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Minimalism is an increasingly popular lifestyle movement in western economies (predominantly in the USA, Japan and Europe) that involves voluntarily reducing consumption and limiting one’s possessions to a bare minimum. This is with the intention of making space for the ‘important’ (potentially immaterial) things that are seen to add meaning and value to one’s life. Drawing on interviews with minimalists in the UK, this article reveals that minimalists practice sustainable (non)consumption via limiting their consumption. This is achieved by actively buying less, using up and maintaining what is owned, and, when objects are acquired, only practising highly intentional, considered and (sometimes) ethical consumption. For some, such practices are predominantly based on strong ethical and environmental motivations or are seen as a positive ‘by-product’ of their minimalist lifestyles. Whilst for others, their motivations are primarily aligned to personal well-being. The article subsequently argues that the limited and considered practices of minimalist consumption can be seen as sustainable practices in outcome, if not always in intent.

ObjectiveTo generate comparative efficacy evidence of belimumab versus anifrolumab in SLE that can inform treatment practices.MethodsThe SLE Responder Index (SRI)-4 response at 52 weeks of belimumab versus anifrolumab was evaluated with an indirect treatment comparison. The evidence base consisted of randomised trials that were compiled through a systemic literature review.A feasibility assessment was performed to comprehensively compare the eligible trials and to determine the most appropriate indirect treatment comparison analysis method. A multilevel network meta-regression (ML-NMR) was implemented that adjusted for differences across trials in four baseline characteristics: SLE Disease Activity Index-2K, anti–double-stranded DNA antibody positive, low complement (C)3 and low C4. Additional analyses were conducted to explore if the results were robust to different sets of baseline characteristics included for adjustment, alternative adjustment methods and changes to the trials included in the evidence base.ResultsThe ML-NMR included eight trials: five belimumab trials (BLISS-52, BLISS-76, NEA, BLISS-SC, EMBRACE) and three anifrolumab trials (MUSE, TULIP-1, TULIP-2). Belimumab and anifrolumab were comparable in terms of SRI-4 response (OR (95% credible interval), 1.04 (0.74–1.45)), with the direction of the point estimate slightly favouring belimumab. Belimumab had a 0.58 probability of being the more effective treatment. The results were highly consistent across all analysis scenarios.ConclusionsOur results suggest that the SRI-4 response of belimumab and anifrolumab are similar at 52 weeks in the general SLE population, but the level of uncertainty around the point estimate means we cannot rule out the possibility of a clinically meaningful benefit for either treatment. It remains to be seen if specific groups of patients could derive a greater benefit from anifrolumab or from belimumab, and there is certainly an unmet need to identify robust predictors towards more personalised selection of available biological agents in SLE.

BackgroundAntigen-specific CD8+ T cells are critical components of mounting an effective immune response against tumors. Generation of antigen-specific T cells require interactions with multiple signals produced by antigen presenting cells (APCs). These signals are comprised of three components: (signal 1) the peptide-MHC complex binding to the T cell receptor, (signal 2) costimulatory molecules on the surface of APCs, and (signal 3) inflammatory cytokines binding to cognate receptors on T cells.MethodsTo engineer all major cell subsets of human peripheral blood mononuclear cells (PBMCs) to become enhanced APCs (eAPCs), we used Cell Squeeze® technology to deliver multiple mRNA encoding for non-self-antigens (signal 1), CD86 (signal 2), and/or membrane-bound cytokines (signal 3). The signal 3 molecules, membrane-bound IL-12 (mbIL-12) and membrane-bound IL-2 (mbIL-2), are chimeric proteins designed to increase the localized concentration of the cytokines and limit off-target effects. Flow cytometry and western blots were used to confirm the translation of each of the delivered mRNA. The increased capabilities of these enhanced APCs were assessed in vitro by culturing the APCs with antigen-specific T cells for multiple days before measuring the functionality of antigen-specific T cells via intracellular cytokine staining or ELISA.ResultsWe demonstrate that Cell Squeeze® processing of PBMCs with mRNA encoding for signals 1, 2, and 3 results in highly effective enhanced APCs in vitro. In a single squeeze process, efficient delivery and translation of up to five mRNA is observed in all major PBMC cell subsets including T cells, B cells, NK cells, and monocytes. Once translated, the chimeric mbIL-2 and mbIL-12 can bind to their cognate receptors and exhibit minimal shedding from the surface. We show that enhanced APCs can present antigenic peptides derived from mRNA encoding for a foreign antigen on MHC complexes in an HLA agnostic manner, which drives antigen-specific T cell responses. The addition of CD86, mbIL-2, and mbIL-12 further enhance the activation and potency of antigen-specific T cells, as measured by an increase in the secretion of inflammatory cytokines upon restimulation (i.e. IFNγ).ConclusionsCell squeezing of human PBMCs with mRNA encoding for signals 1, 2, and 3 has the potential to generate enhanced APCs that drive robust CD8+ T cell response against multiple targets across several disease areas. The versatility of the Cell Squeeze® technology potentially enables rapid exchange of mRNA to other antigens or T cell activation signals.

This systematic literature review compared clinical outcomes post-stem cell transplantation (SCT) among patients with vs. without the measurable residual disease (MRD) pre-transplant. Relevant literature on adults undergoing transplant with known MRD status pre-transplant was extracted from the MEDLINE, Embase, and CENTRAL databases (through 8 May 2018) and oncology conferences (2014-2018) using keywords for acute lymphoblastic leukemia and MRD. Thirty primary studies reporting SCT outcomes were identified. Hazard ratios (HRs) for overall survival indicated that patients with MRD pre-transplant were more likely to die post-SCT vs. patients with no detectable MRD (HR: 1.51-3.856). In post-SCT relapse studies, 16-100% of patients with MRD vs. 0-50% of patients without MRD relapsed. This review found evidence of markedly worse outcomes post-transplant among patients with vs. without MRD pre-transplant, including shorter median survival (overall, relapse-free, and event-free survival), higher risk of death, more relapse events, and decreased likelihood of remaining in hematologic remission.

