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Summary T cells participate directly in the body's immune response to cancer, allowing immunotherapy treatments to effectively recognize and target cancer cells. We previously developed DeepCAT to demonstrate that T cells serve as a biomarker of immune response in cancer patients and can be utilized as a diagnostic tool to differentiate healthy and cancer patient samples. However, DeepCAT’s reliance on tumor bulk RNA-seq samples as training data limited its further performance improvement. Here, we benchmarked a new approach, AutoCAT, to predict tumor-associated TCRs from targeted TCR-seq data as a new form of input for DeepCAT, and observed the same level of predictive accuracy. Availability and implementation Source code is freely available at https://github.com/cew88/AutoCAT, and data is available at 10.5281/zenodo.5176884. Supplementary information Supplementary data are available at Bioinformatics online.

Dopamine D2/3 receptor agonists are less likely to trigger dyskinesias than L-dopa while still offering relief from the motor symptoms of Parkinson's disease (PD). However, these drugs can cause serious impulse control problems and gambling disorders. Adjunctive therapies capable of blocking these side effects without impacting the antiparkinsonian effect would be clinically useful. G-protein-coupled receptor 52 (GPR52) is an orphan Gs-protein-coupled receptor that is coexpressed with striatal D₂ receptors. Activating GPR52 attenuates behaviors associated with increased striatal dopamine release without altering basal function. Iatrogenic gambling disorder may be mediated, at least partly, by striatal dopamine signaling. We therefore investigated whether 2 potent small-molecule GPR52 agonists (BD442618, BD502657) could block the increase in preference for uncertain outcomes caused by acute d-amphetamine and chronic ropinirole, without altering baseline choice patterns. In the rat betting task (rBT), subjects choose between a guaranteed reward (the "wager") versus the 50:50 chance of double the wager or nothing. Although wager size varies across trial blocks, both options are constantly matched for expected value. The effects of BD442618 on the rBT were acutely assessed alone or in combination with d-amphetamine and subsequently in combination with chronic ropinirole. The latter experiment was then repeated with BD502657. BD442618 did not alter baseline decision making but attenuated the increase in preference for uncertainty caused by both acute amphetamine and chronic ropinirole administration. Similarly, BD502657 abrogated chronic ropinirole's effects. These data provide the first evidence that GPR52 agonists may be useful in treating iatrogenic gambling disorder or other conditions hallmarked by hyperdopaminergic states. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Background The integration of behavioral economics (BE) principles and electronic health records (EHRs) using clinical decision support (CDS) tools is a novel approach to improving health outcomes. Meanwhile, the American Geriatrics Society has created the Choosing Wisely (CW) initiative to promote less aggressive glycemic targets and reduction in pharmacologic therapy in older adults with type 2 diabetes mellitus. To date, few studies have shown the effectiveness of combined BE and EHR approaches for managing chronic conditions, and none have addressed guideline-driven deprescribing specifically in type 2 diabetes. We previously conducted a pilot study aimed at promoting appropriate CW guideline adherence using BE nudges and EHRs embedded within CDS tools at 5 clinics within the New York University Langone Health (NYULH) system. The BE-EHR module intervention was tested for usability, adoption, and early effectiveness. Preliminary results suggested a modest improvement of 5.1% in CW compliance. Objective This paper presents the protocol for a study that will investigate the effectiveness of a BE-EHR module intervention that leverages BE nudges with EHR technology and CDS tools to reduce overtreatment of type 2 diabetes in adults aged 76 years and older, per the CW guideline. Methods A pragmatic, investigator-blind, cluster randomized controlled trial was designed to evaluate the BE-EHR module. A total of 66 NYULH clinics will be randomized 1:1 to receive for 18 months either (1) a 6-component BE-EHR module intervention + standard care within the NYULH EHR, or (2) standard care only. The intervention will be administered to clinicians during any patient encounter (eg, in person, telemedicine, medication refill, etc). The primary outcome will be patient-level CW compliance. Secondary outcomes will measure the frequency of intervention component firings within the NYULH EHR, and provider utilization and interaction with the BE-EHR module components. Results Study recruitment commenced on December 7, 2020, with the activation of all 6 BE-EHR components in the NYULH EHR. Conclusions This study will test the effectiveness of a previously developed, iteratively refined, user-tested, and pilot-tested BE-EHR module aimed at providing appropriate diabetes care to elderly adults, compared to usual care via a cluster randomized controlled trial. This innovative research will be the first pragmatic randomized controlled trial to use BE principles embedded within the EHR and delivered using CDS tools to specifically promote CW guideline adherence in type 2 diabetes. The study will also collect valuable information on clinician workflow and interaction with the BE-EHR module, guiding future research in optimizing the timely delivery of BE nudges within CDS tools. This work will address the effectiveness of BE-inspired interventions in diabetes and chronic disease management. Trial Registration ClinicalTrials.gov NCT04181307; https://clinicaltrials.gov/ct2/show/NCT04181307 International Registered Report Identifier (IRRID) DERR1-10.2196/28723

Background This study draws on qualitative insights on the barriers and facilitators to HIV testing, as well as perceptions of HIV self-testing (HIVST), to propose a framework to understand the benefits, but also potential knock-on implications of introducing HIVST in the context of other STI testing. Methods We conducted semi-structured, in-depth interviews with 30 gay, bisexual and other men who have sex with men (GBMSM) aged 18 and 39 years old in Singapore. Interview topics included barriers and facilitators to HIV and other STI testing, as well as perceptions of HIVST. Interviews were audio-recorded, transcribed, coded, and analysed using thematic analysis. Results For HIV testing, participants cited the perceived risk of acquiring, susceptibility to, and symptoms of HIV as internal motivators, while social influence and accessibility of HIV testing services were external motivators. For STI testing, perceived symptoms and partner notification of STI were reported as an internal and external motivator, respectively. Availability of bundle tests, starting a new relationship, and instances of mandatory testing motivated both simultaneous HIV and other STI testing. The fear of a positive diagnosis and lack of confidentiality were cited as internal and external barriers to HIV testing, respectively, while low perceived severity of other STI and the cost of STI tests were cited as internal and external barriers to other STI testing, respectively. We identified pathways to HIV and other STI testing and discussed how the introduction of HIVST may reduce opportunities for other STI testing. Conclusions The findings of this study suggest that introducing HIVST might weaken linkages to other STI testing if alternative strategies of promoting other STI testing are not simultaneously implemented. We recommend that future interventions address both the risks of HIV and other STI simultaneously, and that structural interventions promoting HIV and other STI prevention be balanced accordingly.

not available.

