measures of alcohol consumption and drink refusal self-efficacy (DRSE). Results: In bivariate analysis, success during Dry January was predicted by measures of more moderate alcohol consumption and greater social DRSE. Multivariate analyses revealed that success during Dry January was best predicted by a lower frequency of drunkenness in the month prior to Dry January. Structural Equation Modelling revealed that participation in Dry January was related to reductions in alcohol consumption and increases in DRSE among all respondents at 6-month follow-up, regardless of success, but these changes were more likely among people who successfully completed the challenge. Conclusions: The findings suggest that participation in abstinence challenges such as “Dry January” may be associated with changes toward healthier drinking and greater DRSE, and is unlikely to result in undesirable “rebound effects”: very few people reported increased alcohol consumption following a period of voluntary abstinence.

This article examines the relationship between collective memory, historical interpretation and political identity. It focuses on the dissolution of the Communist Party of Great Britain (CPGB) as constructed through collective narrative memory, and on Marxist interpretations of history. The divisions within the party and the wider Marxist community, stretching from 1956 until 1991, were often framed around questions of historical interpretation. The events of 1989–1991 created an historical and mnemonic crisis for CPGB members who struggled to reconcile their past identities with their present situation. Unlike the outward-facing revisionism of other political parties, this was an intensely personal affair. The solution for many was to emphasise the need to find new ways to progress socialist aims, without relying on a discredited grand narrative. In contrast, other Communist parties, such as the Communist Party of Britain, which had been established (or ‘re-established’) in 1988, fared rather better. By adhering to the international party line of renewal and continued struggle, the party was able to hold its narrative together, condemning the excesses of totalitarian regimes, while reaffirming the need for international class struggle.

The generation of antibody-secreting plasma cells is a step-wise process involving initial B-cell activation and expansion, followed by the persistence of end-stage effector cells that reside in supportive niches. The transition through these stages requires reprogramming for high levels of secretion and adaptation to the bioenergetic demands of producing immunoglobulin. To improve our understanding of the pathways involved, we applied gene co-expression network analysis to temporal data derived from in vitro differentiating human plasma cells. We identified salt-inducible kinase 1 (SIK1) as a highly connected hub gene involved in the transition from a cycling plasmablast to a quiescent plasma cell. SIK1 is part of a kinase family previously linked to the control of metabolism and the negative regulation of TLR signaling, in part through the inactivation of cAMP-regulated transcriptional co-activators (CRTCs). To assess the contribution of SIK family kinases during plasma cell differentiation, we utilized the SIK inhibitors HG-9-91-01 and YKL-05-099. In contrast to macrophages where SIK inhibition enhances anti-inflammatory polarization, exposure of primary human or murine B-cells that have activated plasma cell differentiation to the SIK inhibitors lead to a profound reduction in cell viability. These effects were also replicated in a subset of multiple myeloma cell lines. The results are consistent with the described requirement for CRTC2 inactivation to exit the germinal center reaction and initiate plasma cell differentiation. Our findings extend these earlier observations and provide scope for identification of additional mechanisms that control plasma cell quiescence and secretory capacity.

Food consumption and preferences may be shaped by exposure to stressful environments during sensitive periods in development, and even small changes in consumption can have important effects on long term health. Adolescence is increasingly recognized as a sensitive period, in which adverse experiences can alter development, but the specific programming effects that may occur during adolescence remain incompletely understood. The current study seeks to explore the effects of stress during late adolescence on consumption of a palatable, high-fat, high-sugar food in adulthood—under basal conditions, as well following acute stress. Male Long-Evans rats were exposed to a regimen of variable stress for seven days in late adolescence (PND 45–51). During the stress regimen, stressed animals gained significantly less weight than control animals, but weight in adulthood was unaffected by adolescent stress. Palatable food consumption differed between experimental groups, and the direction of effect depended on context; stressed rats ate significantly more palatable food than controls upon first exposure, but ate less following an acute stressor. Leptin levels and exploratory behaviors did not differ between stressed and non-stressed groups, suggesting that other factors regulate preference for a palatable food. Altered food consumption following adolescent stress suggests that rats remain sensitive to stress during late adolescence, and that adult feeding behavior may be affected by previous adverse experiences. Such programming effects highlight adolescence as a period of plasticity, with the potential to shape long term food consumption patterns and preferences.

The past decade has seen a dramatic increase in the number of bilateral implant-based breast reconstructions performed in the United States. This increase correlates with the exponential rise in bilateral mastectomies. Prosthesis-based reconstruction remains the leading modality used by reconstructive surgeons. Bilateral two-stage reconstruction has a low rate of both short- and long-term complications, comparable to unilateral reconstructions. Staged bilateral implant-based reconstruction confers several advantages. Bilateral two-stage expander/implant reconstruction is often favored as it can decrease operative time and recovery, create a desired breast size in women without adequate autologous tissue, and provide higher overall cosmesis compared with unilateral reconstruction due to enhanced control over inframammary fold positioning, breast contour, and ptosis. Two-stage reconstruction affords the patient a greater degree of input over final breast appearance and allows for collaboration between patient and surgeon during the expansion period. Additional procedures at the second stage can then be implemented to focus on recreating the IMF and maximizing symmetry in order to improve patient satisfaction and long-term outcomes.

Exercise can have anti-inflammatory effects in obesity, but the optimal type and intensity of exercise are not clear. This study compared short-term high-intensity interval training (HIIT) with moderate-intensity continuous training (MICT) in terms of improvement in cardiorespiratory fitness, markers of inflammation, and glucose control in previously inactive adults at elevated risk of developing type 2 diabetes. Thirty-nine inactive, overweight/obese adults (32 women) were randomly assigned to 10 sessions over 2 wk of progressive HIIT ( n = 20, four to ten 1-min sessions at ∼90% peak heart rate, 1-min rest periods) or MICT ( n = 19, 20-50 min at ∼65% peak heart rate). Before and 3 days after training, participants performed a peak O2 uptake test, and fasting blood samples were obtained. Both HIIT (1.8 ± 0.4 vs. 1.9 ± 0.4 l/min, pre vs. post) and MICT (1.8 ± 0.5 vs. 1.9 ± 0.5 l/min, pre vs. post) improved peak O2 uptake ( P < 0.001) and lowered plasma fructosamine ( P < 0.05). Toll-like receptor (TLR) 4 (TLR4) expression was reduced on lymphocytes and monocytes after both HIIT and MICT ( P < 0.05) and on neutrophils after MICT ( P < 0.01). TLR2 on lymphocytes was reduced after HIIT and MICT ( P < 0.05). Plasma inflammatory cytokines were unchanged after training in both groups, but MICT led to a reduction in fasting plasma glucose ( P < 0.05, 5.9 ± 1.0 vs. 5.6 ± 1.0 mmol/l, pre vs. post). Ten days of either HIIT or MICT can improve cardiorespiratory fitness and glucose control and lead to reductions in TLR2 and TLR4 expression. MICT, which involved a longer duration of exercise, may be superior for reducing fasting glucose.

