The risks and benefits of technologised sexual practice scale: a quantitative measure of technology facilitated sex and intimacy.

BACKGROUND: Technologies such as the Internet, smartphones, and sex toys have demonstrated the capacity to facilitate and enhance sexual and intimate practice by offering new ways to meet sexual partners, maintain and establish intimate connections, and providing access to sexual education and exposure to new ways of engaging in sex. They have also afforded novel risks to safety, privacy, and sexual autonomy. Understanding how people perceive and experience both the risks and benefits of using technology to facilitate sex and intimacy is important to understanding contemporary sexual practice, health, and pleasure. However, research in this space is currently hampered by a lack of quantitative measures to accurately and holistically assess both the risks and benefits in the context of technologised sexual practices. METHODS: To facilitate a nuanced quantitative exploration of these concepts, we present the psychometric properties of the newly developed Risks and Benefits of Technologised Sexual Practice Scale . RESULTS: Using an exploratory (Study 1, n =445) and confirmatory factor analysis (Study 2, n =500), this paper presents evidence for a 6-factor scale (Benefits (3): 'sexual gratification', 'connection', and 'access to information and culture'; Risks (3): 'concerns', 'worries', and 'knowledge of rights and ownership'). CONCLUSION: This scale may be used to contribute to research areas including sexual health, sexual behaviour, sexual education, online connection, online safety, and digital literacy with the aim to contribute to a sex- and technology-positive framework for understanding sexual health and pleasure.

ENTERPRET: A Randomized Controlled Trial of Vedolizumab Dose Optimization in Patients With Ulcerative Colitis Who Have Early Nonresponse.

BACKGROUND & AIMS: Patients with ulcerative colitis (UC) may experience nonresponse to biologics, possibly as a result of low drug exposure. This trial assessed the efficacy of dose optimization in patients with UC who have early nonresponse to vedolizumab and high drug clearance. METHODS: ENTERPRET was a phase 4, open-label, randomized, controlled trial that included patients with moderate to severe UC who had high drug clearance at week 5 (serum concentration, <50 µg/mL) and nonresponse to standard vedolizumab treatment at week 6. At week 6, eligible patients were randomized 1:1 to receive standard dosing (300 mg every 8 weeks) or dose-optimized vedolizumab (600 mg at week 6, then 300 mg every 4 weeks; or 600 mg at week 6, then 600 mg every 4 weeks [based on week 5 serum concentration]). The primary end point was endoscopic improvement at week 30. RESULTS: Of 278 enrolled patients, 132 (47.5%) had a clinical response at week 6. From week 6, 108 patients received standard (n = 53) or dose-optimized vedolizumab (n = 55); among patients with nonresponse at week 6, 86.5% had high drug clearance. At week 30, 10 patients (18.9%) who received standard vedolizumab had endoscopic improvement vs 8 patients (14.5%) who received dose-optimized vedolizumab. Five patients (9.4%) who received standard vedolizumab had clinical remission at week 30 vs 5 patients (9.1%) who received dose-optimized vedolizumab; clinical response was observed in 17 (32.1%) and 17 patients (30.9%), respectively. Safety event rates were similar among treatment groups. CONCLUSIONS: In patients with early nonresponse and high drug clearance, vedolizumab dose optimization is probably not required. A proportion of patients benefited from continued treatment irrespective of the dose received. CLINICALTRIALS: gov: NCT03029143.

Vedolizumab, Adalimumab, and Methotrexate Combination Therapy in Crohn's Disease (EXPLORER).