Antigen-specific CD8+ T cells are critical for mounting an effective immune response against tumors. Generation of antigen-specific T cells require interactions with multiple signals produced by antigen presenting cells (APCs). These signals are comprised of three components: (signal 1) the peptide-MHC complex binding to the T cell receptor, (signal 2) costimulatory molecules on the surface of APCs, and (signal 3) inflammatory cytokines binding to cognate receptors on T cells. To engineer all major cell subsets of human peripheral blood mononuclear cells (PBMCs) to become enhanced APCs (eAPCs), we used Cell Squeeze® technology to deliver multiple mRNAs encoding for non-self-antigens (signal 1), CD86 (signal 2), and/or membrane-bound cytokines (signal 3). The signal 3 molecules, membrane-bound IL-12 (mbIL-12) and membrane-bound IL-2 (mbIL-2), are chimeric proteins designed to increase the localized concentration of the cytokines at the immune synapse and limit off-target effects. Flow cytometry confirmed translation of delivered signal 2/3 mRNAs by all major subsets within PBMCs: T cells, B cells, NK cells, and monocytes. The potency of these SQZ™ eAPCs was assessed in vitro by culturing the eAPCs with antigen-specific T cells for multiple days before measuring the functionality of antigen-specific T cells via intracellular cytokine staining or ELISA. Using this approach, we demonstrate that Cell Squeeze® co-delivery of antigen mRNA and signal 2/3 mRNAs significantly enhances CD8+ T cell responses to a variety of antigens, including CMV pp65, Influenza M1, HPV16 E6, and HPV16 E7. Furthermore, we demonstrate that SQZ™ eAPCs drive significant expansion of antigen-specific CD8+ T cells in a humanized mouse model. Thus, we demonstrate that Cell Squeeze® can deliver multiple mRNAs encoding for signals 1, 2, and 3 to human PBMCs and has the potential to generate enhanced APCs that drive strong CD8+ T cell responses against multiple antigens. The versatility of this approach has the potential to enable rapid exchange of mRNA to encode for other antigens or T cell activation signals. Citation Format: Michael F. Maloney, Emrah Ilker Ozay, Katarina Blagovic, Carolyne Smith, Andrea A. Silva, Amber Martin, Sanjana Manja, Madhav Upadhyay, Lindsay J. Moore, Ryan Stagg, Henry Mack, Christine Trumpfheller, Pablo Umana, Armon Sharei, Howard Bernstein, Scott M. Loughhead. Co-delivery of antigen-encoding mRNA and signal 2/3 mRNAs to PBMCs by Cell Squeeze® technology generates SQZ™ eAPCs that prime CD8+T cells in a humanized mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2853.

Background: Despite the availability of medium-to-high-dose inhaled corticosteroid-and-long-acting beta agonist (ICS-LABA) combination therapies, some adult patients with asthma remain uncontrolled. This can impact patients’ health-related quality of life (HRQoL), the magnitude of which is currently unknown. Aims: This study aimed to identify and summarize the literature on the humanistic burden in asthma patients who are inadequately controlled on medium-to-high-dose ICS-LABA therapy. Methods: Systematic searches were conducted in MEDLINE, Embase, and the National Health Service’s Economic Evaluation Databases to identify studies published from 1/1/2009-3/20/2019. Methods followed PRISMA guidelines. Observational studies were included and data on humanistic outcomes are presented here. Results: The searches identified 7,496 records, of which 22 studies reporting humanistic outcomes met the criteria for inclusion. Moderate burden was indicated by both mean baseline Asthma Quality of Life Questionnaire scores (n=19) and baseline St. George’s Respiratory Questionnaire total score (n=2); the former ranged from 3.0 to >5.0 while the latter ranged from 45.9 (SD: 2.1) to 53.2 (95% CI: 8.9, 85.0). High burden among patients with severe uncontrolled asthma was evident as measured by the EuroQol Five Dimensions (EQ-5D) questionnaire in selected studies. Baseline EQ-5D-3L (n=4) scores ranged from 0.48 (SD: 0.36) to 0.59 (SD: 0.25). Scores from the 36-item Short Form (SF-36) tool also indicated HRQoL burden in one study. Conclusions: The results suggest that the humanistic burden for adults with asthma remains high despite the availability of efficacious therapies. Method: GSK [HO-18-17246].

There are limited published data on the burden of moderate/severe uncontrolled asthma.We conducted a systematic literature review to better understand the impact of moderate-to-severe asthma in the US, the UK, Germany, France, Italy, Spain, Canada, Japan, and Australia in terms of prevalence, clinical measures, health-related quality of life (HRQoL) and economic burden, for patients whose asthma is uncontrolled despite inhaled corticosteroid/long-acting βThe prevalence of uncontrolled asthma among patients with moderate/severe disease varied but was as high as 100% in some subgroups. Patients with uncontrolled asthma generally had poor lung function (mean/median pre-bronchodilator forced expiratory volume in 1 second [FEVOur findings suggest that significant unmet needs exist for patients with uncontrolled asthma despite the availability of ICS/LABA therapy. Novel treatments are needed to help reduce the burden to patients, healthcare systems and society.