Nurse preceptors play an important role in supporting newly qualified nurses during transition periods. However, limited attention is given to the needs and experience of nurse preceptors with expected responsibilities. This study aimed to examine the perceived needs of nurse preceptors in three public acute hospitals by using a sequential mixed method approach conducted between March and August 2017. A questionnaire that comprised socio-demographic data, Clinical Teaching Behaviour Inventory (CTBI), and RN Preceptor Learning Needs Assessment, was distributed to all nurse preceptors. Semi-structured qualitative interviews were conducted with a purposive sample of 10 informants to complement the quantitative findings. We received 260 completed questionnaires, giving a response rate of 78.8%. The highest mean CTBI domain score was “Using appropriate teaching strategies” (Mean = 3.65, SD = 0.56), whereas the lowest was “Providing feedback and evaluation” (Mean = 3.51, SD = 0.60). The top five topics identified as the most important in nurse preceptor training were critical thinking, prioritising, teaching techniques, conflict management and teamwork. Qualitative findings revealed that the informants experienced tension with their dual roles and strained relationships with co-workers. The expectations of the informants for support were recognition from management level and highlighting coaching tactics, reciprocal learning and collegiate support.

Immune checkpoint blockers (ICBs) have failed in all phase III glioblastoma (GBM) trials. Here, we show that regulatory T (Treg) cells play a key role in GBM resistance to ICBs in experimental gliomas. Targeting glucocorticoid-induced TNFR-related receptor (GITR) in Treg cells using an agonistic antibody (αGITR) promotes CD4 Treg cell differentiation into CD4 effector T cells, alleviates Treg cell-mediated suppression of anti-tumor immune response, and induces potent anti-tumor effector cells in GBM. The reprogrammed GBM-infiltrating Treg cells express genes associated with a Th1 response signature, produce IFNγ, and acquire cytotoxic activity against GBM tumor cells while losing their suppressive function. αGITR and αPD1 antibodies increase survival benefit in three experimental GBM models, with a fraction of cohorts exhibiting complete tumor eradication and immune memory upon tumor re-challenge. Moreover, αGITR and αPD1 synergize with the standard of care treatment for newly-diagnosed GBM, enhancing the cure rates in these GBM models.

Background Suboptimal uptake of HIV testing remains a primary bottleneck to HIV prevention and treatment for men who have sex with men (MSM) and transgender women (TGW) in Thailand. The World Health Organization has recommended HIV self-testing (HIVST) as an additional strategic HIV service. However, HIVST has not been fully endorsed and implemented in many countries in Southeast Asia. The aim of this study was to assess the uptake of oral fluid-based HIVST in MSM and TGW populations in Thailand. Methods During 2017 and 2018, we conducted a cross-sectional study using convenience sampling to enroll 2,524 participants from three major urban areas. Participants were recruited during outreach and online activities and were offered unassisted or assisted HIVST, or referral to HIV testing services. A descriptive analysis was performed for summarizing data. Results A total of 2,502 participants (1,422 MSM and 1,082 TGW) were included in the analysis with about one-third (36.1%) of them being first-time testers. Among all participants enrolled in the study, a total of 2,486 participants (99.3%) selected HIVST versus referral to HIV testing services. Of those who selected HIVST, 2,095 (84.3%) opted for assisted HIVST while the rest opted for unassisted HIVST: 1,148 of 1,411 MSM (81.4%) and 947 of 1,075 TGW (88.1%) selected assisted HIVST. While no serious adverse events were reported during the study, we found that among 179 participants who needed a confirmatory test and were referred to HIV testing services, 108 (60.3.4%) accessed these later services. Conclusions This study demonstrated a high uptake of oral fluid-based HIVST among MSM and TGW populations in Thailand and that HIVST could be scaled up through the national epidemic control program. However, a better understanding of HIV testing-seeking behavior and innovative follow-up solutions are needed to improve and monitor linkages to services for people who undertake HIVST.

Our objective was to assess the quality of acne-related medical information present on TikTok, the world's fastest growing social media platform. We queried the TikTok mobile application for videos tagged with "#acne" on May 1, 2020, and assessed the top 100 videos meeting inclusion criteria for content quality using DISCERN, a validated and reliable instrument for evaluating consumer health information. The mean content quality rating of videos was 2.03 (SD 0.47) which, according to the DISCERN instrument, indicates information with serious to potentially important shortcomings. Dermatologists should be aware that adolescents are using TikTok to gather acne-related information, and should prioritize acne education in this patient demographic due to the generally low content quality of such information.

Background Suicide risk screening is recommended in pediatric care. To date, no previous studies illustrate the implementation of suicide risk screening in pediatric subspecialty care, even though chronic medical conditions are associated with a higher risk of suicide. Methods A large multidivision pediatric ambulatory clinic implemented annual suicide risk screening. Patients ages 9-21 years participated in suicide risk screening using the Ask Suicide-Screening Questions during the project. A multidisciplinary team employed quality improvement methods and survey-research design methods to evaluate the feasibility and acceptability of the screening process for patients, families, and medical providers. Results During the quality improvement project period, 1,934 patients were offered screening; 1,301 (67.3%) patients completed screening; 82 patients (6.3% of 1,301 patients) screened positive. The monthly compliance rate held steady at 86% following several Plan-Do-Study-Act cycles of improvement. The survey results demonstrate that providers rated the suicide risk screening process positively; however, a subset of providers indicated that the screening process was out of their scope of practice or impeded their workflow. Conclusions Suicide risk screening is feasible in pediatric specialty care and can identify at-risk patients. Continued efforts are needed to standardize suicide risk screening practices. Future directions include identifying factors associated with suicide risk in patients in pediatric subspecialty care settings.