We observed the relief of hot flashes in breast cancer survivors taking tamoxifen and treated with sertraline for depression. Our objective was to assess the effect of sertraline on the frequency and severity of hot flashes, mood status, and health-related quality of life. We used a randomized, double-blind, placebo-controlled, crossover study using 6 weeks of sertraline (50 mg each morning) versus placebo. Study participants were 62 breast cancer survivors from an oncology clinic in a tertiary care center on adjuvant tamoxifen reporting bothersome hot flashes. Patients were asked to keep a daily hot flash diary to record hot flash frequency and severity, from which hot flash scores (frequency × severity) were calculated. The Center for Epidemiologic Studies depression scale and Functional Assessment of Cancer Therapy—Breast (FACT-B) (at baseline, 6 weeks, and 12 weeks) were used to assess mood and quality of life. Sixty-two women were accrued. Forty-seven women (median age 53.9 years, range 36.6–77.1 years; 89% postmenopausal; 85.5% Caucasian) completed the first 6 weeks and 39 completed 12 weeks. The baseline daily hot flash frequency and score were 5.8 (standard deviation 4.1) and 11.5 (14.0), respectively. At the end of the first 6 weeks, hot flash frequency decreased by 50% in 36% of those taking sertraline compared to 27% taking placebo. In the crossover analysis, sertraline was significantly more effective than placebo: women crossing from placebo to sertraline had a decrease (−0.9 and −1.7) in hot flash frequency and score, whereas those crossing from sertraline to placebo had an increase (1.5 and 3.4) in hot flash frequency and score (p = 0.03 and 0.03). Forty-eight percent preferred the sertraline period, 11% preferred the placebo period, and 41% had no preference (p = 0.006). Measures of depression and quality of life were within normal range and did not change significantly within treatment groups. Sertraline decreases hot flashes in breast cancer survivors taking tamoxifen and women prefer sertraline to placebo. Further study of sertraline for the management of hot flashes is warranted.

Much emphasis has been laid on the need for the police to be representative of all parts of the community. In this article the authors approach police recruitment from a different angle, arguing that a higher level of graduate recruitment would improve police effectiveness.

Background An acute bout of exercise can improve endothelial function and insulin sensitivity when measured on the day following exercise. Our aim was to compare acute high-intensity continuous exercise (HICE) to high-intensity interval exercise (HIIE) on circulating endothelial microparticles (EMPs) and insulin sensitivity in overweight/obese men and women. Methods Inactive males (BMI = 30 ± 3, 25 ± 6 yr, n = 6) and females (BMI = 28 ± 2, 21 ± 3 yr, n = 7) participated in three experimental trials in a randomized counterbalanced crossover design: 1) No exercise control (Control); 2) HICE (20 min cycling @ just above ventilatory threshold); 3) HIIE (10 X 1-min @ ∼90% peak aerobic power). Exercise conditions were matched for external work and diet was controlled post-exercise. Fasting blood samples were obtained ∼18 hr after each condition. CD62E+ and CD31+/CD42b- EMPs were assessed by flow cytometry and insulin resistance (IR) was estimated by homeostasis model assessment (HOMA-IR). Results There was a significant sex X exercise interaction for CD62E+ EMPs, CD31+/CD42b- EMPs, and HOMA-IR (all P

This publication includes a series of short essays that offer interesting, alternative, exciting, sobering, unusual, out-of-the box perspectives, observations, or reflections at the intersection of news, digital media, and youth - broadly defined. The contributions in this publication reflect the diversity of ideas and perspectives that form the core and spirit of the Berkman community. Some of the essays are closely connected to specific research and publications conducted by the Youth and Media team (www.youthandmedia.org) at the Berkman Center for Internet & Society at Harvard University, others reflect more generally on personal observations and/or opinions, or highlight and discuss insights and learnings from other studies or concrete projects.

Aims. High-intensity interval training (HIIT) leads to improvements in various markers of cardiometabolic health but adherence to HIIT following a supervised laboratory intervention has yet to be tested. We compared self-report and objective measures of physical activity after one month of independent exercise in individuals with prediabetes who were randomized to HIIT (n=15) or traditional moderate-intensity continuous training (MICT,n=17).Method. After completing 10 sessions of supervised training participants were asked to perform HIIT or MICT three times per week for four weeks.Results. Individuals in HIIT (89 ± 11%) adhered to their prescribed protocol to a greater extent than individuals in MICT (71 ± 31%) as determined by training logs completed over one-month follow-up (P = 0.05, Cohen’sd = 0.75). Minutes spent in vigorous physical activity per week measured by accelerometer were higher in HIIT (24 ± 18) as compared to MICT (11 ± 10) at one-month follow-up (P = 0.049, Cohen’sd = 0.92). Cardiorespiratory fitness and systolic blood pressure assessed at one-month follow-up were equally improved (P’s Conclusions. This study provides preliminary evidence that individuals with prediabetes can adhere to HIIT over the short-term and do so at a level that is greater than MICT.