BACKGROUND & AIMS: Although biologics have revolutionized the treatment of Crohn's disease (CD), an efficacy ceiling has been reached. Combining biologic therapies may improve remission rates. METHODS: EXPLORER, a phase 4, single-arm, open-label study, evaluated triple combination therapy with vedolizumab (300 mg on day 1, weeks 2 and 6, and then every 8 weeks), adalimumab (160 mg on day 2, 80 mg at week 2, then 40 mg every 2 weeks), and methotrexate (15 mg weekly) in biologic-naïve patients with newly diagnosed, moderate- to high-risk CD. Endoscopic remission at week 26 (primary end point; Simple Endoscopic Score for CD ≤2), clinical remission at weeks 10 and 26 (secondary end point; Crohn's Disease Activity Index <150), and incidences of adverse events and serious adverse events were evaluated. RESULTS: Among 55 enrolled patients, the mean CD duration was 0.4 years, the mean baseline Simple Endoscopic Score for CD was 12.6, and the mean baseline Crohn's Disease Activity Index was 265.5. At week 26, 19 patients (34.5%) were in endoscopic remission. At weeks 10 and 26, 34 (61.8%) and 30 patients (54.5%), respectively, were in clinical remission. Post hoc Bayesian analysis showed that the probabilities that triple combination therapy produced a higher endoscopic remission rate (33.5%; 95% credible interval, 22.4-45.7) than placebo (14%), vedolizumab monotherapy (27%), or adalimumab monotherapy (30%) were 99.9% or higher, 86.3%, and 71.4%, respectively. Six patients had serious adverse events. CONCLUSIONS: Combination therapy resulted in endoscopic and clinical remission at week 26 in 34.5% and 54.5% of patients, respectively, with no safety signal related to the treatment regimen. This supports further evaluation of combination therapy in CD. CLINICALTRIALS: gov number: NCT02764762.

Sex on screens: the language of sexting and amateur pornography.

Frequently referred to as 'sexting' or 'amateur pornography', digital sexual images and videos form an increasingly common part of adult sexual relationships. However, the vocabulary available to speak about these practices is limited, with 'sexting' often associated with young people in negative terms. This study is based on 23 interviews with adults in Australia who are 25 years and older. It explores the language adults employ to discuss and comprehend the creation and sharing of sexualised images and videos. Findings show that negative or positive connotations associated with the terms used to discuss sexual images and videos influenced the ways participants drew on, or rejected, terms to align digital practices with their sexual subjectivity. Reticence to engage in active communication about digital sexual practices, and participant's distancing of their own practices from the terms commonly understood to refer to such practices, made it difficult to engage in conversations about consent or desire in the context of digitally mediated sex. Findings provide insight into the ways that -digital sexual subjectivities are discursively framed and extend these implications for sexual health promotion with respect to how to frame messages of digital sexual safety in a sex-positive and open way.

Hepatitis B prophylaxis among recipients of a hepatitis B core antibody positive liver transplant.

OBJECTIVE: Using organs from donors with a history of hepatitis B virus (HBV) infection has expanded the pool for solid organ transplant. The purpose of this study was to assess the efficacy of HBV postexposure prophylaxis among recipients of a hepatitis B core antibody positive (HBcAb+) liver transplant and compare post-transplant outcomes with those who received a hepatitis B core antibody negative (HBcAb-) liver transplant. METHODS: This was a retrospective, single-center cohort analysis of liver transplant recipients at our institution. All adult liver transplant recipients between January 1, 2014, and August 30, 2020, were reviewed for inclusion. Recipients of an HBcAb+ organ who were administered antiviral therapy were matched 1:2 with recipients of an HBcAb- organ using propensity score matching. The primary outcome was breakthrough HBV infection. Secondary outcomes included graft survival, patient survival, and allograft rejection. Postexposure prophylaxis strategies for HBV were also assessed. Outcomes were analyzed for the first 12 months after transplant. RESULTS: Twenty-four HBcAb+ patients were matched to 48 HBcAb- patients. There were no documented cases of breakthrough HBV infection. Patient and graft survival was similar between both groups. Seven HBcAb+ patients (29%) experienced an episode of rejection within the first year compared with zero HBcAb- patients. CONCLUSIONS: Results of this study suggest that current strategies for HBV postexposure prophylaxis are effective. Patient and graft survival rates at 30 days after transplant were similar to institutional reported values. Rejection was more prominent in the HBcAb+ group.

Talking about health: Community ambassadors as a health promotion strategy to increase breast and bowel cancer screening in regional Australia.