Background In 2016, the World Health Organization estimated the global incidence of gonorrhea (GC) to be 86.9 million, and the reported incidence of GC in 2017 was 145.8 cases per 100,000 females and 212.8 cases per 100,000 males in the US. GC therefore represents a significant global healthcare burden; as the infection can be recurrent, overall costs can accumulate. We undertook a systematic literature review (SLR) to examine the economic burden of illness for GC in key countries. Methods Systematic searches were conducted in MEDLINE, EMBASE, and Cochrane databases to identify English-language articles published from January 1, 2009–December 1, 2019 reporting data on the economic burden of uncomplicated urogenital GC (uuGC) in the US, the UK, Germany, Japan and China. The SLR was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (2009). Articles were evaluated for eligibility using population, intervention, comparison, outcome, study design and time period criteria (Table). Dual-independent screening was used at both the abstract and full-text levels; data were captured by a single reviewer with validation by a second reviewer. Table. PICOS-T Study Selection Criteria Results The SLR identified 27 eligible articles (Figure), of which 17 studies (16 US, 1 UK) reported the economic burden of uuGC. The studies primarily reported cost data, with a subset reporting limited resource use. Lifetime costs for uuGC, when elaborated upon, considered the potential for pelvic inflammatory disease among women, and epididymitis in men, as well as lifetime medical costs associated with human immunodeficiency virus. Among the 16 studies reporting costs, the total estimated lifetime cost of uuGC in the US reached as high as $162.1 million. Costs varied vastly based on sex, with one study reporting lifetime estimates up to $163,433 for men but $7,534,692 for women in 2005. Nine studies described costs per patient/infection and found average costs ranging from $26.92–$438.46, though most fell in the range of $79–$354. Figure. PRISMA flow diagram of study inclusion and exclusion Conclusion We identified a large body of evidence detailing the economic burden of GC. The cost burden varied by sex and was higher for females. However, the vast majority of the evidence came from the US, highlighting the need for more global research. Disclosures Amber Martin, BS, Evidera (Employee)GlaxoSmithKline plc. (Other Financial or Material Support, Funding) Fanny S. Mitrani-Gold, MPH, GlaxoSmithKline plc. (Employee, Shareholder) Monica Turner, MPH, Evidera (Employee)GlaxoSmithKline plc. (Other Financial or Material Support, Funding) Emma Schiller, BA, Evidera (Employee)GlaxoSmithKline plc. (Other Financial or Material Support, Funding) Ashish V. Joshi, PhD, GlaxoSmithKline plc. (Employee, Shareholder)

This paper explores the changing spatiality of the sex retail industry in England and Wales, from highly regulated male-orientated sex shops, pushed to the legislative margins of the city and social respectability, towards the emergence of unregulated female-orientated ‘erotic boutiques’ located visibly in city centres. This is achieved through an exploration of the oppositional binaries of perceptions of sex shops as dark, dirty, male-orientated, and ‘seedy’ and erotic boutiques as light, female-orientated and stylish, showing how such discourses are embedded in the physical space, design and marketing of the stores and the products sold within them. More specifically, the paper analyses how female-orientated sex stores utilise light, colour and design to create an ‘upscaling’ of sexual consumerism and reflects on what the emergence of up-scale female spaces for sexual consumption in the central city might mean in terms of theorisations of the intersectionality between agency, power, gender and class. The paper thus considers how the shifting packaging and presentation of sex-product consumption in the contemporary city alters both its acceptability and visibility.

Sex shops in England have traditionally been perceived as masculinised consumption spaces, located at the margins of both the city and the clock (in decaying urban zones, hidden from view and frequented under the cover of darkness). Recent decades have witnessed the emergence of fashion conscious and female-orientated ‘erotic boutiques’, keen to disassociate themselves away from negative stereotypical representations of sex shops, through marketing themselves as stylish, fun, acceptable and safe, and, above all, empowering spaces for women to explore their sexuality. This article considers how erotic boutiques offer a post-feminist sexual address to women through claims of female empowerment, an embrace of traditional femininity and an endorsement of the aestheticisation of the female body. More specifically, I explore the post-feminist tensions between female sexual subjectivity and objectivity, by unpacking, and reflecting on, the relations between erotic boutiques and the space of the body. Thi...

In newly diagnosed multiple myeloma (MM), patients ineligible for front-line autologous stem cell transplantation (ASCT), melphalan and prednisone (MP) with thalidomide (MPT) or bortezomib (VMP) are standard first-line therapeutic options. Despite new treatment regimens incorporating bortezomib or lenalidomide, MM remains incurable. The FIRST study demonstrated significant improvement in progression-free survival (PFS) and overall survival (OS) for the combination of lenalidomide and low-dose dexamethasone (Rd) until progression vs. MPT in transplant-ineligible ndMM patients. However, to date no head-to-head randomized controlled trials (RCTs) have compared Rd or MPT versus VMP. We conducted a network meta-analysis using RCTs identified through a systematic literature review to evaluate the relative efficacy of Rd versus other regimens on survival endpoints in previously untreated MM patients ineligible for ASCT. In this analysis, Rd was associated with a significant PFS and survival advantage versus other first-line treatments (VMP, MPT, MP), challenging the role of alkylators in this setting.

This study quantified mortality associated with serious infections caused by carbapenem-resistant (CRE) and carbapenem-susceptible Enterobacteriaceae (CSE). A systematic literature review was conducted, evaluating outcomes in hospitalized patients with CRE infections from a blood, urinary, pulmonary, or intra-abdominal source. A meta-analysis (MA) calculating odds ratios (ORs) for mortality was performed. Twenty-two studies met the criteria for inclusion in the MA: 12 included mortality data for CRE vs CSE populations. Compared with CSE, CRE was associated with a significantly higher risk of overall mortality (OR, 3.39; 95% confidence interval [CI], 2.35–4.89), as was monotherapy (vs combination therapy) treatment of patients with CRE infections (OR, 2.19; 95% CI, 1.00–4.80). These results document the increased mortality associated with serious CRE infections compared with CSE infections among hospitalized adults. It will be important to reevaluate the mortality in CRE and CSE populations, especially among patients who receive early appropriate therapy, as new antibiotics become available.

This article proposes that the extensive sales and widespread popularity of the Fifty Shades trilogy has placed BDSM in the sexual spotlight and explores how this is being capitalized upon by some sex shops and sex toy retailers by encouraging consumers to bring the erotic fiction of Fifty Shades into their own sexual reality through the purchase of particular commodities and the acquisition of BDSM related sexual knowledge. This article argues that this is based upon a particular ‘ Fifty Shades’ brand of BDSM that is constructed as fun, fashionable and exciting as opposed to extreme, marginalized and dangerous.

Rate and rhythm control are two well established treatment objectives for atrial fibrillation (AF) patients. While symptom reduction is a primary treatment goal, therapeutic practice related to cardioversion varies by region and patient, with several precautions associated with the use of current therapies. No comprehensive literature review on the relative efficacy of existing cardioversion approaches compared to newly available therapies has been conducted. A systematic literature review and meta-analysis were undertaken to evaluate the efficacy of pharmacologic therapies in eliciting cardioversion within 2 and 8–24 h among patients with recent-onset, short duration AF. Eligible studies included randomized controlled trials in which cardioversion rates were evaluated in at least 2 treatment groups. Bayesian mixed-treatment comparisons estimated odds ratios (95% credible intervals) for successful cardioversion. Results within 2 h showed vernakalant IV, propafenone IV and flecainide (IV and oral) were more efficacious in pair-wise comparisons to placebo. Results were mixed in analyses comparing efficacy rates between 8 and 24 h. Few adverse events were reported, with the most common being bradycardia and hypotension. In pair-wise comparisons of active treatment arms to one another, results suggest vernakalant IV, propafenone IV and flecainide appear to be effective in achieving rapid cardioversion in patients with short duration AF compared to other agents. Application of these findings to clinical practice need to account for the variable comorbidity profiles of patients, important determinants in the selection of appropriate therapy for individual patients. Though best practice methods were used, further research comparing treatments through direct head-to-head comparisons may be warranted to confirm these findings and further inform clinical practice.