Poor inhibitory control and bold-approach have been found to predict the development of externalizing behavior problems in young children. Less research has examined how positive affect may influence the development of externalizing behavior in the context of low inhibitory control and high approach. We used a multimethod approach to examine how observed toddler inhibitory control, bold-approach, and positive affect predicted externalizing outcomes (observed, adult- and self-reported) in additive and interactive ways at the beginning of kindergarten. 24-month-olds (N = 110) participated in a laboratory visit and 84 were followed up in kindergarten for externalizing behaviors. Overall, children who were low in inhibitory control, high in bold-approach, and low in positive affect at 24-months of age were at greater risk for externalizing behaviors during kindergarten.

Peripheral blood mononuclear cells (PBMCs) are known to respond to systematic changes in nutrient availability. The impact of a short-term high fat diet (HFD), with and without acute glucose ingestion, on the energy-sensing enzyme 5' AMP-activated protein kinase (AMPK) as well as mitochondrial oxidative phosphorylation (OXPHOS) proteins in PBMCs is currently unknown.Nine healthy, lean young males participated in a 7 day HFD intervention, designed to induce transient glucose intolerance. The phosphorylation status and total protein content of AMPK and inflammatory mitogen-activated protein kinases (MAPKs), and total OXPHOS protein in PBMCs, along with circulating cytokines, were assessed in the fasted state and following an oral glucose tolerance test (OGTT) before and after the HFD.One week of HFD resulted in relative glucose intolerance. The HFD resulted in a reduction of AMPK phosphorylation under fasting basal conditions and following the OGTT (both P0.05), while there were no differences in OXPHOS protein expression. Although the short-term HFD had no effect on basal phosphorylation of p38, JNK or ERK1/2, the activation of MAPKs signalling in response to glucose ingestion was attenuated post-HFD as compared to pre-HFD (P0.05 for all). Circulating cytokines were not significantly affected by the HFD.We conclude that impaired glucose tolerance in response to 7 day HFD resulted in decreased AMPK activity and impaired glucose-stimulated MAPK activation following glucose ingestion in vivo in PBMCs from young, lean subjects. Further studies are warranted to explore how dietary manipulations impact interplay between AMPK and inflammatory signalling, along with immune function, in PBMCs.

The purpose of this study was to assess potential differences in genetic counseling services delivered by board-certified genetic health-care providers versus non–genetic health-care providers. We evaluated (i) patient recall and content of pretest genetic counseling for hereditary breast and ovarian cancer and (ii) whether full BRCA1 and 2 gene sequencing was performed when less expensive single-site or Ashkenazi Jewish founder mutation testing may have been sufficient. Participants completed a questionnaire and provided BRCA test reports that included testing provider and type of test. Chi-square tests and logistic regression were used for analysis. Of 473 participants, >90% were white, female, and BRCA mutation carriers. Of the 276 (58%) with genetic health-care provider involvement, 97% recalled a pretest discussion as compared with 59% of those without genetic health-care provider involvement (P < 0.001). Among the subgroup who recalled a pretest discussion (n = 385), those with genetic health-care provider involvement indicated higher adherence to eight recognized genetic counseling elements, four of which were statistically significant. Furthermore, involvement of a genetic health-care provider halved the likelihood that comprehensive BRCA testing was ordered among the 266 for whom single-site or multisite-3 testing may have been sufficient (P = 0.02). Our results suggest that genetic health-care provider involvement is associated with adherence to nationally recommended genetic counseling practices and could potentially reduce costs of BRCA genetic testing. Genet Med advance online publication 12 June 2014

The aggregation of amyloid beta in Alzheimer’s disease can be affected by free transition metals such as copper and zinc in the brain. Addition of copper and zinc with amyloid acts to increase aggregation and copper additionally promotes the formation of reactive oxygen species. We propose that reduction of brain copper by blocking uptake of copper from the diet is a viable strategy to regulate the formation of insoluble amyloid beta in the brain of Tg2576 mice. Mice were treated with regimens of zinc acetate, which acts with metallothionein to block copper uptake in the gut, at various times along their lifespan to model prevention and treatment paradigms. We found that the mice tolerated zinc acetate well over the six month course of study. While we did not observe significant changes in cognition and behavior, there was a reduction in insoluble amyloid beta in the brain. This observation coincided with a reduction in brain copper and interestingly no change in brain zinc. Our findings show that blocking copper uptake from the diet can redistribute copper from the brain and reduce amyloid beta aggregation.

On 22 January 2009 David Cameron launched the ‘Progressive Conservatism Project’ at Demos, a think tank previously associated with the centre-left. He made clear that he considered this a new departure both for the Conservative Party and for the country. His words were widely interpreted as an attempt to distance the party from Thatcherism and to move towards values more usually associated with the Lib–Lab ‘progressive tradition’ in British politics. This paper questions the efficacy of this rhetorical strategy in reorienting voters’ impressions of the Conservative Party. It uses a 2012 YouGov/University of Nottingham survey to show that the word ‘progressive’ is not well understood by the British public. A plurality of survey respondents felt unable to define the word, and those who did tended to use politically neutral terms such as forward movement, improvement and change. Very few defined it in terms of liberalism, left politics or social justice. Moreover, while many respondents did view Conservative politicians as ‘progressive’, they included Margaret Thatcher within this. The idea of ‘progressive conservatism’ might have seemed attractive to voters in that it signified optimism and change. However, for the majority, it is unlikely to have indicated a shift to the left.

Few studies have assessed the time-dependent response of fatigue (i.e., loss of force) during submaximal exercise without the use of maximum contractions. There is unexplored potential in the use of the superimposed muscle twitch (SIT), evoked by transcranial magnetic stimulation (TMS) or motor nerve stimulation (MNS), to assess fatigue during voluntary submaximal contractions. For the human triceps surae muscles, there are also no data on TMS-evoked twitches.To optimise the TMS stimulus for assessment of fatigue, we first tested the effects of TMS power (40, 55, 70, 85, 100% max) on SIT force during contractions (0-100% MVC in 10% increments) in six subjects. Then, we compared SIT responses (TMS and MNS) during submaximal contractions and MVCs (all at 60 s intervals) during a continuous protocol of intermittent contractions (30% MVC) consisting of consecutive 5 min periods of baseline, fatigue (ischaemia) and recovery.For TMS, SIT force increased as a diminishing function of TMS power (P0.05), the relationships between SIT force and the force of voluntary contraction at all TMS powers were parabolic, and SIT force was maximised at ~20-40% MVC. During intermittent contractions, MVC and SIT forces were stable during baseline, decreased similarly during ischaemia by 40-50% (P0.05), and recovered similarly to baseline values (P0.05) before the end of the protocol.TMS can be used to evoke twitches during submaximal contractions of the human calf muscle and, along with MNS, used to assess fatigue during submaximal exercise.