ISSUE ADDRESSED: In Australia, cancer is the leading contributor to disease burden, with breast and bowel cancer among the most commonly diagnosed cancers. Despite the presence of community-wide health promotion activities and screening programs, people living in regional and rural locations experience a number of factors that reduce breast and bowel cancer survival outcomes. This study investigates the ways that high-risk community members in a regional area of Australia interact with health messaging about breast and bowel cancer screening. METHODS: A qualitative research method was used to conduct 31 in-depth one-on-one interviews with community members, leaders and essential service providers. A thematic approach was used to analyse data. RESULTS: Findings provided insight to the ways that health is spoken about within the community, what prompts discussion of health, trustworthy sources of health information and the significance of peer-to-peer communication. CONCLUSIONS: Existing community communication lines can be used to assist in delivering public health messages among high-risk and vulnerable population groups. Utilising community ambassadors is identified as a health promotion method for hard-to-reach populations. SO WHAT?: Conversations about health and screening amongst community members, and led by community members, play a key role in shaping engagement with cancer screening programs and represent an important site for health promotion activities. These findings have implications for future public health initiatives amongst high-risk groups in regional locations.

Continued treatment with nintedanib in patients with systemic sclerosis-associated interstitial lung disease: data from SENSCIS-ON.

OBJECTIVES: In the SENSCIS trial in patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD), nintedanib reduced the rate of decline in forced vital capacity (FVC) versus placebo, with adverse events that were manageable for most patients. An open-label extension trial, SENSCIS-ON, is assessing safety and FVC decline during longer term nintedanib treatment. METHODS: Patients who completed the SENSCIS trial or a drug-drug interaction (DDI) study of nintedanib and oral contraceptive on treatment were eligible to enter SENSCIS-ON. Adverse events and changes in FVC over 52 weeks of SENSCIS-ON were assessed in patients who received nintedanib in SENSCIS and continued nintedanib in SENSCIS-ON ('continued nintedanib' group) and in patients who received placebo in SENSCIS and initiated nintedanib in SENSCIS-ON or who received nintedanib for ≤28 days in the DDI study ('initiated nintedanib' group). RESULTS: There were 197 patients in the continued nintedanib group and 247 in the initiated nintedanib group. Diarrhoea was reported in 68.0% and 68.8% of patients in these groups, respectively. Adverse events led to discontinuation of nintedanib in 4.6% and 21.5% of the continued nintedanib and initiated nintedanib groups, respectively. Mean (SE) changes in FVC from baseline to week 52 of SENSCIS-ON were -58.3 (15.5) mL in the continued nintedanib group and -44.0 (16.2) mL in the initiated nintedanib group. CONCLUSIONS: The safety profile of nintedanib over 52 weeks of SENSCIS-ON was consistent with that reported in SENSCIS. The change in FVC over 52 weeks of SENSCIS-ON was similar to that observed in the nintedanib group of SENSCIS.

Traversing TechSex: benefits and risks in digitally mediated sex and relationships.

BACKGROUND: Digital technologies play a significant role in people's sexual and intimate lives via smart phones, cameras, dating apps and social media. Although there is a large body of research on the potential risks posed by these technologies, research on benefits and pleasures is limited. METHODS: This study explored digital sexual practices, including perceptions of risks and benefits among a sample of Australian adults (n =445). Data were collected in 2020 via an online survey. Descriptive and bivariate analyses were undertaken to identify significant relationships between demographic variables and the use of technologies in relation to perceived risks and benefits. The mean age of participants was 42 years, over half were women (58.5%) and identified as heterosexual (61.1%). RESULTS: Findings reveal that use of digital media was common in participants' sex lives and relationships; 60.3% of participants had viewed pornography online, 34.9% had used dating apps, and 33.9% had sent sexual or naked self-images to another person. Over one in three reported positive outcomes from this: 38.2% felt emotionally connected to their partners due to online communication; 38.0% agreed that digital technologies facilitated closer connections;however, the majority of participants were aware of potential risks associated with online sexual engagement, particularly non-consensual exposure of their sexual or naked images, with women expressing greater concern. CONCLUSIONS: Policy, legal and educational responses should be based on holistic understanding of digital sexual engagement, acknowledging the ways in which technologies can support sexual relationships while also building people's knowledge and capacity to manage risks.

Efficacy of Vedolizumab Induction and Maintenance Therapy in Patients With Ulcerative Colitis, Regardless of Prior Exposure to Tumor Necrosis Factor Antagonists.