This article reproduces and discusses a series of blog posts posted by academics in anticipation of the report on commercialisation, sexualisation and childhood, 'Letting Children Be Children' by Reg Bailey for the UK Department of Education in June 2011. The article discusses the difficulty of 'translating' scholarly work for the public in a context where 'impact' is increasingly important and the challenges that academics face in finding new ways of speaking about sex in public. © 2012 Copyright Taylor and Francis Group, LLC.

Background Topical retinoids have been in clinical use for the treatment of chronic skin conditions, including acne, photodamage, and psoriasis, for 30 years. Objective A systematic literature review was conducted to assess the incidence of noncutaneous adverse events (AE) among patients treated with topical retinoids with a focus on topical tretinoin studies reported before the Veterans Affairs Topical Tretinoin Chemoprevention trial. Methods Electronic literature searches were conducted in Embase and MEDLINE for literature reporting development of nonteratogenic, noncutaneous AE among patients treated with topical retinoids published through September 2008. Results The search yielded 2778 citations, of which 20 studies met inclusion criteria. Tretinoin was used in 14 of the studies. Other retinoids assessed included isotretinoin, adapalene, alitretinoin, and tazarotene. Within patients receiving topical tretinoin, 27.9% reported the occurrence of at least one noncutaneous AE. The majority of noncutaneous AE were transient and judged not to be related to tretinoin treatment. Limitations The conclusions of this study apply largely to tretinoin compared with other topical retinoids. Many of the included trials were designed to evaluate the efficacy of topical treatment and reporting of safety events concentrated on incidence of localized AE, rather than systemic or noncutaneous events. Conclusion We found no clear evidence of a relationship between the use of topical tretinoin and the development of noncutaneous AE before a recent report of excess mortality in a clinical trial. The majority of noncutaneous AE reported by patients receiving topical retinoids consisted of nonsevere, nonspecific symptoms that were judged not to be related to treatment.

BACKGROUND AND PURPOSE Hand-assisted laparoscopic surgery (HALS) is an integral part of the urologist's armamentarium. We aimed to perform a comprehensive meta-analysis comparing HALS renal surgery with open and laparoscopic techniques. METHODS A systematic review and meta-analysis of HALS renal procedures (donor nephrectomy, nephrectomy, or nephroureterectomy) from 1996 to 2007 was performed. RESULTS Sixty-two studies of 30 donor nephrectomy, 21 radical nephrectomy, and 14 nephroureterectomy procedures in 5446 patients were included in the analysis. In donor nephrectomy, estimated blood loss (EBL) was statistically significant for HALS vs the open and laparoscopic cohorts, -69.0 mL (95% confidence interval [CI], -129.7, -8.2) and -40.1 mL (95% CI, -68.2, -12.0), respectively. Length of stay (LOS) was shorter compared with the open group, -1.7 days (95% CI, -2.3, -1.1). For nephroureterectomy, EBL (-29.9 mL (95% CI, -242.3, 182.5)), and LOS (-1.5 d [95% CI, -2.8, -0.3]) again favored HALS vs open procedures. Operating room (OR) time and warm ischemia time (WIT) were statistically significant in favor of HALS donor nephrectomy vs the laparoscopic cohort; -36.8 minutes (95% CI, -61.3, -12.3) and -1.3 minutes (95% CI, -1.8, -0.7), respectively. For radical nephrectomy, both EBL -232.9 mL (95% CI, -383.6, -82.2) and LOS -2.4 days (95% CI, -3.5, -1.3) were statistically significant, favoring HALS vs the open group. CONCLUSION We report the largest meta-analysis of HALS renal surgery to date. When compared with open surgery, HALS allows for a significant decrease in EBL and LOS. Compared with laparoscopic donor nephrectomy, HALS resulted in a significant decrease in blood loss, OR time, and WIT.

Background: A carbon monoxide-releasing molecule (tricarbonyldichlororuthenium (II) dimer; CORM-2) enhances coagulation and attenuates vulnerability to fibrinolysis in normal and hemophiliac human plasma. We tested the hypothesis that plasma diluted with resuscitative fluids would demonstrate improved coagulation and decreased fibrinolytic vulnerability after exposure to CORM-2. Methods: Normal, platelet-poor plasma was diluted 0%, 20%, 30%, 40%, or 50% with 0.9% NaCl (NS) or low-molecular-weight hydroxyethyl starch (VOL) and, subsequently, exposed to 0 μmol/L or 100 μmol/L CORM-2 before activation with tissue factor (n = 4 per condition). Additional plasma samples diluted with NS or VOL (0% or 30%) were exposed to 0 μmol/L or 100 μmol/L CORM-2 and 0 U/mL or 100 U/mL tissue-type plasminogen activator to assess fibrinolytic vulnerability (n = 8 per condition). Thrombelastographic data were collected until either clot strength stabilized or clot lysis occurred, as appropriate. Results: CORM-2 exposure maintained normal to supranormal velocity of clot formation and strength in plasma diluted up to 40% with NS. In contrast, although CORM-2 exposure improved coagulation kinetics, dilution with VOL markedly degraded thrombus formation kinetics. Similarly, fibrinolytic vulnerability to tissue-type plasminogen activator was markedly improved by CORM-2 exposure in samples diluted with NS, whereas VOL-diluted thrombi were still abnormally weak and easily lysed compared with undiluted samples despite CORM-2 exposure. Conclusions: CORM-2 exposure attenuated the decrease in coagulation kinetics and enhancement of fibrinolytic vulnerability associated with hemodilution. Extensive preclinical investigation remains to be performed to determine the route of administration, safety, and efficacy of CORM-2 and other CORMs to treat trauma-associated bleeding.