ObjectivesThis study draws on qualitative insights on the barriers and facilitators to HIV testing, as well as perceptions of HIV self-testing (HIVST), to propose a framework to understand not only the benefits but also potential knock-on implications of introducing HIVST in the context of other STI testing.MethodsWe conducted semistructured, in-depth interviews with 30 gay, bisexual and other men who have sex with men aged 18 and 39 years old in Singapore. Interview topics included barriers and facilitators to HIV and other STI testing, as well as perceptions of HIVST. Interviews were audio-recorded, transcribed, coded and analysed using thematic analysis.ResultsFor HIV testing, participants cited the perceived risk of acquiring, susceptibility to and symptoms of HIV as internal motivators, while social influence and accessibility of HIV testing services were external motivators. For STI testing, perceived symptoms and partner notification of STI were reported as internal and external motivators, respectively. Availability of bundle tests, starting a new relationship and instances of mandatory testing motivated both simultaneous HIV and other STI testing. The fear of a positive diagnosis and lack of confidentiality were cited as internal and external barriers to HIV testing, respectively, while low perceived severity of other STI and the cost of STI tests were cited as internal and external barriers to other STI testing, respectively. We identified pathways to HIV and other STI testing and discussed how the introduction of HIVST may reduce opportunities for other STI testing.ConclusionsThe findings of this study suggest that introducing HIVST might weaken linkages to other STI testing if alternative strategies of promoting other STI testing are not simultaneously implemented. We recommend that future interventions address both the risks of HIV and other STI simultaneously, and that structural interventions promoting HIV and other STI preventions be balanced accordingly.

BACKGROUND: Intensive glycemic control is of unclear benefit and carries increased risk for older adults with diabetes. The American Geriatrics Society’s (AGS) Choosing Wisely (CW) guideline promotes less aggressive glycemic targets and reduction in pharmacologic therapy for older adults with type II diabetes. Meanwhile, behavioral economic (BE) approaches offer promise in influencing hard-to-change behavior, and previous studies have shown the benefits of using electronic health record (EHR) technology to encourage guideline adherence. OBJECTIVE: This study aimed to develop and pilot test an intervention that leverages BE with EHR technology to promote appropriate diabetes management in older adults. DESIGN: A pilot study within the New York University Langone Health (NYULH) EHR and Epic system to deliver BE-inspired nudges at five NYULH clinics at varying time points from July 12, 2018, through October 31, 2019. PARTICIPANTS: Clinicians across five practices in the NYULH system whose patients were older adults (age 76 and older) with type II diabetes. INTERVENTIONS: A BE-EHR module comprising six nudges was developed through a series of design workshops, interviews, user-testing sessions, and clinic visits. BE principles utilized in the nudges include framing, social norming, accountable justification, defaults, affirmation, and gamification. MAIN MEASURES: Patient-level CW compliance. KEY RESULTS: CW compliance increased 5.1% from a 16-week interval at baseline to a 16-week interval post intervention. From February 14 to June 5, 2018 (prior to the first nudge launch in Vanguard clinics), CW compliance for 1278 patients was mean (95% CI)—16.1% (14.1%, 18.1%). From July 3 to October 22, 2019 (after BE-EHR module launch at all five clinics), CW compliance for 680 patients was 21.2% (18.1%, 24.3%). CONCLUSIONS: The BE-EHR module shows promise for promoting the AGS CW guideline and improving diabetes management in older adults. A randomized controlled trial will commence to test the effectiveness of the intervention across 66 NYULH clinics. NIH TRIAL REGISTRY NUMBER: NCT03409523 ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s11606-020-06119-z) contains supplementary material, which is available to authorized users.

A 54-year-old man with a past medical history of paraplegia, osteomyelitis, sacral decubitus ulcer, suprapubic catheter, and several reported drug eruptions was seen for evaluation of skin sloughing without any tenderness to palpation. He reported being on chronic oral antibiotics including amoxicillin/clavulanic acid and ciprofloxacin over the past two years for osteomyelitis. Two days prior to evaluation, he had been hospitalized for osteomyelitis of the left iliac bone and was treated with intravenous vancomycin and meropenem. Initial evaluation revealed widespread Nikolsky sign with extensive involvement of the back, abdomen, and extremities without any tenderness. Involving 30-40% body surface area were scattered deep red macules and patches. The histopathologic findings were consistent with the diagnosis of acute generalized exanthematous pustulosis (AGEP). Clinically, AGEP appears as diffuse erythema with several small, non-follicular pustules and possible peripheral neutrophilia or eosinophilia. A positive Nikolksy sign can be seen with AGEP, but is not specific, and has been referred to as a ‘pseudo-Nikolsky sign.’ Systemic involvement, such as renal insufficiency, has been reported in AGEP. There are few reports in the literature describing AGEP with TEN-like features. We present an interesting patient with AGEP and TEN-like features who improved after cessation of vancomycin and meropenem and a short course of systemic steroids.

Introduction: Cigarette smoking is associated with increased cerebrovascular disease risk and reduced cognitive performance, particularly in domains sensitive to vascular insults, such as executive function and processing speed. Short-term blood pressure variability (BPV) is associated with cognitive decline among older adults with and without hypertension (HTN) and BPV is significantly greater among smokers than non-smokers. However, it is unknown if greater short-term BPV contributes to lower cognitive performance in smokers. We hypothesized that greater beat-to-beat BPV would be associated with lower cognitive performance in smokers and that this relation would be independent of mean blood pressure (BP). Methods: Twenty-three smokers (3 current/20 former; age 69 ± 9; pack-years 33 ± 17; systolic BP (SBP) 133 ± 18; diastolic BP (DBP) 71 ± 8; anti-HTN medication use 16Y/7N)), without chronic obstructive pulmonary disease, completed measurements of beat-to beat BPV by 10 minutes of finger plethysmography and electrocardiography, and neuropsychological testing. Age-adjusted neuropsychological test t-scores were grouped into four cognitive domains (executive function, processing speed, language and memory recall). Results: Greater systolic BPV was associated with lower cognitive performance in the executive function (r=-0.59, p Conclusion: These data suggest that greater beat-to-beat BP variability may contribute to lower cognitive performance in smokers and that this relation is independent of mean SBP.