BACKGROUND & AIMS: The efficacy and safety of vedolizumab, a humanized immunoglobulin G1 monoclonal antibody against the integrin α4ß7, were demonstrated in multicenter, phase 3, randomized, placebo-controlled trials in patients with moderately to severely active ulcerative colitis (UC) or Crohn's disease. We analyzed data from 1 of these trials to determine the effects of vedolizumab therapy in patients with UC, based on past exposure to anti-tumor necrosis factor-α (TNF) antagonists. METHODS: We performed a post hoc analysis of data from the GEMINI 1 study, collected from 464 patients who received vedolizumab or placebo but had not received a previous TNF antagonist (naive to TNF antagonists) and 367 patients with an inadequate response, loss of response, or intolerance to TNF antagonists (failure of TNF antagonists). Predefined outcomes of GEMINI 1 were evaluated in these subpopulations. RESULTS: At Week 6, there were greater absolute differences in efficacy between vedolizumab and placebo in patients naive to TNF antagonists than patients with failure of TNF antagonists, although the risk ratios (RRs) for efficacy were similar for each group. Week 6 rates of response to vedolizumab and placebo were 53.1% and 26.3%, respectively, among patients naive to TNF antagonists (absolute difference, 26.4%; 95% confidence interval [CI], 12.4-40.4; RR, 2.0; 95% CI, 1.3-3.0); these rates were 39.0% and 20.6%, respectively, in patients with failure of TNF antagonists (absolute difference, 18.1%; 95% CI, 2.8-33.5; RR, 1.9; 95% CI, 1.1-3.2). During maintenance therapy, the absolute differences were similar but the RR for efficacy was higher for patients with failure of TNF antagonists than for patients naive to TNF antagonists, for most outcomes. Week 52 rates of remission with vedolizumab and placebo were 46.9% and 19.0%, respectively, in patients naive to TNF antagonists (absolute difference, 28.0%; 95% CI, 14.9-41.1; RR, 2.5; 95% CI, 1.5-4.0) and 36.1% and 5.3%, respectively, in patients with failure of TNF antagonists (absolute difference, 29.5%; 95% CI, 12.8-46.1; RR, 6.6; 95% CI, 1.7-26.5). No differences in adverse events were observed among groups. CONCLUSIONS: Vedolizumab demonstrated significantly greater efficacy as induction and maintenance therapy for UC than placebo in patients naive to TNF antagonists and patients with TNF antagonist failure. There were numerically greater treatment differences at Week 6 among patients receiving vedolizumab who were naive to TNF antagonists than patients with TNF antagonist failure. ClinicalTrials.gov no: NCT00783718.

Expert Stakeholders' Perspectives on How Cisgender Heterosexual Boys and Young Men Navigate Sex and Intimacy in Australia: A Case for "Heterosexual Intimacies" in Policy and Practice.

Introduction: Cisgender heterosexual boys and young men in Australia may experience or perpetuate a range of harms in their romantic and sexual encounters with women due to expectations that they adhere to problematic ideals and norms concerning masculinity and heterosexuality. This paper explores expert stakeholders' perceptions on these key issues, and their broader implications for policy and practice. Methods: Using inductive thematic analysis techniques, this paper draws on semi-structured interviews from 23 expert stakeholders working across sectors of gendered violence prevention, sexual health, relationships and sexuality education, sport, and emotional and physical wellbeing. Results: Findings note several key concerns, including (1) hesitation and lack of adequate information regarding relationships with women; (2) the potential negative influence of pornography; (3) the lack of opportunities to be engaged in sexual health promotion initiatives; and (4) limited opportunities to have meaningful conversations about dating, sex, and intimacy. Conclusions: Expert stakeholders note several important gaps in policy and practice that need to be addressed to better support cisgender heterosexual boys and young men, and to confront gendered violence and sexual violence. Social and Policy Implications: Understanding these gaps is vital for policymakers, content and program creators, and service providers working with cisgender heterosexual boys and men. We advocate for thinking about a strategy that is centred around "heterosexual intimacies", in which addressing boys and young men's sexual health and wellbeing is brought together with gendered violence prevention and sexual violence prevention initiatives.

ECHO (Extension for Community Healthcare Outcomes) Autism STAT: A Diagnostic Accuracy Study of Community-Based Primary Care Diagnosis of Autism Spectrum Disorder.