The purpose of this study was to perform a systematic review and meta-analysis to evaluate the safety and efficacy of radiofrequency ablation (RFA) of typical atrial flutter (AFL) and atrioventricular node-dependent supraventricular tachycardia (SVT) in adult patients. Medline and EMBASE were searched (1990 to 2007) for all study design trials of RFA. Data relating to single- and multiple-procedure success, arrhythmia recurrence, repeat ablation, adverse events, and death were extracted. For RFA in AFL, 18 primary studies with 22 treatment arms and 1,323 patients were identified. Single-procedure success for AFL was 91.7% (95% confidence interval [CI] 88.4% to 94.9%). Multiple-procedure success was 97.0% (95% CI 94.7% to 99.4%). Postablation arrhythmia was noted in 13.2% of patients (95% CI 7.5% to 18.9%), while repeat ablation was reported in 8% (95% CI 4.5% to 11.4%). For RFA of SVT, 39 primary studies with 49 treatment arms in 7,693 patients with accessory pathways and atrioventricular nodal reentrant tachycardia were identified. Single-procedure success for SVT was 93.2% (95% CI 90.8% to 95.5%). Multiple-procedure success was 94.6% (95% CI 92.4% to 96.9). Postablation arrhythmia was noted in 5.6% patients (95% CI 4.1% to 7.2%). Repeat ablation occurred in 6.5% (95% CI 4.7% to 8.3%). For AFL studies, all-cause mortality was 0.6%, and adverse events were reported in 0.5% of patients. For SVT studies, all-cause mortality was 0.1%, and adverse events were reported in 2.9% of patients. In conclusion, studies of RFA for the treatment of patients with AFL and SVT report high efficacy rates and low rates of complications.

Background— Although radiofrequency catheter ablation (RFA) has evolved from an experimental procedure to an important treatment option for atrial fibrillation, the relative safety and efficacy of catheter ablation relative to that of antiarrhythmic drug (AAD) therapy has not been established. Methods and Results— Two separate systematic reviews were conducted: one on RFA and the other on AAD to provide accurate and broadly representative estimates of the clinical efficacy and safety of both therapies in the treatment of atrial fibrillation. Electronic searches were conducted in EMBASE and MEDLINE from 1990 to 2007. For the RFA review, all study designs were accepted. For the AAD review, articles were limited to prospective studies on the following drugs of interest: amiodarone, dofetilide, sotalol, flecainide, and propafenone. Data were extracted by 1 reviewer, with a second reviewer performing independent confirmation of extracted data. Sixty-three RFA and 34 AAD studies were included in the reviews. Patients enrolled in RFA studies tended to be younger (mean age, 55 versus 62 years), had longer duration of atrial fibrillation (6.0 versus 3.1 years), and had failed a greater number of prior drug trials (2.6 versus 1.7). The single-procedure success rate of ablation off AAD therapy was 57% (95% CI, 50% to 64%), the multiple procedure success rate off AAD was 71% (95% CI, 65% to 77%), and the multiple procedure success rate on AAD or with unknown AAD usage was 77% (95% CI, 73% to 81%). In comparison, the success rate for AAD therapy was 52% (95% CI, 47% to 57%). A major complication of catheter ablation occurred in 4.9% of patients. Adverse events for AAD studies, although more common (30% versus 5%), were less severe. Conclusions— Studies of RFA for treatment of atrial fibrillation report higher efficacy rates than do studies of AAD therapy and a lower rate of complications.

Objective : This study was conducted to evaluate data on chemotherapy-associated anemia and throm- bocytopenia, and cycle delays in patients with cancer in a community oncology practice. Methods : Data on adult patients (age ≥18 years) with cancer treated in outpatient oncology clinics throughout the United States between 2000 and 2007 were obtained from a large electronic medical records database. All types of cancer were included, although the focus was on solid cancers (ie, lung, breast, ovarian, head and neck, and colorectal cancers). Chemotherapy regimens were grouped from most to least toxic as follows: platinum-based, anthracycline-based, gemcitabine-based, taxane-based, and all other regimens. Anemia (defined as hemoglobin 9 /L), red blood cell (RBC) and platelet transfusions, and use of erythropoietin-stimulating agents (ESAs) were examined by tumor and regimen type. Cycle delays (>7 days) during chemotherapy were also evaluated. Results : A total of 47,159 patients were included in the study (58.4% female; mean [SD] age, 60.76 [13.9] years). The most common cancer was breast cancer (19.5%), followed by non—small cell lung cancer (14.9%), colorectal cancer (11.9%), ovarian cancer (3.1%), and head and neck cancer (2.5%). At baseline, 20.9% of patients had anemia and 11.1% had thrombocytopenia. A total of 75,243 chemotherapy regimens were administered. During the course of chemotherapy, from 46.4% to 59.0% of patients developed anemia. The prevalence of thrombocytopenia ranged from 21.9% in patients treated with taxanebased regimens to 64.2% in patients treated with gemcitabine-based regimens. In patients from a single hospital-based outpatient center that had the most complete transfusion data (representing 18.3% of the population), the use of RBC transfusion ranged from 4.5% in patients treated with anthracycline-based regimens to 11.6% in patients treated with platinumbased regimens. ESAs were received at some point during chemotherapy by 49.1% of patients. For those with complete dose information, dose delay occurred in 8.2% of chemotherapy cycles; the mean delay was 17 days. Conclusion : In this study of anemia and thrombocytopenia in a large cohort of patients undergoing chemotherapy for solid tumors in an outpatient oncology clinic in 2000–2007, the burden of anemia and thrombocytopenia remained high.