18 Background: Impaired work performance that when significant leads to decreased productivity (work limitations) contribute to the “financial toxicity” of cancer treatment. Factors influencing work limitations and employment outcomes are poorly understood for cancer pts. We prospectively examined the proportion of cancer pts with significant increases in work limitations during curative treatment (co-primary endpoint). Methods: Eligible pts were ≥ 18 years, employed, intended to work during or after end of treatment (EOT), and had received ≤ 1 CT cycle. The Work Limitations Questionnaire (WLQ) survey was administered (baseline [BL], EOT, 3 and 6-months post EOT) to determine change in work limitations (WLQ index scale: 0 = no limitations to 28.6 = limited all of the time). “Significantly affected” pts had > 5-point increase in WLQ - an increase associated with decreased work productivity. Descriptive statistics (estimates with 95% confidence intervals [CI]; means with standard deviations [SD]) were calculated. A two-factor ANOVA (pt, timepoint) was used for analysis of WLQ changes over time. Results: 120 pts enrolled 5/2013 - 10/2015 at 8 sites (85 breast, 16 colon, 19 other). 110 took 1+ surveys: median age 50 (range 24-69), 92 (84%) female, 105 (96%) White; 93 (85%) had surgery, 110 (100%) CT, 57 (52%) RT. The mean increase in WLQ index from BL to EOT was +4.4 (95% CI [+2.1,+6.8], p < 0.001). A total of 44% were “significantly affected” by treatment (37/85, 95% CI [33%,55%]). WLQ index decreased at 3 and 6-mos (as compared to BL or EOT, see table). Conclusions: Among largely White pts getting CT, 44% experienced a significant increase in work limitations from BL to EOT. An improvement in group WLQ scores was noted after EOT. Analysis of factors (e.g., job type, education, symptoms) most associated with work limitations is underway to assist in prospectively identifying at-risk pts. [Table: see text]

Background Previous studies showed that Iowa all-terrain vehicle (ATV) crash victims from off-highway vehicle (OHV) parks practiced safer riding behaviours than off-road crash victims outside the parks. The objective of this study was to determine the effect of regulations and enforcement on the prevalence of safety behaviours among Iowa OHV park users. Methods From May to September of 2014, motion-activated cameras captured photos of users at the entrances of Iowa’s eight OHV parks. Riders were coded by vehicle type, estimated age, sex, and safety behaviours. Descriptive and multivariable logistic regression analyses were performed. Results A total of 6,718 vehicles and 9,083 riders were analysed. Among OHV park users, 44% were on ATVs, 51% on dirt bikes and 5% on side-by-sides (SxSs). Helmet use was 94% overall. Just 6% of single-rider ATVs and 0.8% of dirt bikes had passengers. While only 11% of park users on ATVs were Conclusions Regulated safety behaviours (helmet use and riding without passengers) were highly common among OHV park users. However, unregulated behaviours (SxS restraint use and children driving youth-sized ATVs only) had lower compliance. Moreover, regulated safety behaviours were significantly increased when the parks were patrolled. This study shows that a combination of regulation and enforcement is effective in ensuring safety behaviour compliance in OHV parks. Similar efforts outside parks could have a substantial effect on decreasing off-road vehicle-related deaths and injuries.

Chemotherapy has yielded minimal clinical benefit in pancreatic and biliary tract cancer. A high-dose, short course capecitabine schedule with oxaliplatin, has shown some efficacy with a lower incidence of palmar-plantar erythrodysesthesia. Achieving high exposures of the targeted agent sorafenib may be possible with this shorter schedule of capecitabine by avoiding dermatologic toxicity. All patients had pancreatic or biliary tract cancer. Patients in both cohorts received oxaliplatin 85 mg/m2 followed by capecitabine 2250 mg/m2 PO every 8 hours × 6 doses starting on days 1 and 15 of a 28 day cycle, or 2DOC (2 Day Oxaliplatin/Capecitabine). Cohort 1 used sorafenib 200 mg BID, and cohort 2 used sorafenib 400 mg BID. Sixteen patients were enrolled. Across all cycles the most common grade 1 or 2 adverse events were fatigue (10 pts), diarrhea (10 pts), nausea (9 pts), vomiting (8 pts), sensory neuropathy (8 pts), thrombocytopenia (7 pts), neutropenia (5 pts), and hand-foot syndrome (5 pts). Grade 3 toxicites included neutropenia, mucositis, fatigue, vomiting and diarrhea. Cohort 1 represented the MTD. Two partial responses were seen, one each in pancreatic and biliary tract cancers. The recommended phase II dose of sorafenib in combination with 2DOC is 200 mg BID. There were infrequent grade 3 toxicities, most evident with sorafenib at 400 mg BID.

Summary Subarachnoid haemorrhage (SAH) is a major contributor to the burden of stroke on society. Treatment options are limited and animal models of SAH do not always mimic key pathophysiological hallmarks of the disease, thus hindering development of new therapeutics. Inflammation is strongly associated with brain injury after SAH in animals and patients, and inhibition of the pro-inflammatory cytokine interleukin-1 (IL-1) represents a possible therapeutic target. Here we report that a rupture of the middle cerebral artery in the rat produces heterogeneous infarct patterns similar to those observed in human SAH. Administration of the IL-1 receptor antagonist (IL-1Ra) reduced blood-brain barrier breakdown, and the extent of breakdown correlated with brain injury. After SAH, haem oxygenase-1 (HO-1) was strongly expressed around the bleed site and in the cortex and striatum, indicating the presence of free haem, a breakdown product of haemoglobin. HO-1 expression was also found in the same regions as microglial/macrophage expression of IL-1α. The direct effect of haem on IL-1α expression was confirmed in vitro using organotypic slice culture (OSC). Haem-induced cell death was dependent on IL-1 signalling, with IL-1Ra completely blocking cellular injury. Furthermore, stimulation of mouse primary mixed glial cells with haem induced the release of IL-1α, but not IL-1β. Thus, we suggest that haem, released from lysed red blood cells (RBCs) in the subarachnoid space, acts as a danger-associated molecular pattern (DAMP) driving IL-1-dependent inflammation. These data provide new insights into inflammation after SAH-induced brain injury and suggest IL-1Ra as a candidate therapeutic for the disease.