OBJECTIVE: Children can be reliably diagnosed with autism spectrum disorder (ASD) by a highly trained clinician as early as 12 to 24 months of age, but recent estimates indicate that the average age of diagnosis is 4.4 years. We hypothesized that trained primary care physicians and practitioners can reliably and accurately diagnose children 14 to 48 months with unambiguous symptoms of ASD. METHODS: Through this diagnostic accuracy study, 20 patients diagnosed with ASD by clinicians trained through the ECHO (Extension for Community Healthcare Outcomes) Autism STAT program participated in an independent gold-standard evaluation at a regional autism center. Caregiver perceptions of the diagnostic process were also assessed. RESULTS: Of the 20 patients who received a diagnosis of ASD by a trained clinician and completed the study, 19 diagnoses were confirmed by a gold-standard evaluation. Caregivers indicated that undergoing diagnosis in their local community rather than an autism specialty center was helpful (4.8/5 on a 5-point Likert scale, n = 19). Results of this study demonstrate that primary care clinicians can be trained to reliably diagnose ASD in children 14 to 48 months with unambiguous symptoms. CONCLUSION: Diagnosis in the primary care setting may lead to earlier diagnosis and quicker connection to evidence-based therapies and interventions. Given the potential impact of increasing access to high-quality diagnostic services, the role of primary care clinicians in the diagnosis of ASD should be further evaluated.

Nintedanib in Patients With Autoimmune Disease-Related Progressive Fibrosing Interstitial Lung Diseases: Subgroup Analysis of the INBUILD Trial.

OBJECTIVE: To analyze the efficacy and safety of nintedanib in patients with fibrosing autoimmune disease-related interstitial lung diseases (ILDs) with a progressive phenotype. METHODS: The INBUILD trial enrolled patients with a fibrosing ILD other than idiopathic pulmonary fibrosis, with diffuse fibrosing lung disease of >10% extent on high-resolution computed tomography, forced vital capacity percent predicted (FVC%) ≥45%, and diffusing capacity of the lungs for carbon monoxide percent predicted ≥30% to <80%. Patients fulfilled protocol-defined criteria for progression of ILD within the 24 months before screening, despite management deemed appropriate in clinical practice. Subjects were randomized to receive nintedanib or placebo. We assessed the rate of decline in FVC (ml/year) and adverse events (AEs) over 52 weeks in the subgroup with autoimmune disease-related ILDs. RESULTS: Among 170 patients with autoimmune disease-related ILDs, the rate of decline in FVC over 52 weeks was -75.9 ml/year with nintedanib versus -178.6 ml/year with placebo (difference 102.7 ml/year [95% confidence interval 23.2, 182.2]; nominal P = 0.012). No heterogeneity was detected in the effect of nintedanib versus placebo across subgroups based on ILD diagnosis (P = 0.91). The most frequent AE was diarrhea, reported in 63.4% and 27.3% of subjects in the nintedanib and placebo groups, respectively. AEs led to permanent discontinuation of trial drug in 17.1% and 10.2% of subjects in the nintedanib and placebo groups, respectively. CONCLUSION: In the INBUILD trial, nintedanib slowed the rate of decline in FVC in patients with progressive fibrosing autoimmune disease-related ILDs, with AEs that were manageable for most patients.

Conceptualising the continuum of female genital fashioning practices.

Genital fashioning practices, such as Brazilian waxing and female genital cosmetic surgery, have become increasingly prevalent within contemporary western societies. This paper explores the role of genital fashioning in the construction of contemporary femininity. It uses in-depth interviews and focus groups with Australian women aged 18-30 to investigate female genitalia as a site of alteration. Drawing on broader understandings of the body as socially mediated, this paper contends that multiple modification practices are employed to produce genital appearance. It departs from previous investigations which consider genital fashioning practices in isolation. In identifying the scope of genital fashioning, this research reveals a continuum of genital fashioning practices, both physically and discursively mobilised by women to negotiate their identity, sexuality, and femininity.

Sustained Clinical Remission With Vedolizumab in Patients With Moderate-to-Severe Ulcerative Colitis.

