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There is growing clinical interest in addressing relationship dynamics between service-users and their voices. The Talking With Voices (TwV) trial aimed to establish feasibility and acceptability of a novel dialogical intervention to reduce distress associated with voices amongst adults diagnosed with schizophrenia spectrum disorders. The single-site, single-blind (rater) randomised controlled trial recruited 50 participants who were allocated 1:1 to treatment as usual (TAU), or TAU plus up to 26 sessions of TwV therapy. Participants were assessed at baseline and again at end of treatment (six-months). The primary outcomes were quantitative and qualitative assessments of feasibility and acceptability. Secondary outcomes involved clinical measures, including targeted instruments for voice-hearing, dissociation, and emotional distress. The trial achieved 100 % of the target sample, 24 of whom were allocated to therapy and 26 to TAU. The trial had high retention (40/50 [80 %] participants at six-months) and high intervention adherence (21/24 [87.5 %] receiving ≥8 sessions). Signals of efficacy were shown in targeted measures of voice-hearing, dissociation, and perceptions of recovery. Analysis on the Positive and Negative Syndrome Scale indicated that there were no differences in means of general psychosis symptom scores in TwV compared to the control group. There were four serious adverse events in the therapy group and eight in TAU, none of which were related to study proceedings. The trial demonstrates the acceptability of the intervention and the feasibility of delivering it under controlled, randomised conditions. An adequately powered definitive trial is necessary to provide robust evidence regarding efficacy evaluation and cost-effectiveness. Trial registration: ISRCTN 45308981.

The social withdrawal of many patients with psychosis can be conceptualised as agoraphobic avoidance due to a range of long-standing fears. We hypothesised that greater severity of agoraphobic avoidance is associated with higher levels of psychiatric symptoms and lower levels of quality of life. We also hypothesised that patients with severe agoraphobic avoidance would experience a range of benefits from an automated virtual reality (VR) therapy that allows them to practise everyday anxiety-provoking situations in simulated environments.345 patients with psychosis in a randomised controlled trial were categorised into average, moderate, high, and severe avoidance groups using the Oxford Agoraphobic Avoidance Scale. Associations of agoraphobia severity with symptom and functioning variables, and response over six months to brief automated VR therapy (gameChange), were tested.Greater severity of agoraphobic avoidance was associated with higher levels of persecutory ideation, auditory hallucinations, depression, hopelessness, and threat cognitions, and lower levels of meaningful activity, quality of life, and perceptions of recovery. Patients with severe agoraphobia showed the greatest benefits with gameChange VR therapy, with significant improvements at end of treatment in agoraphobic avoidance, agoraphobic distress, ideas of reference, persecutory ideation, paranoia worries, recovering quality of life, and perceived recovery, but no significant improvements in depression, suicidal ideation, or health-related quality of life.Patients with psychosis with severe agoraphobic avoidance, such as being unable to leave the home, have high clinical need. Automated VR therapy can deliver clinical improvement in agoraphobia for these patients, leading to a number of wider benefits.

Long-term care facility (LTCF) residents have been disproportionately affected by coronavirus disease 2019 (COVID-19), from increased mortality and restrictive public health measures. The current study aims to describe the experiences of residents relocating between LTCFs at the onset of the COVID-19 pandemic. Emphasis was placed on residents' sense of home and how the pandemic and ensuing isolation affected their transition. This qualitative study follows the principles of constructivist grounded theory. Seven of 10 residents interviewed had cognitive impairment (mean age = 84 years). Four primary themes were elicited from the interviews focusing on residents' perceptions of their environment and highlights the value placed on privacy and control, the multifaceted feeling of loss during the pandemic, the importance of relationships as a source of comfort and pleasure, and resilience shown by residents in times of hardship. Our study indicates that residents experienced dichotomy and paradox during the pandemic, attempting to strike a balance between isolation and camaraderie, infection risk and mental health, and loss and resilience. The need for familial contact and socialization must be balanced against infection control measures. [ Journal of Gerontological Nursing, 48 (1), 29–33.]