In order to understand the persistence of History, we need to understand the appeal of historical work, its pleasures. Without such an understanding, theory and research will continue to talk at cross purposes, the one insisting that the past is unknowable; the other unable to ignore the vitality of its sources. The contention of this essay is that historical research is an affective experience of such intensity that it has been able to withstand the challenges of post-structuralism and postmodernism and so continue with ‘business as usual’ (Jenkins 2003, 15). While the intensity of the archival encounter is not often admitted in print, it continues to motivate the efforts of individual historians. The abstractions of theory cannot intrude upon the physical experience of holding a piece of the past. It demands our attention. But the intellectual consequences of the physicality of the archival encounter need to be effectively theorised: what is the role of touching and feeling in the pursuit of knowing? The archive is the place where historians can literally touch the past, but in doing so are simultaneously made aware of its unreachability. In a maddening paradox, concrete presence conveys unfathomable absence. In the archive, researchers are both confronted with the absolute alterity of the past and tempted by the challenge of trying to overcome it. It is suggested that this impossibility underpins the powerful attraction of the historical endeavour.

Background Increasing emphasis on integrated control of neglected tropical diseases (NTDs) requires identification of co-endemic areas. Integrated surveys for lymphatic filariasis (LF), schistosomiasis and soil-transmitted helminth (STH) infection have been recommended for this purpose. Integrated survey designs inevitably involve balancing the costs of surveys against accuracy of classifying areas for treatment, so-called implementation units (IUs). This requires an understanding of the main cost drivers and of how operating procedures may affect both cost and accuracy of surveys. Here we report a detailed cost analysis of the first round of integrated NTD surveys in Southern Sudan. Methods and Findings Financial and economic costs were estimated from financial expenditure records and interviews with survey staff using an ingredients approach. The main outcome was cost per IU surveyed. Uncertain variables were subjected to univariate sensitivity analysis and the effects of modifying standard operating procedures were explored. The average economic cost per IU surveyed was USD 40,206 or USD 9,573, depending on the size of the IU. The major cost drivers were two key categories of recurrent costs: i) survey consumables, and ii) personnel. Conclusion The cost of integrated surveys in Southern Sudan could be reduced by surveying larger administrative areas for LF. If this approach was taken, the estimated economic cost of completing LF, schistosomiasis and STH mapping in Southern Sudan would amount to USD 1.6 million. The methodological detail and costing template provided here could be used to generate cost estimates in other settings and readily compare these to the present study, and may help budget for integrated and single NTDs surveys elsewhere., Author Summary Control of neglected tropical diseases (NTDs) is suggested to be more cost-effective when drugs are co-administered through a single integrated delivery system rather than separate systems. An essential prerequisite for such efficiency gains is sufficient geographical overlap of the targeted diseases – lymphatic filariasis (LF), onchocerciasis, schistosomiasis, soil-transmitted helminth infection and trachoma. Lack of data on geographical NTD distribution currently hampers the implementation of integrated control in many African countries. To generate the required data quickly and efficiently, integrated surveys of several NTDs simultaneously have been recommended. However, experience with integrated surveys is limited and requires additional research on cost and effectiveness to inform improvements in methodology and to guide scale-up. Here we analyse costs of the first integrated NTD survey round in Southern Sudan, generating average costs per implementation unit surveyed. Cost estimates are presented for use of the existing survey method and for modified versions. Key cost drivers were survey consumables and personnel, both of which are recurrent costs. These inputs could be reduced or put to more efficient use by modifying sampling for LF. To generate comparable cost estimates and identify key cost drivers in other settings we provide detailed cost data and guidance on how to replicate this work.

Background Trachoma is thought to be endemic over large parts of Southern Sudan, but empirical evidence is limited. While some areas east of the Nile have been identified as highly endemic, few trachoma surveys have been conducted in the remainder of the country. This study aimed to determine whether trachoma constitutes a problem to public health in Northern Bahr-el-Ghazal and Unity State, both located west of the Nile. Methods and Principal Findings Trachoma rapid assessments (TRA) were conducted between July and September 2009. Seven villages in Northern Bahr-el-Ghazal State and 13 villages in Unity State were surveyed; an average of 50 children (age 1–9 years) and 44 women (age 15 years and above) were examined per village. Samples for analysis using the APTIMA Combo-2 nucleic acid amplification test (NAAT) were collected from participants with active trachoma in eight villages in Unity State. In Northern Bahr-el-Ghazal State, only three children with active trachoma (trachomatous inflammation follicular (TF) and/or trachomatous inflammation intense (TI)) and two women with trichiasis (TT) were found, in two of the seven villages surveyed. In Unity State, trachoma was endemic in all thirteen villages surveyed; the proportion of children with active trachoma ranged from 33% to 75% between villages, while TF in children ranged from 16% to 44%. Between 4% to 51% of examined women showed signs of TT. Samples from active trachoma cases tested using the NAAT were positive for Chlamydia trachomatis infection for 46.6% of children and 19.0% of women. Conclusions Trachoma presents a major problem to public health Unity State, while the disease is of low priority in Northern-Bahr-el-Ghazal State. Implementation of a population-based prevalence survey is now required in Unity State to generate baseline prevalence data so that trachoma interventions can be initiated and monitored over time.

Objective— To report inguinal herniation of the ascending colon in a Standardbred colt. Study Design— Case report. Animals— A 6-month-old Standardbred colt. Methods— The colt underwent surgical exploration of the hernia with large colon resection and anastomosis. Results— A successful large colon resection and anastomosis was completed, however, the colt was euthanatized at the end of surgery upon owner request. Conclusions and Clinical Relevance— Although uncommon, indirect inguinal herniation of the ascending colon can occur in young horses.