PrEP is effective in preventing HIV transmission among at-risk HIV-negative MSM. A qualitative descriptive study with five focus group discussions (N = 33) involving a purposively recruited sample of Singaporean MSM was conducted from August 2016 to April 2017 to understand local perspectives on potential barriers and motivators to the adoption of PrEP, prior to the implementation of PrEP services in Singapore. Knowledge of PrEP was high, and many viewed PrEP as an attractive alternative to condoms for HIV prevention. Concerns about PrEP included the cost of PrEP and related services, the frequency of PrEP-related clinic visits, fear of side effects, and the stigma associated with using PrEP. Participants felt PrEP was best provided by MSM-friendly providers, and more needed to be done to increase awareness of the effectiveness of PrEP. Access to PrEP for MSM in Singapore has to be affordable, patient-centered, and convenient to maximize the potential benefits of PrEP.

Upper respiratory tract infections (URTIs) account for substantial attendances at emergency departments (EDs). There is a need to elucidate determinants of antibiotic prescribing in time-strapped EDs – popular choices for primary care despite highly accessible primary care clinics. Semi-structured in-depth interviews were conducted with purposively sampled physicians (n = 9) in an adult ED in Singapore. All interviews were analysed using thematic analysis and further interpreted using the Social Ecological Model to explain prescribing determinants. Themes included: (1) reliance on clinical knowledge and judgement, (2) patient-related factors, (3) patient–physician relationship factors, (4) perceived practice norms, (5) policies and treatment guidelines and (6) patient education and awareness. The physicians relied strongly on their clinical knowledge and judgement in managing URTI cases and seldom interfered with their peers’ clinical decisions. Despite departmental norms of not prescribing antibiotics for URTIs, physicians would prescribe antibiotics when faced with uncertainty in patients’ diagnoses, treating immunocompromised or older patients with comorbidities, and for patients demanding antibiotics, especially under time constraints. Participants had a preference for antibiotic prescribing guidelines based on local epidemiology, but viewed hospital policies on prescribing as a hindrance to clinical judgement. Participants highlighted the need for more public education and awareness on the appropriate use of antibiotics and management of URTIs. Organisational practice norms strongly influenced antibiotic prescribing decisions by physicians, who can be swayed by time pressures and patient demands. Clinical decision support tools, hospital guidelines and patient education targeting at individual, interpersonal and community levels could reduce unnecessary antibiotic use.

Background: Despite improvements in outcome for patients treated with triplet and quadruplet based regimens, multiple myeloma is still a relapsing and ultimately fatal disease. We previously reported that targeting an investigational attenuated form of IFNα, or Attenukine™, to multiple myeloma (MM) tumor cells via direct fusion to an anti-CD38 antibody (TAK-573) has direct anti-proliferative activity on MM cancer cells in vitro and induces robust and durable responses in MM xenograft tumor models, alone and in combination with standard-of-care (SOC) agents. Here, we further elucidate the broad immunomodulatory impact and antitumor activity of a murine reactive version of TAK-573, anti-mouse CD38-attenuated murine IFNα (mCD38-mATT), alone and in combination with SOC agents in immunocompetent murine tumor models of MM. Methods: Murine CD38 receptor expression and direct sensitivity to murine IFNα (mIFNα) of 2 murine MM cell lines were characterized. Murine MM cell line-derived tumor models were established in immunocompetent mice and antitumor activity of mCD38-mATT treatment was evaluated alone and in combination with approved SOC agents for MM. Pharmacodynamic changes in the tumor immune microenvironment post-treatment were determined using multicolor flow cytometry. Results: Both MM murine tumor cell lines were insensitive to direct mIFNα treatment, indicating a reliance on immune-mediated antitumor activity when tested in vivo. Immunoprofiling analyses post-administration with single-agent mCD38-mATT indicated increased prevalence and activation of NK cells in peripheral blood and increased intratumoral CD8+ T: Treg and CD8+ T: CD4+ T cell ratios, compared to anti-mCD38 antibody or murine IFNα alone. Follow-on experiments evaluating single-agent mCD38-mATT indicated modest activity on tumor growth in vivo. Combination administration of mCD38-mATT with SOC agents had increased anti-tumor activity compared to either single-agent administration alone. Conclusion: Administration of mCD38-mATT induced broad immunomodulation and antitumor responses, alone and in combination with SOC agents in immunocompetent mouse models, highlighting the impact of this agent on CD38+ cells, both tumor and immune. These results support further investigation of combination therapies in the ongoing clinical evaluation of TAK-573 in a Phase 1 trial in patients with relapsed refractory MM. Citation Format: Tomoya Hara, Christina Wong, Jie Yu, Sabrina Collins, Haiqing Wang, Hiroshi Sugimoto, Hong Zhang, Pia Bjorck, Michael D. Curley. A murine reactive version of TAK-573 (anti-CD38 attenuated IFNα fusion protein) shows immunomodulatory and antitumor activity, alone and in combination with standard-of-care agents, in IFNa-insensitive, immunocompetent murine multiple myeloma tumor models [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5546.

Objectives The skin biopsy care process is prone to communication failures. We sought to solicit dermatopathologists about their opinions on the quality of clinical information provided in the requisition form (RF) that accompanies skin specimens and their suggestions on how to improve the process. Methods A self-administered survey of the membership of the American Society of Dermatopathology was performed. Qualitative methods were used to analyze free-text comments. Results Of 1,102 participants, 153 completed the final question in the survey (response rate 14%). Respondent opinions fell into four critical themes: (1) quality of clinical information in the RF and adequacy of biopsy specimens, (2) training of residents and nondermatologist providers, (3) information transfer via electronic medical records, and (4) practice constraints. Conclusions Dermatopathologists communicated that missing clinical information in the RF and inadequate specimens are common and adversely affect the quality of care. Multiple provider- and practice-related factors contribute to communication failures and deserve further investigation.