BACKGROUND: Sustaining clinical remission is an important treatment goal in moderate-to-severe UC. This post hoc exploratory analysis assessed the long-term efficacy of vedolizumab in the subset of patients with UC in the GEMINI 1 study who were in clinical remission by week 14 after 3 induction doses, administered at weeks 0, 2, and 6. METHODS: Sustained clinical remission (primary endpoint) was evaluated using 2 definitions: (1) a partial Mayo Score (pMS) of ≤2 with no subscore >1 and (2) a rectal bleeding subscore (RBS) of 0 throughout weeks 14, 26, 38, and 52. RESULTS: The proportion of patients in clinical remission at week 14 was significantly higher in patients receiving vedolizumab (n = 620) compared with placebo (n = 149) (pMS: 32.7% vs 20.1% [percentage-point difference (∆) 12.6%; 95% confidence interval [CI], 5.2-20.0]; RBS: 47.3% vs 28.9% [∆18.4%; 95% CI, 10.1-26.7]). Of patients in clinical remission at week 14, a significantly higher proportion of vedolizumab-treated patients achieved sustained clinical remission compared with placebo (pMS: 66.5% vs 26.7%; ∆39.8%; 95% CI, 22.7-56.9; RBS: 56.7% vs 20.9%; ∆35.7%; 95% CI, 22.3-49.1). Findings were consistent in tumor necrosis factor (TNF) antagonist-naive and antagonist-failure patients. CONCLUSION: Compared with placebo, 35%-40% more patients receiving a full induction course of vedolizumab had sustained clinical remission after 52 weeks of therapy. This result was observed irrespective of TNF antagonist treatment history. Clinical remission at week 14 may therefore be a predictor for sustained clinical remission with vedolizumab.

Efficacy and Safety of Vedolizumab in Ulcerative Colitis and Crohn's Disease Patients Stratified by Age.

INTRODUCTION: The efficacy and safety of vedolizumab, a gut-selective α4ß7 integrin antibody, were demonstrated in the GEMINI 1 and GEMINI 2 clinical trials of adults aged 18-80 years. We investigated the efficacy and safety of vedolizumab in patients stratified by age from the GEMINI trials. METHODS: Safety and efficacy, including clinical response, clinical remission, and corticosteroid-free remission, at week 6 and/or 52 were determined post hoc in patients aged <35, 35 to <55, and ≥55 years. RESULTS: At baseline, 353, 412, and 130 ulcerative colitis (UC) and 582, 443, and 90 Crohn's disease (CD) patients were aged <35, 35 to <55, and ≥55. Of these patients, 56 were aged ≥65 years (UC: 33, CD: 23). Trends favoring vedolizumab over placebo were observed for most efficacy endpoints irrespective of patient age; some variability between subgroups was observed. Safety profiles of vedolizumab and placebo were similar in all age groups. Vedolizumab-treated patients aged ≥55 had the lowest incidence of serious infections (0.9 per 100 person-years) and adverse events leading to hospitalization (14.8 per 100 person-years). There were no age-related differences in the incidence of adverse hematological events, malignancy, or death. CONCLUSIONS: The safety and efficacy of vedolizumab in patients with UC or CD were similar for all age groups. The number of patients in the oldest age group in these analyses was small; thus further studies of vedolizumab in larger cohorts of elderly patients are warranted. FUNDING: Millennium Pharmaceuticals, Inc. (d/b/a Takeda Pharmaceuticals International Co.).

Vedolizumab as Induction and Maintenance Therapy for Crohn's Disease in Patients Naïve to or Who Have Failed Tumor Necrosis Factor Antagonist Therapy.

BACKGROUND: Vedolizumab is a gut-selective α4ß7 integrin antagonist for the treatment of moderately to severely active Crohn's disease (CD). Aims of this study were to characterize the efficacy and safety of vedolizumab induction and maintenance therapy in patients who were naïve to tumor necrosis factor-alpha (TNF-α) antagonist therapy (TNF-naïve) or who had discontinued TNF-α antagonist therapy because of inadequate response (i.e., primary nonresponse), loss of response, or intolerance (collectively classified as the TNF-failure population). METHODS: Post hoc analyses of the efficacy data for 516 TNF-naïve and 960 TNF-failure patients from the GEMINI 2 and GEMINI 3 trials were evaluated at weeks 6, 10, and 52 and included clinical remission (CD Activity Index [CDAI] score ≤150), enhanced clinical response (≥100-point decrease from baseline in CDAI score), durable clinical remission (remission at ≥80% of visits), and corticosteroid-free remission. Adverse events were summarized for the TNF-naïve and TNF-failure subgroups by treatment received. RESULTS: Among patients who responded to vedolizumab induction at week 6, 48.9% of TNF-naïve and 27.7% of TNF-failure patients were in remission with vedolizumab at week 52 (versus 26.8% and 12.8% with placebo). Clinical efficacy was similar between the different types of TNF-α antagonist failure or the number of prior TNF-α antagonists failed. Safety profiles were similar in both subpopulations. CONCLUSIONS: Vedolizumab had increased efficacy over placebo in CD patients irrespective of TNF-α antagonist treatment history. Overall, rates of response and remission were numerically higher in patients receiving vedolizumab as a first biologic than in patients who had experienced TNF failure.