Background There are few detailed data on the geographic distribution of most neglected tropical diseases (NTDs) in post-conflict Southern Sudan. To guide intervention by the recently established national programme for integrated NTD control, we conducted an integrated prevalence survey for schistosomiasis, soil-transmitted helminth (STH) infection, lymphatic filariasis (LF), and loiasis in Northern Bahr-el-Ghazal State. Our aim was to establish which communities require mass drug administration (MDA) with preventive chemotherapy (PCT), rather than to provide precise estimates of infection prevalence. Methods and Findings The integrated survey design used anecdotal reports of LF and proximity to water bodies (for schistosomiasis) to guide selection of survey sites. In total, 86 communities were surveyed for schistosomiasis and STH; 43 of these were also surveyed for LF and loiasis. From these, 4834 urine samples were tested for blood in urine using Hemastix reagent strips, 4438 stool samples were analyzed using the Kato-Katz technique, and 5254 blood samples were tested for circulating Wuchereria bancrofti antigen using immunochromatographic card tests (ICT). 4461 individuals were interviewed regarding a history of ‘eye worm’ (a proxy measure for loiasis) and 31 village chiefs were interviewed regarding the presence of clinical manifestations of LF in their community. At the village level, prevalence of Schistosoma haematobium and S. mansoni ranged from 0 to 65.6% and from 0 to 9.3%, respectively. The main STH species was hookworm, ranging from 0 to 70% by village. Infection with LF and loiasis was extremely rare, with only four individuals testing positive or reporting symptoms, respectively. Questionnaire data on clinical signs of LF did not provide a reliable indication of endemicity. MDA intervention thresholds recommended by the World Health Organization were only exceeded for urinary schistosomiasis and hookworm in a few, yet distinct, communities. Conclusion This was the first attempt to use an integrated survey design for this group of infections and to generate detailed results to guide their control over a large area of Southern Sudan. The approach proved practical, but could be further simplified to reduce field work and costs. The results show that only a few areas need to be targeted with MDA of PCT, thus confirming the importance of detailed mapping for cost-effective control., Author Summary Integrated control of neglected tropical diseases (NTDs) is being scaled up in a number of developing countries, because it is thought to be more cost-effective than stand-alone control programmes. Under this approach, treatments for onchocerciasis, lymphatic filariasis (LF), schistosomiasis, soil-transmitted helminth (STH) infection, and trachoma are administered through the same delivery structure and at about the same time. A pre-requisite for implementation of integrated NTD control is information on where the targeted diseases are endemic and to what extent they overlap. This information is generated through surveys that can be labour-intensive and expensive. In Southern Sudan, all of the above diseases except onchocerciasis require further mapping before a comprehensive integrated NTD control programme can be implemented. To determine where treatment for which disease is required, integrated surveys were conducted for schistosomiasis, STH infection, LF, and loiasis, throughout one of ten states of the country. Our results show that treatment is only required for urinary schistosomiasis and STH in a few, yet separate, geographical area. This illustrates the importance of investing in disease mapping to minimize overall programme costs by being able to target interventions. Integration of survey methodologies for the above disease was practical and efficient, and minimized the effort required to collect these data.

Background Trachoma is thought to be common over large parts of Southern Sudan. However, many areas of the country, particularly west of the Nile, have not yet been surveyed. The aim of this study was to confirm whether trachoma extends into Western Equatoria State from neighboring Central Equatoria, where trachoma is highly prevalent, and whether intervention with the SAFE strategy is required. Methods and Findings Population-based cross-sectional surveys were conducted using a two-stage cluster random sampling method to select the study population. Subjects were examined for trachoma by experienced graders using the World Health Organization (WHO) simplified grading scheme. Two counties thought to be most likely to have trachoma were surveyed, Maridi and Mundri. In Maridi, prevalence of one of the signs of active trachoma (trachomatous inflammation-follicular (TF)) in children aged 1–9 years was 0.4% (95% confidence interval (CI), 0.0%–0.8%), while no children showing the other possible sign, trachomatous inflammation-intense (TI), were identified. No trachomatous trichiasis (TT) was found in those aged under 15, and prevalence was 0.1% (95% CI, 0.0%–0.4%) in those aged 15 years and above. In Mundri, active trachoma was also limited to signs of TF, with a prevalence of 4.1% (95% CI, 1.4%–6.9%) in children aged 1–9 years. Again, no TT was found in those aged under 15, and prevalence in those aged 15 years and above was 0.3% (95% CI, 0.0%–0.8%). Conclusion Trachoma prevalence in the east of Western Equatoria State is below the WHO recommended intervention threshold for mass drug administration of antibiotic treatment in all villages. However, the prevalence of TF and TT in some villages, particularly in Mundri County, is sufficiently high to warrant targeted interventions at the community level. These results demonstrate that trachoma is not a major public health problem throughout Southern Sudan. Further studies will be required to determine trachoma prevalence in other areas, particularly west of the Nile, but there are presently no resources to survey each county. Studies should thus be targeted to areas where collection of new data would be most informative., Author Summary Baseline data on trachoma prevalence is a prerequisite for intervention. Prior to the present study, all surveys in Southern Sudan reported trachoma prevalences that exceeded the threshold for large-scale intervention. This gave rise to the notion that the disease may be endemic throughout the country. The present study was conducted under the auspices of the National Program for Integrated Control of Neglected Tropical Diseases, to verify whether prevalences in two counties west of the Nile exceeded the WHO recommended intervention threshold for mass drug administration (MDA) of antibiotic treatment. The results show that trachoma prevalence at county level was below this threshold. However, prevalences in some communities within the county were above the threshold, meaning that they should be targeted with MDA of antibiotics, as well as with other interventions such as trichiasis surgery, health promotion and improved water and sanitation. This finding reminds us of the need for geographical targeting of resources, both for surveys and subsequent intervention. Current resources are insufficient to conduct population-based prevalence surveys for trachoma throughout Southern Sudan. Further surveys should thus be conducted in areas where collection of additional information will be most informative. We propose that a combination of risk-mapping and rapid assessments is used to identify such areas.