Summary Background & aims Parenteral nutrition (PN) provides nourishment and hydration as an intravenous infusion to patients with intestinal failure (IF). The aim of the study is to generate theory that explains the experiences of adult patients living with home parenteral nutrition (HPN) and complex medication regimens. Methods A grounded theory methodology was used to explore the experiences of twelve patients receiving HPN. A semi-structured interview was conducted and recorded in each participant's home setting. Each interview was transcribed verbatim. The simultaneous process of data collection and analysis was followed reflecting the principles of the constant comparative approach. Results A total of 15 patients gave written consent, with 12 of them agreeing to be interviewed. All the participants had previously undergone surgery as a result of chronic ill health or sudden illness. Analysis revealed two core categories: stoma and HPN, and these were supported by the subcategories: maintaining stoma output, access to toilets, managing dietary changes, maintaining the HPN infusion routine, access to technical help to set up an HPN infusion, mobility with HPN equipment and general health changes. The strategy of living with loss was demonstrated by all the participants, and this was supported by the action strategies of maintaining daily activities and social interactions. Conclusions This study generates new understanding and insight into the views and experiences of patients receiving HPN in the UK. The findings from these participants have been shown to resonate with the Kubler-Ross Model [1] of the five stages of grief. The theory of living with loss was generated by the use of a grounded theory methodology. This small scale exploratory study reveals opportunities for improvements in practice to be considered by the nutrition support team (NST) and other healthcare professionals involved in the patient's hospital stay prior to discharge on HPN.

Aim The aim of this review is to summarise the literature relating to patients’ experiences with home parenteral nutrition (HPN). Method This literature review is based on searches of CINAHL, PubMed, Web of Knowledge and Web of Science for articles published between 1970 and 2013. Additional studies were included from Department of Health publications, NICE clinical guidance, UK patient support group with interests in HPN or intestinal failure (IF). Results Patients with severe IF have been successfully treated with HPN since the 1970s. Early published studies evaluated clinical outcomes such as catheter-related infections, metabolic complications, thrombosis of the catheterised vein and liver impairment. Since the 1980s questionnaire studies were used to evaluate the quality of life (QoL) of patients treated with HPN. These early studies used QoL assessment tools which were not validated for patients treated with HPN. Internationally, there were published qualitative research studies which explored the experiences of patients treated with HPN. Conclusions The long-term outcome of patients treated with HPN continues to attract research interest. The review of the literature did not identify any published qualitative studies on the experiences of patients treated with HPN in the UK, suggesting a gap in the research. The UK National Health Service advocates a patient-centred approach for service design and delivery in primary and secondary care. This literature review has highlighted opportunities for qualitative research into the experiences of patients living with HPN to achieve better understanding and awareness of the rehabilitation of these patients.

Early attempts at using TNF superfamily members for anticancer therapies, TNF and FAS, led to serious systemic toxicities. However, the discovery of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) introduced an agonist capable of killing tumor cells via apoptosis without the side effects observed with TNF and FAS agonists. First generation TRAIL agonists included a recombinant version of human TRAIL (dulanermin), as well as multiple DR4 and DR5 agonist antibodies. Despite some isolated responders, the initial clinical results were poor. The first-generation TRAIL agonists were limited by poor pharmacokinetics (the half-life for dulanermin was between 30 and 60 minutes) or by poor agonist activity and the need for Fc-mediated cross linking. Here we present the development and evaluation of two second generation TRAIL agonists, MM-201a and MM-201b. Both versions are composed of an IgG1 Fc fused to a single chain TRAIL trimer (Fc-scTRAIL). Mutations within the TRAIL domains, selected from a random mutagenesis library, were introduced to improve stability, expression, and DR5 binding. MM-201a has 5 mutations in each monomeric unit (R130G/N228S/I247V/Y213W/S215D) and MM-201b has 3 mutations in each monomer (R130G/N228S/I247V). In a panel of 27 colorectal carcinoma and sarcoma cell lines, both versions of MM-201 were observed to be significantly more active than all comparators, including the TRAIL cytokine and both DR4 and DR5 antibodies. MM-201a had a level of activity similar to ABBV-621, a single chain TRAIL fused to the N-terminus of an IgG1 Fc that is currently the subject of a Phase 1 trial. However, MM-201b was significantly more active than both MM-201a and ABBV-621, with up to 11-fold lower IC50 across a panel of 12 CRC cell lines. MM-201b treatment reduced cell viability to less than 20% in 10 out 12 colorectal cancer cell lines and in 8 of these cell lines, this was achieved at concentrations less than 1 nM. MM-201 also induced complete cell death at 1 nM or less in 3 of 8 synovial sarcoma and chondrosarcoma cell lines tested. For example, MM-201b reduced the viability of the SW-982 synovial sarcoma cell line to 17% at a dose of 1.5 pM, which is nearly twice the reduction in viability from the same dose of ABBV-621. We next evaluated both versions of MM-201 in multiple colorectal cancer and sarcoma patient-derived xenograft (PDX) models. In the Ewing’s sarcoma PDX model TM01617, MM-201b treatment resulted in 90% tumor growth inhibition. In the same model, treatment with 10 mg/kg docetaxel resulted in 73% growth inhibition; however, in combination with MM-201a, the same dose resulted in a 100% complete response rate. Similar results were observed in the SK-UT1 uterine sarcoma xenograft. Based on this evidence, we believe that MM-201b is best in class and, when combined with an appropriate patient selection strategy, has significant potential for the treatment of sarcomas and colorectal cancer in patients. Citation Format: Andrew J. Sawyer, Sara Ghassemifar, Christina Wong, Jennifer Richards, Stephanie Grabow, James Suchy, Alexander Koshkaryev, Maja Razlog, Eric Tam, Daryl C. Drummond. Engineering and preclinical activity of MM-201, a best-in-class TRAIL receptor agonist [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2491.

Background Recruitment challenges and restrictions on intercourse frequency and timing have stymied previous attempts to implement true contraceptive efficacy clinical trials. Study Design Qualitative research was conducted in Madagascar, South Africa, and the United States to explore the acceptability of three potential true contraceptive efficacy study designs and the feasibility of recruitment for such trials, including characteristics of potential participants who may be willing to join. Results Participants preferred the study design with the least restrictive sex criteria: participants have sex with assigned contraceptive method/no method on days around ovulation and use condoms on other days. Participants suggested that condom adherence would be low. Differences were noted across sites on whether female participants should be actively seeking pregnancy or not actively seeking pregnancy but willing to accept a pregnancy. Recruitment of participants was expected to be difficult. Conclusions Data suggest that a true contraceptive efficacy clinical trial may not be feasible at this time in these settings.