Background This study investigated the relationship between changes in lung function (as measured by forced expiratory volume in one second [FEV1]) and the St. George’s Respiratory Questionnaire (SGRQ) and economically significant outcomes of exacerbations and health resource utilization, with an aim to provide insight into whether the effects of COPD treatment on lung function and health status relate to a reduced risk for exacerbations. Methods A systematic literature review was conducted in MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials to identify randomized controlled trials of adult COPD patients published in English since 2002 in order to relate mean change in FEV1 and SGRQ total score to exacerbations and hospitalizations. These predictor/outcome pairs were analyzed using sample-size weighted regression analyses, which estimated a regression slope relating the two treatment effects, as well as a confidence interval and a test of statistical significance. Results Sixty-seven trials were included in the analysis. Significant relationships were seen between: FEV1 and any exacerbation (time to first exacerbation or patients with at least one exacerbation, p = 0.001); between FEV1 and moderate-to-severe exacerbations (time to first exacerbation, patients with at least one exacerbation, or annualized rate, p = 0.045); between SGRQ score and any exacerbation (time to first exacerbation or patients with at least one exacerbation, p = 0.0002) and between SGRQ score and moderate-to-severe exacerbations (time to first exacerbation or patients with at least one exacerbation, p = 0.0279; annualized rate, p = 0.0024). Relationships between FEV1 or SGRQ score and annualized exacerbation rate for any exacerbation or hospitalized exacerbations were not significant. Conclusions The regression analysis demonstrated a significant association between improvements in FEV1 and SGRQ score and lower risk for COPD exacerbations. Even in cases of non-significant relationships, results were in the expected direction with few exceptions. The results of this analysis offer health care providers and payers a broader picture of the relationship between exacerbations and mean change in FEV1 as well as SGRQ score, and will help inform clinical and formulary-making decisions while stimulating new research questions for future prospective studies.

Two populations have been found to exhibit delays in theory of mind (ToM): deaf children of hearing parents and children with autism spectrum disorder (ASD). Deaf children exposed to sign from birth by their deaf parents, however, show no such delay, suggesting that early language exposure is key to ToM development. Sign languages also present frequent opportunities with visual perspective-taking (VPT), leading to the question of whether sign exposure could benefit children with ASD. We present the first study of children with ASD exposed to sign from birth by their deaf parents. Seventeen native-signing children with a confirmed ASD diagnosis and a chronological- and mental age-matched control group of 18 typically developing (TD) native-signing deaf children were tested on American Sign Language (ASL) comprehension, two minimally verbal social cognition tasks (ToM and VPT), and one spatial cognition task (mental rotation). The TD children outperformed the children with ASD on ASL comprehension (p 0.0001), ToM (p = 0.02), and VPT (p 0.01), but not mental rotation (p = 0.12). Language strongly correlated with ToM (p 0.01) and VPT (p 0.001), but not mental rotation (p = ns). Native exposure to sign is thus insufficient to overcome the language and social impairments implicated in ASD. Contrary to the hypothesis that sign could provide a scaffold for ToM skills, we find that signing children with ASD are unable to access language so as to gain any potential benefit sign might confer. Our results support a strong link between the development of social cognition and language, regardless of modality, for TD and ASD children. Autism Res 2016, 9: 1304-1315. © 2016 International Society for Autism Research, Wiley Periodicals, Inc.

BACKGROUND: In 2010 the COPD Foundation established the COPD Biomarkers Qualification Consortium (CBQC) as a partnership between the Foundation, the Food and Drug Administration (FDA), and the pharmaceutical industry to pool publicly-funded and industry data to develop innovative tools to facilitate the development and approval of new therapies for COPD. We present data from the initial project seeking regulatory qualification of fibrinogen as a biomarker for the stratification of COPD patients into clinical trials. METHODS: This analysis pooled data from 4 publicly-funded studies and 1 industry study into a common database resulting in 6376 individuals with spirometric evidence of COPD. We used a threshold of 350 mg/dL to determine high vs. low fibrinogen, and determined the subsequent risk of hospitalizations from exacerbations and death using Cox proportional hazards models. RESULTS: High fibrinogen levels at baseline were present in 2853 (44.7%) of individuals with COPD. High fibrinogen was associated with an increased risk of hospitalized COPD exacerbations within 12 months (hazard ratio [HR]: 1.64; 95% confidence interval [CI]: 1.39-1.93) among participants in the Atherosclerosis Risk in Communities Study (ARIC), the Cardiovascular Health Study (CHS), and the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) study. High fibrinogen was associated with an increased risk of death within 36 months (HR: 1.94; 95% CI: 1.62-2.31) among all participants. CONCLUSIONS: Fibrinogen levels ≥ 350 mg/dL identify COPD individuals at an increased risk of exacerbations and death and could be a useful biomarker for enriching clinical trials in the COPD population. BACKGROUND: In 2010 the COPD Foundation established the COPD Biomarkers Qualification Consortium (CBQC) as a partnership between the Foundation, the Food and Drug Administration (FDA), and the pharmaceutical industry to pool publicly-funded and industry data to develop innovative tools to facilitate the development and approval of new therapies for COPD. We present data from the initial project seeking regulatory qualification of fibrinogen as a biomarker for the stratification of COPD patients into clinical trials. METHODS: This analysis pooled data from 4 publicly-funded studies and 1 industry study into a common database resulting in 6376 individuals with spirometric evidence of COPD. We used a threshold of 350 mg/dL to determine high vs. low fibrinogen, and determined the subsequent risk of hospitalizations from exacerbations and death using Cox proportional hazards models. RESULTS: High fibrinogen levels at baseline were present in 2853 (44.7%) of individuals with COPD. High fibrinogen was associated with an increased risk of hospitalized COPD exacerbations within 12 months (hazard ratio [HR]: 1.64; 95% confidence interval [CI]: 1.39-1.93) among participants in the Atherosclerosis Risk in Communities Study (ARIC), the Cardiovascular Health Study (CHS), and the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) study. High fibrinogen was associated with an increased risk of death within 36 months (HR: 1.94; 95% CI: 1.62-2.31) among all participants. CONCLUSIONS: Fibrinogen levels ≥ 350 mg/dL identify COPD individuals at an increased risk of exacerbations and death and could be a useful biomarker for enriching clinical trials in the COPD population.