BACKGROUND: Chemotherapy followed by autologous T cells that are genetically modified to express a CD19-specific chimeric antigen receptor (CAR) has shown promise as a novel therapy for patients with relapsed or refractory B cell acute lymphoblastic leukemia (B-ALL); however, the risk of severe cytokine release syndrome (sCRS) and neurotoxicity has tempered enthusiasm for widespread application of this approach. The functional heterogeneity that is inherent in CAR-T cell products that are manufactured from undefined T cell subsets has hindered definition of dose-response relationships and identification of factors that may impact efficacy and toxicity. METHODS: We are conducting the first clinical trial that administers CD19 CAR-T cells manufactured from a defined composition of T cell subsets to adults with relapsed or refractory B-ALL. CD8+ and CD4+ T cells were enriched from each patient, transduced with a CD19 CAR lentivirus and separately expanded in vitro before formulation for infusion in a 1:1 ratio of CD8+:CD4+ CAR+ T cells at 2x105, 2x106 or 2x107 CAR-T cells/kg. Prior to CAR-T cell infusion, patients underwent lymphodepletion with a high-dose cyclophosphamide (Cy)-based regimen with or without fludarabine (Flu). RESULTS: Twenty-nine adults with B-ALL (median age 40, range 22 - 73 years; median 17% marrow blasts, range 0 - 97%), including 10 patients who had relapsed after allogeneic transplantation, received at least one CAR-T cell infusion. Twenty-four of 26 restaged patients (92%) achieved bone marrow (BM) complete remission (CR) by flow cytometry. CD4+ and CD8+ CAR-T cells expanded in vivo after infusion and their number in blood correlated with the infused CAR-T cell dose. Thirteen patients received lymphodepletion with Cy-based regimens without Flu. Ten of 12 restaged patients (83%) achieved BM CR by flow cytometry; however, 7 of these (70%) relapsed a median of 66 days after CAR-T cell infusion. Disease relapse correlated with a loss of CAR-T cell persistence in blood. We observed a CD8 cytotoxic T cell response to the murine scFv component of the CAR transgene that contributed to CAR-T cell rejection, and resulted in lack of CAR-T cell expansion after a second CAR-T cell infusion in 5 patients treated for persistent or relapsed disease. To minimize immune-mediated CAR-T cell rejection 14 patients were treated with Cy followed by Flu lymphodepletion (Cy/Flu, Cy 60 mg/kg x 1 and Flu 25 mg/m2 x 3-5) before CAR-T cell infusion. All patients (100%) who received Cy/Flu lymphodepletion achieved BM CR after CAR-T cell infusion. CAR-T cell expansion and persistence in blood was higher in Cy/Flu-lymphodepleted patients compared to their counterparts who received Cy alone (Day 28 after 2x106 CAR-T cells/kg: CD8+ CAR-T cells, mean 55.8/μL vs 0.10/μL, p CAR-T cell infusion was associated with sCRS, characterized by fever and hypotension requiring intensive care in 7 of 27 patients (26%) and neurotoxicity (≥ grade 3 CTCAE v4.03) in 13 of 27 patients (48%). Two patients died following complications of sCRS. Patients with sCRS or neurotoxicity had higher peak serum levels of IL-6, IFN-γ, ferritin and C-reactive protein compared to those without serious toxicity. Importantly IL-6, IFN-γ and TNF-α levels in serum collected on day 1 after CAR-T cell infusion from those who subsequently developed neurotoxicity were higher than those collected from their counterparts who did not develop neurotoxicity (IL-6, p CONCLUSION: Risk-stratified dosing of CD19 CAR-T cells of defined subset composition is feasible and safe in a majority of patients with refractory B-ALL, and results in a CR rate of 92%. Addition of Flu to Cy-based lymphodepletion improves CAR-T cell expansion, persistence and DFS. Disclosures Turtle: Juno Therapeutics: Patents & Royalties, Research Funding. Berger:Juno Therapeutics: Patents & Royalties. Jensen:Juno Therapeutics: Equity Ownership, Patents & Royalties, Research Funding. Riddell:Adaptive Biotechnologies: Consultancy; Juno Therapeutics: Equity Ownership, Patents & Royalties, Research Funding; Cell Medica: Membership on an entity's Board of Directors or advisory committees. Maloney:Seattle Genetics: Honoraria; Janssen Scientific Affairs: Honoraria; Roche/Genentech: Honoraria; Juno Therapeutics: Research Funding.