Caleb Parker,1 Amy Corneli,1 Kawango Agot,2 Jacob Odhiambo,2 Jesse Asewe,2 Khatija Ahmed,3 Joseph Skhosana,3 Malebo Ratlhagana,3 Michele Lanham,1 Christina Wong,1 Jennifer Deese,1 Rachel Manongi,4 Lut Van Damme,1On behalf of the FEM-PrEP recruitment group 1FHI 360, Global Health, Population and Nutrition, Durham, NC, USA; 2Impact Research and Development Organization, Kisumu, Kenya; 3Setshaba Research Centre, Soshanguve, Pretoria, South Africa; 4Kilimanjaro Christian Medical Centre, Moshi, Tanzania Abstract: We implemented an empirically informed, geographically based recruitment approach for FEM-PrEP, a human immunodeficiency virus (HIV) prevention clinical trial of daily oral emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF) for HIV prevention. During the formative research phase, we conducted a modification of the Priorities for Local AIDS Control Efforts (PLACE) method and used those data and staff experiences to identify and prioritize for recruitment geographic areas where HIV incidence might be high. During the clinical trial, we implemented a routinely monitored and flexible recruitment plan in the geographical areas identified in the formative research. We describe three lessons learnt from implementing this approach: 1) the PLACE data were critical in identifying places presumed to be high risk; 2) staff experiences, in combination with PLACE data, were needed to inform a practical recruitment strategy; and 3) recruiting in establishments in priority areas identified by the PLACE data led to screening many HIV-positive women at the Bondo site (Kenya), placing additional burden on clinic staff. These lessons learnt highlight the critical importance of having a flexible and monitored recruitment strategy. Although we successfully recruited a study population at higher risk for HIV, FEM-PrEP was unable to determine the effectiveness of FTC/TDF for HIV prevention, due to low adherence to the study product among participants. We must shift the paradigm of recruitment for clinical trials of new products from focusing on identifying populations with high incidence to identifying populations at risk who are motivated and able to adhere to the study product regimen. Keywords: recruitment, PrEP, PLACE, FEM-PrEP, HIV prevention clinical trial, women

Background Patients with basal cell carcinoma (BCC) frequently develop further tumors during follow-up. Objective We sought to elucidate the relative effects of pattern of ultraviolet radiation exposure, and site and histologic type of the first tumor, on the rate of increase in BCC numbers. Methods We used negative binomial regression analysis to study the association of selected variables on the rate of increase in BCC numbers in 266 Caucasian patients who first presented with a tumor on the head/neck or trunk with nodular or superficial histology. Results Patients with an initial truncal BCC with superficial histology demonstrated significantly faster increases in BCC numbers than did patients with other site and histology combinations. Conclusions These data indicate that site and histology define subsets of patients with BCC.

While sunlight is critical in basal cell carcinoma (BCC) pathogenesis the relationship between exposure and tumor site and histology is unclear. We determined if tumor site (trunk or head/neck) or histology (nodular or superficial) is determined by exposure pattern. In 66 cases with truncal and 362 patients with head/neck BCC at first presentation, average hours exposure/year, intermittency score, childhood sunburning and skin type were not significantly associated with tumor site or histology. However, often sunbathing was associated with a five-fold increased risk of truncal BCC. Average sunbathing score was significantly greater in 22 cases with truncal compared with 325 cases with head/neck nodular tumors and also in 44 cases with superficial truncal compared with superficial head/neck BCC. Thus, sunbathing determined tumor site but not histology.

Brain metastases represent a devastating progression of luminal breast cancer. While targeted therapies are often effective systemically, they fail to adequately control brain metastases. In preclinical models that faithfully recapitulate the disparate clinical responses in these microenvironments, we observed that brain metastases evade PI3K inhibition despite efficient drug delivery. In comparison to extracranial disease, there is increased HER3 expression and phosphorylation in the brain lesions. HER3 blockade overcomes the resistance of both HER2-amplified and/or PIK3CA-mutant breast cancer brain metastases to PI3K inhibitors, leading to striking tumor growth delay and significant improvement of mouse survival. Collectively, these data provide a mechanistic basis underlying therapeutic resistance in the brain microenvironment and identify rapidly translatable treatment strategiesfor HER2-amplified and/or PIK3CA-mutant breast cancer brain metastases. Citation Format: Gino B. Ferraro, David P. Kodack, Vasileios Askoxylakis, Qing Sheng, Mark Badeaux, Shom Goel, Xiaolong Qi, Ram Shankaraiah, Alexander Z. Cao, Rakesh R. Ramjiawan, Divya Bezwada, Bhushankumar Patel, Youngchul Song, Carlotta Costa, Kamila Naxerova, Christina Wong, Jonas Kloepper, Rita Das, Angela Tam, Jantima Tanboon, Dan G. Duda, Ryan C. Miller, Marni B. Siegel, Carey K. Anders, Melinda Sanders, Valeria M. Estrada, Robert Schlegel, Carlos L. Arteaga, Elena Brachtel, Alan Huang, Dai Fukumura, Jeffrey A. Engelman, Rakesh K. Jain. The brain microenvironment mediates resistance in luminal breast cancer to PI3K inhibition through HER3 activation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5008. doi:10.1158/1538-7445.AM2017-5008

BACKGROUND FEM-PrEP was unable to demonstrate the effectiveness of oral emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) as pre-exposure prophylaxis for HIV prevention because of low adherence. We hypothesized that one reason for the poor adherence was low perceived HIV risk. METHODS At enrollment and at quarterly follow-up visits, we assessed participants' perceived HIV risk for the subsequent 4 weeks. We used logistic regression to assess factors associated with some (small, moderate, or high) perceived HIV risk. We also used logistic regression with robust variance estimation to assess the association between risk perceptions (none versus some) reported at enrollment and at weeks 12, 24, and 36 and good adherence based on drug concentrations of plasma tenofovir and intracellular tenofovir diphosphate in specimens collected 4 weeks later (at weeks 4, 16, 28, and 40) among 150 randomly selected participants assigned FTC/TDF. RESULTS Multiple factors were statistically associated with having some perceived risk, including having sex without a condom, having multiple partners, and not knowing if a partner has HIV. We observed a significant association between having some risk perception and good adherence (odds ratio: 2.0; 95% confidence interval: 1.1 to 3.5; P = 0.016). CONCLUSIONS Data suggest that participants are likely knowledgeable about factors that increase their HIV risk. Perceived risk seemed to have influenced some participants' decisions to adhere to the study pill within the context of a placebo-controlled clinical trial. Future research can explore the role of risk perception in the uptake of and adherence to pre-exposure prophylaxis, now that FTC/TDF has been shown efficacious.