Objectives. To examine relationships between conventional MRI measures and the paced auditory serial addition test (PASAT) and symbol digit modalities test (SDMT).Methods.A systematic literature review was conducted. Included studies had ≥30 multiple sclerosis (MS) patients, administered the SDMT or PASAT, and measured T2LV or brain atrophy. Meta-analysis of MRI/information processing speed (IPS) correlations, analysis of MRI/IPS significance tests to account for reporting bias, and binomial testing to detect trends when comparing correlation strengths of SDMT versus PASAT and T2LV versus atrophy were conducted.Results. The 39 studies identified frequently reported only significant correlations, suggesting reporting bias. Direct meta-analysis was only feasible for correlations between SDMT and T2LV (r=-0.45,P<0.001) and atrophy in patients with mixed-MS subtypes (r=-0.54,P<0.001). Familywise Holm-Bonferroni testing found that selective reporting was not the source of at least half of significant results reported. Binomial tests (P=0.006) favored SDMT over PASAT in strength of MRI correlations.Conclusions. A moderate-to-strong correlation exists between impaired IPS and MRI in mixed MS populations. Correlations with MRI were stronger for SDMT than for PASAT. Neither heterogeneity among populations nor reporting bias appeared to be responsible for these findings.

Distracted driving is a significant contributor to motor vehicle accidents and fatalities, and texting is a particularly significant form of driver distraction that continues to be on the rise. The present study examined the influence of driver age (18-59 years old) and other factors on the disruptive effects of texting on simulated driving behavior. While 'driving' the simulator, subjects were engaged in a series of brief text conversations with a member of the research team. The primary dependent variable was the occurrence of Lane Excursions (defined as any time the center of the vehicle moved outside the directed driving lane, e.g., into the lane for oncoming traffic or onto the shoulder of the road), measured as (1) the percent of subjects that exhibited Lane Excursions, (2) the number of Lane Excursions occurring and (3) the percent of the texting time in Lane Excursions. Multiple Regression analyses were used to assess the influence of several factors on driving performance while texting, including text task duration, texting skill level (subject-reported), texting history (#texts/week), driver gender and driver age. Lane Excursions were not observed in the absence of texting, but 66% of subjects overall exhibited Lane Excursions while texting. Multiple Regression analysis for all subjects (N=50) revealed that text task duration was significantly correlated with the number of Lane Excursions, and texting skill level and driver age were significantly correlated with the percent of subjects exhibiting Lane Excursions. Driver gender was not significantly correlated with Lane Excursions during texting. Multiple Regression analysis of only highly skilled texters (N=27) revealed that driver age was significantly correlated with the number of Lane Excursions, the percent of subjects exhibiting Lane Excursions and the percent of texting time in Lane Excursions. In contrast, Multiple Regression analysis of those drivers who self-identified as not highly skilled texters (N=23) revealed that text task duration was significantly correlated with the number of Lane Excursions. The present studies confirm past reports that texting impairs driving simulator performance. Moreover, the present study demonstrates that for highly skilled texters, the effects of texting on driving are actually worse for older drivers. Given the increasing frequency of texting while driving within virtually all age groups, these data suggest that 'no texting while driving' education and public service messages need to be continued, and they should be expanded to target older drivers as well.

Introduction Sildenafil was the first oral phosphodiesterase type 5 (PDE5) inhibitor introduced as primary therapy for erectile dysfunction (ED). In the 7 years following its market launch, sildenafil was prescribed by more than 750,000 physicians to more than 23 million men worldwide. To date, few studies have evaluated the economic impact of sildenafil in treating ED. Aim To evaluate the cost‐effectiveness and impact of sildenafil on health care costs for patients with ED in multiple countries. Main Outcomes Measures. Economic outcomes including cost, cost‐effectiveness, cost of illness, cost consequence, resource use, productivity, work loss, and willingness to pay (WTP) were investigated. Methods Using keywords related to economic outcomes and sildenafil, we systematically searched literature published between July 2001 and July 2011 using MEDLINE and EMBASE. Included articles pertained to costs, WTP, and economic evaluations. Results In the last 10 years, 12 studies assessed economic outcomes associated with sildenafil for ED. Most studies were conducted in the United States and the United Kingdom, with one study identified in Canada and one from Mexico. Six studies evaluated cost of illness, cost consequence, or cost of care, and four studies evaluated WTP or drug pricing by country in the United States and the United Kingdom. In the United States and the United Kingdom, costs to health care systems have increased with demand for treatment. Cost analyses suggested that sildenafil would lower direct costs compared with other PDE5 inhibitors. US and UK studies found that patients exhibited WTP for sildenafil. The two cost‐effectiveness models we identified examined ED sub‐groups, those with spinal cord injury and those with diabetes or hypertension. These models indicated favorable cost‐effectiveness profiles for sildenafil compared with other active‐treatment options in both Mexico and Canada. Conclusions The relative value of sildenafil vs. surgically implanted prosthetic devices and other PDE5 inhibitors, is underscored by patients' WTP, and cost‐effectiveness in ED patients with comorbidities.

Attention-deficit/hyperactivity disorder (ADHD) is a common child and adolescent disorder that is associated with negative outcomes (e.g., emotional and behavioral problems, substance use) and is often comorbid with Conduct Problems (CP). Research findings are mixed as to whether youth with ADHD alone or comorbid ADHD/CP suffer from low self-esteem. Research has also shown links between low self-esteem and ADHD (alone and with CP) with substance use; yet, no research has examined the links between self-esteem and substance use in adolescents with ADHD and CP. The current study examined the relation between ADHD with and without comorbid CP and self-esteem, and whether self-esteem moderated the relation between ADHD and ADHD/CP with substance use among adolescents. We hypothesized that adolescents with comorbid ADHD/CP would experience lower self-esteem than adolescents with ADHD alone or with neither disorder and that self-esteem would moderate the association between ADHD, CP, and substance use. Participants were 62 adolescents who completed the laboratory-based study with a parent. Results suggested that adolescents with comorbid ADHD and CP had significantly lower self-esteem than adolescents with ADHD alone or neither disorder. Self-esteem was not significantly different for adolescents with ADHD alone versus those in the control group. There was one marginally significant interaction between ADHD and self-esteem predicting substance use, such that individuals with comorbid ADHD/CP who also had low self-esteem tended to use more substances. Results have implications for treatments that target adolescents with ADHD and comorbid CP, as these adolescents are at risk for many deleterious outcomes.