The Cost of Transplant Immunosuppressant Therapy: Is This Sustainable?

A solid organ transplant is life-saving therapy that engenders the use of immunosuppressive medications for the lifetime of the transplanted organ and its recipient. Conventional therapy includes both induction therapy (a biologic that is infused peri-operatively) followed by maintenance therapy. The cost of these medications is a constant concern and the advent of generics has brought this cost down modestly. For those lacking long term insurance coverage, this may be a significant out of pocket expense that is not affordable. Moreover, transplant Centers are managing higher risk transplant recipients that require more complex induction regimens and longer term use of such biologic agents in the context of desensitization or abrogation of de novo antibody mediated injury. While in kidney transplantation, Medicare part B covers three years of medication, there is frequent non-adherence due to cost after that time-point. The impact of the Affordable Care Act remains uncertain at this time. Finally the pipeline of new therapies is limited due to the cost of development of a drug, the inherent cost of clinical studies, and lack of defined endpoints for newer therapies in high risk patients. These new therapies are of high value to the community but will contribute additional burden to current drug costs.

Notch signaling functions in retinal pericyte survival.

PURPOSE: Pericytes, the vascular cells that constitute the outer layer of capillaries, have been shown to have a crucial role in vascular development and stability. Loss of pericytes precedes endothelial cell dysfunction and vascular degeneration in small-vessel diseases, including diabetic retinopathy. Despite their clinical relevance, the cellular pathways controlling survival of retinal pericytes remain largely uncharacterized. Therefore, we investigated the role of Notch signaling, a master regulator of cell fate decisions, in retinal pericyte survival. METHODS: A coculture system of ligand-dependent Notch signaling was developed using primary cultured retinal pericytes and a mesenchymal cell line derived from an inducible mouse model expressing the Delta-like 1 Notch ligand. This model was used to examine the effect of Notch activity on pericyte survival using quantitative PCR (qPCR) and a light-induced cell death assay. The effect of Notch gain- and loss-of-function was analyzed in monocultures of retinal pericytes using antibody arrays to interrogate the expression of apoptosis-related proteins. RESULTS: Primary cultured retinal pericytes differentially expressed key molecules of the Notch pathway and displayed strong expression of canonical Notch/RBPJK (recombination signal-binding protein 1 for J-kappa) downstream targets. A gene expression screen using gain- and loss-of-function approaches identified genes relevant to cell survival as downstream targets of Notch activity in retinal pericytes. Ligand-mediated Notch activity protected retinal pericytes from light-induced cell death. CONCLUSIONS: Our results have identified signature genes downstream of Notch activity in retinal pericytes and suggest that tight regulation of Notch signaling is crucial for pericyte survival.

Inhalation of 7.5% carbon dioxide increases threat processing in humans.

Inhalation of 7.5% CO(2) increases anxiety and autonomic arousal in humans, and elicits fear behavior in animals. However, it is not known whether CO(2) challenge in humans induces dysfunction in neurocognitive processes that characterize generalized anxiety, notably selective attention to environmental threat. Healthy volunteers completed an emotional antisaccade task in which they looked toward or away from (inhibited) negative and neutral stimuli during inhalation of 7.5% CO(2) and air. CO(2) inhalation increased anxiety, autonomic arousal, and erroneous eye movements toward threat on antisaccade trials. Autonomic response to CO(2) correlated with hypervigilance to threat (speed to initiate prosaccades) and reduced threat inhibition (increased orienting toward and slower orienting away from threat on antisaccade trials) independent of change in mood. Findings extend evidence that CO(2) triggers fear behavior in animals via direct innervation of a distributed fear network that mobilizes the detection of and allocation of processing resources toward environmental threat in humans.