Background Several clinical trials have demonstrated the safety and effectiveness of oral tenofovir disoproxil fumarate (TDF), with or without emtricitabine (FTC), as pre-exposure prophylaxis (PrEP) for reducing the risk of HIV acquisition. Adherence to the study product was insufficient to demonstrate the effectiveness of FTC/TDF in 2 PrEP clinical trials conducted among women (FEM-PrEP and the Vaginal and Oral Interventions to Control the Epidemic study), but further analyses of adherence in these studies may inform PrEP demonstration projects and future HIV prevention clinical trials. Methods We randomly selected a subcohort of 150 participants randomized to FTC/TDF in 3 FEM-PrEP sites (Bondo, Kenya; Bloemfontein, South Africa; and Pretoria, South Africa) to examine adherence levels over time and to assess factors associated with adherence, based on plasma tenofovir and intracellular tenofovir diphosphate drug concentrations in specimens collected at 4-week visit intervals. Results We observed drug concentrations consistent with good adherence in 28.5% of all visit intervals when drug was available to use, but only 12% of participants achieved good adherence throughout their study participation. In multivariate analysis, the Bloemfontein site [odds ratio (OR): 2.43; 95% confidence interval (CI): 1.32 to 4.48] and liking the pill color (OR: 2.93; 95% CI: 1.18 to 7.27) were positively associated with good adherence, whereas using oral contraceptive pills at enrollment was negatively associated with good adherence (OR: 0.37; 95% CI: 0.18 to 0.74). Conclusions Most participants did not regularly adhere to the study product throughout their trial participation, although a small minority did. Few factors associated with good adherence to the study product were identified in FEM-PrEP.

The use of qualitative methods in public health inquiry can be traced to some of the earliest civilizations, and has continued through the centuries. And although qualitative methods have not historically comprised the vanguard of public health research, they have gained increasing acceptance, particularly over the past four decades. Qualitative research is now commonly used and accepted within most fields of public health. In this entry we describe some of the common features of qualitative research, including a range of data collection techniques and approaches to data analysis. We then briefly discuss criteria for assessing the quality of qualitative research studies and their findings. Finally, we provide several examples of studies that employed qualitative methods in order to highlight their potential use in formative or evaluation research, or in primary or secondary data analysis. Keywords: Keywords: public health; qualitative methods; research methods

In 1996, a health promotion program began to increase condom use for oral sex among female brothel-based sex workers in Singapore. It was initiated based upon increasing evidence of HIV transmission through oral sex as well as increased oral sex among these workers and their clients. Condom use for oral sex increased from 42.2 percent in 1996 prior to the program to 91.7 percent in mid-2000, with a corresponding decline in pharyngeal gonorrhea from its peak of 10.7 percent to 3.6 percent (compared to no significant changes in the two-year period before intervention). A significant increase in oral condom use with decreased pharyngeal gonorrhea incidence was observed among sex workers where brothel educational interventions took place compared with matched controls without brothel interventions. This case study describes the application of a health promotion framework to effect behavior change. Major differences in the behavioral risk-education strategies and message contents between this program and our earlier program on condom use for vaginal sex also are highlighted.

Background As pre-exposure prophylaxis (PrEP) moves closer to availability in developing countries, practical considerations for implementation become important. We conducted a consultation with district-level community stakeholders experienced in HIV-prevention interventions with at-risk populations in Bondo and Rarieda, Kenya to generate locally grounded approaches to the future rollout of oral PrEP to four populations: fishermen, widows, female sex workers, and serodiscordant couples. Methods The 20 consultation participants represented the Ministry of Health, faith- and community-based organizations, health facilities, community groups, and nongovernmental organizations. Participants divided into breakout groups and followed a structured discussion guide asking them to identify barriers to implementing HIV-prevention interventions (including PrEP) with each population. Questions also solicited solutions for addressing these barriers, as well as other facilitators for PrEP implementation. In particular, questions focused on how to encourage people to screen for PrEP eligibility by having HIV and other blood tests and how to encourage compliance with ongoing HIV testing. Results The barriers and facilitators/solutions discussants provided were frequently population-specific, but there were also broad-level similarities across populations. Service delivery barriers to HIV-prevention interventions concerned the need for staff trained to address the needs of particular populations. Service delivery facilitators to provision of ongoing HIV testing consisted of offering testing options besides facility-based testing. Stigma was the main community-level barrier for all groups, whereas barriers at the level of target populations included mobility; lifestyle and life circumstances, especially cultural norms among fishermen and widows; and fears, lack of awareness, and misinformation. Proposed facilitators and strategies for addressing community- and population-level barriers included topic-specific education within the populations and community, involvement of partners and family members, mass HIV testing, and peer educators. Barriers to PrEP uptake included non-adherence to pill taking and missing clinic visits. For drug adherence, facilitators were counselling and involving family members. Discussants suggested that client reminders, e.g., home visits, were needed to encourage clients to keep their clinic appointments. Conclusions Strategies for encouraging eligibility screening and ongoing HIV testing will have local and population-specific aspects. Our results nonetheless apply to similar populations throughout sub-Saharan Africa and reach beyond oral PrEP to other ARV-based PrEP formulations.