BACKGROUND: Autologous T cells genetically modified to express a CD19-specific chimeric antigen receptor (CAR) have demonstrated activity in patients with relapsed or refractory B cell NHL and CLL. The functional heterogeneity that is inherent in CAR-T cell products that are manufactured from undefined T cell subsets has hindered definition of dose-response relationships and identification of factors that may impact efficacy and toxicity, such as the lymphodepletion regimen and infused cell dose. We manufactured anti-CD19 CAR-T cells from a defined composition of CD4+ and CD8+ T cell subsets to treat adults with relapsed or refractory B cell NHL or CLL. T cell subsets were enriched from each patient, transduced with a CD19 CAR lentivirus and separately expanded in vitro before formulation for infusion in a 1:1 ratio of CD8+:CD4+ CAR+ T cells at one of three dose levels (2x105, 2x106 or 2x107 CAR-T cells/kg). CAR-T cells were administered 48-96 hours after lymphodepletion with either cyclophosphamide (Cy, 60 mg/kg)+/- etoposide or Cy (60 mg/kg) and fludarabine (25 mg/m2 daily for 3-5 days (Cy/Flu). RESULTS: Adult patients with relapsed/refractory CD19 expressing B cell NHL (n=28, median age 59 years, range 36-70) or CLL (n=6, median age 60 years, range 54-64) were treated with at least one CAR-T cell infusion. NHL histologies include diffuse large B cell or transformed NHL (DLBCL, n=18), follicular NHL (FL, n= 6) or mantle cell lymphoma (MCL, n=4). 15 patients had failed prior autologous (n=13) or allogeneic (n=3) transplants. Twelve of the 28 NHL patients received lymphodepletion with Cy-based regimens without fludarabine. Expansion of CAR-T cells and clinical responses were observed in 50% (CR=1 (DLBCL), PR=5 (2 FL, 2 DLBCL, 1 MCL), no response=6). Patients were treated at all three dose levels without dose limiting toxicity or severe cytokine release syndrome (sCRS). With this regimen, we observed short CAR-T cell persistence in most patients and demonstrated a CD8-mediated immune response to the murine scFv component of the CAR transgene that correlated with loss of CAR-T cells. Retreatment with CAR-T cells with or without chemotherapy in 5 patients led to no significant T cell expansion or clinical responses. To minimize transgene rejection fludarabine was added to the lymphodepletion regimen administered to the subsequent 16 NHL patients. Clinical responses were evaluated in 12 of 16 patients (2 not yet evaluable, 2 early deaths). Addition of Flu to the lymphodepletion regimen increased the CR rate to 42%, compared to 8% with Cy alone. Clinical responses were identified in 6 of 8 patients with DLBCL (3 CR, 3 PR) and 2 of 3 patients with FL (2 CR). The overall response rate was 67%. We noted higher peak CAR-T cell levels in blood in the Cy/Flu group (n=13) compared with the Cy only group (n=11) (CD8+ CAR-T cells, median 31.9 cells/ml vs 0.55 cells/ml, p = 0.009; CD4+ CAR-T cells, median 16.5 cells/ml vs 0.31 cells/ml, p= 0.007), and CAR-T cell persistence was longer in Flu-treated patients (see Figure 1 for patients treated at 2 x 107/kg). Surprisingly, 2 of 7 patients who received 2 x 107 CAR-T cells/kg experienced dose-limiting toxicity necessitating dose de-escalation. Markedly elevated IL-6 levels were observed within the first day after CAR-T cell infusion in patients who subsequently developed severe toxicity, which may provide an opportunity to test early interventional approaches to minimize toxicity. Six patients with relapsed and refractory CLL received CAR-T cells. Five of 6 restaged patients had complete clearance of blood and/or marrow disease by high-resolution flow cytometry 4 weeks following treatment. Overall clinical responses included 3 CR, 1 PR and 2 no response. One patient with a PR died from refractory pulmonary aspergillus infection. Patients with CR remain in remission at 1-10 months after therapy. CONCLUSION: Immunotherapy with CD19 CAR-T cells of defined subset composition is feasible in patients with NHL and CLL and has potent anti-tumor activity. Toxicity is related to cell dose. The addition of Flu to a Cy-based lymphodepletion regimen results in greater CAR-T cell expansion and persistence, and improves the CR rate after CD19 CAR-T cell therapy. Disclosures Turtle: Juno Therapeutics: Patents & Royalties, Research Funding. Berger:Juno Therapeutics: Patents & Royalties. Jensen:Juno Therapeutics: Equity Ownership, Patents & Royalties, Research Funding. Riddell:Juno Therapeutics: Equity Ownership, Patents & Royalties, Research Funding; Cell Medica: Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Consultancy. Maloney:Juno Therapeutics: Research Funding; Janssen Scientific Affairs: Honoraria; Seattle Genetics: Honoraria; Roche/Genentech: Honoraria.

The aim of this study was to gain greater insight into the experience of being diagnosed with type 1 diabetes during adolescence, and the factors that influence how a young person makes sense of the condition over time. Interpretative phenomenological analysis (IPA) was employed in an attempt to convey an understanding of what it feels like to be diagnosed with diabetes during adolescence and to highlight implications for health care professionals. The perspectives of eight adults, aged 28 ‐36 years who were diagnosed with diabetes during adolescence, were gathered using an unstructured interview and were analysed using IPA. The results showed that chronic illness impacts on the sense of self and can be especially devastating for an adolescent trying to cope with the conflicting nature of adolescence and the demanding, restrictive nature of diabetes. In some young people this can lead to risky self-care behaviours. However, through active encouragement and support from significant others, young people are able to develop an integrated sense of self, which is more suited to living with a chronic condition. These findings suggest that the relationships between illness beliefs and psychological adjustment lie in the family and social context. It was concluded that health care professionals need to support the young person by having a better understanding of the impact of diabetes on adolescent development and by tailoring their approach to these young people. Psychology teams can be approached to provide consultation and training for diabetes teams to assist in the setting up of developmentally appropriate transition services for young people. A list of training and educational resources for health care professionals and young people is provided. Copyright © 2015 John Wiley & Sons. Practical Diabetes 2015; 32(9): 339 ‐344

6549 Background: Concerns about genomic advances to increase health disparities have been raised. We sought to explore factors associated with receipt of BRCA1 and BRCA2 (BRCA) testing and assess f...

Statement of purpose Safety behaviours of off-highway vehicle (OHV) park users may be better than those riding elsewhere, and census data is required to determine if differences among OHV parks in injuries can be explained by higher use or if other factors are involved. This study’s purpose was to ascertain the photographic capture rate of riders entering OHV parks with motion-activated cameras, and to determine study variable concordance between on-site evaluations and photo appraisement. Methods/approach Panoramic motion-activated cameras were placed at the entrances of all eight public OHV parks in Iowa. On-site assessment and photo image analysis was performed for demographic, vehicle, and safety behaviour variables, and then compared. Results On-site data collection was performed for 114 h for 17 cameras during which 493 off-road vehicles entered the OHV parks. A total of 251 vehicles entering the parks were identified on photos for an overall capture rate of 50.9%. For cameras with at least 5 vehicles noted during on-site evaluation, the capture rate ranged from 38–81%. The number of vehicles entering the parks was segmented by 15 min intervals, and there was no significant variance or decrease in photo capture rate until there were more than 15 vehicles entering a park during a quarter hour period. Variable concordance between on-site and photo derived data ranged from 91–100% which included sex of rider, estimated age group of rider, vehicle type, number of wheels, number of vehicle riders, helmet use, and restraint use for side-by-side vehicles. Conclusions About one-half of riders entering Iowa OHV parks were captured by motion-activated cameras. Concordance of study variables was high between that collected on-site and from photo assessment. Significance and contributions The study validated the use of photo-derived data to determine OHV park users and safety behaviours. Results will also assist in park census estimation.