We are grateful to Brodsky for his thoughtful comments on our manuscript as well as his suggestions for the design of future prospective trials comparing the safety and efficacy of catheter ablation as compared with antiarrhythmic drug (AAD) therapy in the treatment of patients with atrial fibrillation (AF). We agree completely with many of the points that were raised by Brodsky. In particular, we agree that the outcomes of treatment of AF are likely to vary considerably in patients with paroxysmal and persistent AF. This is particularly true in patients with longstanding persistent AF (continuous AF lasting 12 months or longer).1 We also agree with Brodsky that many of the trials of AAD therapy evaluated in our meta-analysis were performed earlier than the trials of AF ablation. This point is presented clearly in Figures 4 through 7 of our article, which list each manuscript and the date of publication. Because of this difference, we cannot exclude the possibility that an increased use of background therapy with angiotensin-converting enzyme inhibitors, β-blockers, lipid-lowering agents, and systemic anticoagulation over time may have contributed to the apparent …

Previous studies of lopinavir/ritonavir (LPV/r) monotherapy have shown that over 70% of patients achieved HIV RNA levels

s of the 46th Annual ICAAC; September 27–30, 2006; San Francisco, CA. Poster A-0374. 8. Kumar PN CD, Steigbigel RT, et al. Efficacy of raltegravir, an integrase inhibitor, in combination with regimens containing enfuvitide, darunavir, or tipranavir in patients with tripleclass resistant virus: combined results from BENCHMRK-1 and BENCHMRK-2. In: Programs and abstracts of the 11th European AIDS Conference; October 24–27, 2007; Madrid, Spain, Poster P7.2/06. 1 10 100 1000 10000 100000 1000000 0 25 50 75 100 125 150 175 200 Follow-Up Period (weeks) H IV R N A ( co p ie s/ m L ) an d C D 4+ L ym p h o cy te (c el ls /μ L ) 0 20 40 60 80 100 120 140 160 180

Background In the treatment of multiple sclerosis (MS), the most important therapeutic aim of disease-modifying treatments (DMTs) is to prevent or postpone long-term disability. Given the typically slow progression observed in the majority of relapsing-remitting MS (RRMS) patients, the primary endpoint for most randomized clinical trials (RCTs) is a reduction in relapse rate. It is widely assumed that reducing relapse rate will slow disability progression. Similarly, MRI studies suggest that reducing T2 lesions will be associated with slowing long-term disability in MS. The objective of this study was to evaluate the relationship between treatment effects on relapse rates and active T2 lesions to differences in disease progression (as measured by the Expanded Disability Status Scale [EDSS]) in trials evaluating patients with clinically isolated syndrome (CIS), RRMS, and secondary progressive MS (SPMS). Methods A systematic literature review was conducted in Medline, Embase, CENTRAL, and PsycINFO to identify randomized trials published in English from January 1, 1993-June 3, 2013 evaluating DMTs in adult MS patients using keywords for CIS, RRMS, and SPMS combined with keywords for relapse and recurrence. Eligible studies were required to report outcomes of relapse and T2 lesion changes or disease progression in CIS, RRMS, or SPMS patients receiving DMTs and have a follow-up duration of at least 22 months. Ultimately, 40 studies satisfied these criteria for inclusion. Regression analyses were conducted on RCTs to relate differences between the effect of treatments on relapse rates and on active T2 lesions to differences between the effects of treatments on disease progression (as measured by EDSS). Results Regression analysis determined there is a substantive clinically and statistically significant association between concurrent treatment effects in relapse rate and EDSS; p

Background Chronic kidney disease (CKD) is a common disorder with increasing prevalence worldwide. This systematic literature review aims to provide insights specific to Japan regarding the burden and treatment of CKD. Methods We reviewed English and Japanese language publications from the last 10 years, reporting economic, clinical, humanistic, and epidemiologic outcomes, as well as treatment patterns and guidelines on CKD in Japan. Results This review identified 85 relevant articles. The prevalence of CKD was found to have increased in Japan, attributable to multiple factors, including better survival on dialysis therapy and a growing elderly population. Risk factors for disease progression differed depending on CKD stage, with proteinuria, smoking, hypertension, and low levels of high-density lipoprotein commonly associated with progression in patients with stage 1 and 2 disease. Serum albumin levels and hemoglobin were the most sensitive variables to progression in patients with stage 3 and 5 disease, respectively. Economic data were limited. Increased costs were associated with disease progression, and with peritoneal dialysis as compared with either hemodialysis or combination therapy (hemodialysis + peritoneal dialysis) treatment options. Pharmacological treatments were found potentially to improve quality of life and result in cost savings. We found no reports of treatment patterns in patients with early-stage CKD; however, calcium channel blockers were the most commonly prescribed antihypertensive agents in hemodialysis patients. Treatment guidelines focused on anemia management related to dialysis and recommendations for peritoneal dialysis treatment and preventative measures. Few studies focused on humanistic burden in Japanese patients; Japanese patients reported greater disease burden but better physical functioning compared with US and European patients. Conclusion A dearth of evidence regarding the earlier stages of kidney disease presents an incomplete picture of CKD disease burden in Japan. Further research is needed to gain additional insight into CKD in Japan.

Background and Purpose: Hand-assisted laparoscopic surgery (HALS) is an integral part of the urologist's armamentarium. We aimed to perform a comprehensive meta-analysis comparing HALS renal surgery with open and laparoscopic techniques. Methods: A systematic review and meta-analysis of HALS renal procedures (donor nephrectomy, nephrectomy, or nephroureterectomy) from 1996 to 2007 was performed. Results: Sixty-two studies of 30 donor nephrectomy, 21 radical nephrectomy, and 14 nephroureterectomy procedures in 5446 patients were included in the analysis. In donor nephrectomy, estimated blood loss (EBL) was statistically significant for HALS vs the open and laparoscopic cohorts, −69.0 mL (95% confidence interval [CI], −129.7, −8.2) and −40.1 mL (95% CI, −68.2, −12.0), respectively. Length of stay (LOS) was shorter compared with the open group, −1.7 days (95% CI, −2.3, −1.1). For nephroureterectomy, EBL (−29.9 mL (95% CI, −242.3, 182.5)), and LOS (−1.5 d [95% CI, −2.8, −0.3]) again favored HALS vs o...