We evaluated the impact of a behavioural intervention programme on condom use and gonorrhoea incidence among female brothel-based sex workers in Singapore. All 128 sex workers from one locality were assigned to an intervention group and 125 sex workers from another relatively comparable locality served as controls. The intervention programme concentrated on developing sex workers' condom negotiation skills, and on gathering support from peers, brothel keepers and health staff in promoting condom use. The three outcome measures are self-reported success in persuading clients to use condoms, refusal of sex without a condom, and cumulative gonorrhoea incidence as measured by the percentage of sex workers with a new occurrence of a positive culture in the 5 month period before and after the intervention. The intervention group showed a statistically greater improvement in negotiation skills as compared to the controls. Sex workers exposed to the intervention were almost twice as likely than controls to always refuse unprotected sex (adjusted rate ratio of 1.90,95% CI: 1.22-2.94). Cumulative gonorrhoea incidence declined considerably (77.1%) in the intervention group but only moderately (37.6%) in the control group.

Introduction NICE quality standards (2011) state palliative care drugs should be fully accessible 24/7. National drug shortages, insufficient local stockholdings and prescriptions for items not on the recommended palliative list can make this problematic especially out of hours (OOH). There is little research on referral patterns for accessing subcutaneous medicines OOH. Objectives Determine if subcutaneous palliative medicines are fully available OOH Investigate whether supplies vary between hospital and community pharmaciesUnderstand referral patterns to access medication Method A 12 month retrospective audit of GP OOH supplies from a hospital pharmacy with a prospective 4 week audit and carer survey in a large community pharmacy providing OOH supplies. Results Locally derived standards from commissioned service set at 100% (n = 68 in GP OOH/hospital, n = 21 in community pharmacy). 100% of core subcutaneous medicines were available 24/7. Use of midazolam, diamorphine and hyoscine butylbromide similar across both settings; however levomepromazine was more common in the community following a national shortage of haloperidol. See table 1. 29% of community pharmacy issues were for formulations not on the recommended palliative list. 80% (4/5) patient referrals were made to the community pharmacy; 20% (1/5) going to more than one pharmacy. Conclusion Subcutaneous palliative care drugs are fully available in the OOH setting however further research should be undertaken to assess referral patterns. Reference National Institute for Health and Care Excellence (NICE). Quality Standard 13 End of life care for adults. London: NICE; 2011

Background: Preexposure prophylaxis with antiretroviral drugs has been effective in the prevention of human immunodeficiency virus (HIV) infection in some trials but not in others. Methods In this randomized, double-blind, placebo-controlled trial, we assigned 2120 HIV-negative women in Kenya, South Africa, and Tanzania to receive either a combination of tenofovir disoproxil fumarate and emtricitabine (TDF-FTC) or placebo once daily. The primary objective was to assess the effectiveness of TDF-FTC in preventing HIV acquisition and to evaluate safety. Results: HIV infections occurred in 33 women in the TDF-FTC group (incidence rate, 4.7 per 100 person-years) and in 35 in the placebo group (incidence rate, 5.0 per 100 person-years), for an estimated hazard ratio in the TDF-FTC group of 0.94 (95% confidence interval, 0.59 to 1.52; P=0.81). The proportions of women with nausea, vomiting, or elevated alanine aminotransferase levels were significantly higher in the TDF-FTC group (P=0.04, P

Acquired immunodeficiency virus (AIDS) and sexually transmitted diseases (STD) control programs targeted at sex workers have focused on condom use. Reasons for non-condom use among female brothel-based sex workers in Singapore were found to be low self-efficacy, lack of condom negotiation skills, and barriers such as fear of annoying clients. Green's PRECEDE framework and Bandura's self-efficacy theory were applied to develop a project aimed at equipping sex workers with negotiation skills, overcoming barriers to condom use, and gathering support from brothel keepers and peers. The experimental group showed significant improvements in negotiation skills and outcome behavior of always refusing sex without a condom, that were supported by a decline in gonorrhea incidence. This article describes the application of behavior change and health education theories to achieve reduction in gonorrhea risk.

We present an infant with generalized palpable purpura, arthritis and fever, whose findings were atypical for classic childhood Henoch-Schonlein purpura (HSP). By describing the clinical symptoms and prognostic differences seen in infants versus school age children, we encourage physicians to be aware of infantile HSP in their differential diagnosis when they encounter a non-toxic infant with generalized purpura.

Cutaneous pseudolymphoma is not a specific disease but rather an inflammatory response to stimuli that result in a lymphomatous-appearing but benign accumulation of inflammatory cells. They can be classified as T cell, B cell or mixed, depending on the predominant cell type in the infiltrate. Although most cases are idiopathic, reported stimuli have included vaccinations. This article focuses on a case pseudolymphoma secondary to vaccination.

Introduction The customs of widow cleansing and widow inheritance are practiced in several communities throughout sub-Saharan Africa. In the Nyanza Province of Kenya, according to tradition, Luo widows are expected to engage in sexual intercourse with a “cleanser,” without the use of a condom, in order to remove the impurity ascribed to her after her husband's death. Luo couples, including widows, are also expected to engage in sex preceding specific agricultural activities, building homes, funerals, weddings, and other significant cultural and social events. Widows who are inherited for the purpose of fulfilling cultural obligation have a higher prevalence of HIV than those who remain un-inherited or are inherited for the purpose of companionship. Methods As part of a larger descriptive qualitative study to inform study procedures for FEM-PrEP, an HIV prevention pre-exposure prophylaxis clinical trial, we conducted 15 semi-structured interviews (SSIs) with widows, 15 SSIs with inheritors, and four focus group discussions with widows in the Bondo and Rarieda districts in Nyanza Province to explore the HIV risk context within widow cleansing and inheritance practices. Thematic qualitative analysis was used to analyze the data. Results The majority of widows reported in the demographic questionnaire being inherited, and most widows in the SSIs described participating in the cleansing ritual. We identified two main themes related to HIV prevention within the context of widow cleansing and inheritance: 1) widows must balance limiting their risk for HIV infection with meeting cultural expectations and ensuring that their livelihood needs are met, and 2) sexual abstinence undermines cultural expectations in widowhood while the use of condoms is deemed inappropriate in fulfilling culturally prescribed sexual rituals, and is often beyond the widow's ability to negotiate. Conclusions Women-controlled HIV prevention methods such as antiretroviral-based oral pre-exposure prophylaxis, vaginal gels, and vaginal rings are needed for HIV-negative widows who engage in sexual rituals related to widowhood.