Background Pandemic events often trigger a surge of clinical trial activity aimed at rapidly evaluating therapeutic or preventative interventions. Ensuring rapid public access to the complete and unbiased trial record is particularly critical for pandemic research given the urgent associated public health needs. The World Health Organization (WHO) established standards requiring posting of results to a registry within 12 months of trial completion and publication in a peer reviewed journal within 24 months of completion, though compliance with these requirements among pandemic trials is unknown. Methods This cross-sectional analysis characterizes availability of results in trial registries and publications among registered trials performed during the 2009 H1N1 influenza, 2014 Ebola, and 2016 Zika pandemics. We searched trial registries to identify clinical trials testing interventions related to these pandemics, and determined the time elapsed between trial completion and availability of results in the registry. We also performed a comprehensive search of MEDLINE via PubMed, Google Scholar, and EMBASE to identify corresponding peer reviewed publications. The primary outcome was the compliance with either of the WHO’s established standards for sharing clinical trial results. Secondary outcomes included compliance with both standards, and assessing the time elapsed between trial completion and public availability of results. Results Three hundred thirty-three trials met eligibility criteria, including 261 H1N1 influenza trials, 60 Ebola trials, and 12 Zika trials. Of these, 139 (42%) either had results available in the trial registry within 12 months of study completion or had results available in a peer-reviewed publication within 24 months. Five trials (2%) met both standards. No results were available in either a registry or publication for 59 trials (18%). Among trials with registered results, a median of 42 months (IQR 16–76 months) elapsed between trial completion and results posting. For published trials, the median elapsed time between completion and publication was 21 months (IQR 9–34 months). Results were available within 24 months of study completion in either the trial registry or a peer reviewed publication for 166 trials (50%). Conclusions Very few trials performed during prior pandemic events met established standards for the timely public dissemination of trial results.

Purpose To present a treatment protocol for delivering Talking With Voices, a novel intervention for people with psychosis that involves dialogical engagement with auditory hallucinations. Method This paper presents a manualized approach to therapy employed in the Talking With Voices trial, a feasibility and acceptability randomized control trial of 50 adult participants. A rationale for following a treatment manual is provided, followed by the theoretical underpinnings of the intervention and its principles and values, including the main tenet that voices can often be understood as dissociated parts of the self which serve a protective function by indicating social-emotional vulnerabilities. The four therapy phases for improving the relationship between the voice-hearer and their voices are outlined: (1) engagement and psychoeducation, (2) creating a formulation, (3) dialoguing with voices, and (4) consolidating outcomes, including key milestones at each phase. Implementation issues are discussed, as well as recommendations for best practice and future research. Results The Talking With Voices treatment protocol indicates that it is feasible to manualize a dissociation-based approach to support service users who are distressed by hearing voices. Conclusion For some individuals, it is possible to engage in productive dialogue with even extremely hostile or distressing voices. Developing coping strategies, creating a formulation, and ultimately establishing a dialogue with voices has the potential to improve the relationship between voice(s) and voice-hearer. Further research is now required to evaluate feasibility, acceptability, and efficacy. Practitioner points It is feasible to integrate a dissociation model of voice-hearing within a psychological intervention for people with psychosis. Combining psychosocial education, formulation and direct dialogue can be used to facilitate a more peaceful relationship between clients and their voices. Practitioners trained in other therapeutic modalities can draw on existing transferrable skills to dialogue with their clients' voices. The input of those with lived experience of mental health difficulties has an important role in guiding treatment design and delivery.

This article outlines the practical considerations of establishing student placements in occupational health services. The placements have enhanced recruitment to both the occupational health service and the wider NHS environment. It is anticipated that the ongoing programme will offer practical placements and increase the wider understanding of the value of occupational health in the working-age population.

The COVID-19 pandemic has created opportunities for innovation in diabetes care that were not possible before. From the lens of this “new normal” state, we have an opportunity to rapidly implement, test, and iterate models of diabetes care to achieve the quadruple aim of improving medical outcomes, patient experience, provider satisfaction, and reducing costs. Two of the biggest threats to optimal diabetes care have been lack of access to specialty diabetes care and fractured care. In this perspective, we discuss several innovative diabetes models of care which promote collaborative care models and improve access to high-quality specialty diabetes care. We discuss ongoing challenges to diabetes care innovation, and offer practical solutions to foster innovation and sustain current strides made during the pandemic.

Objectives Electronic consultation, or e-consult, systems improve specialty care access by conveying specialist expertise to primary care clinicians (PCCs) without requiring specialist visits. Our study evaluates organizational factors for e-consult implementation across 5 publicly financed, county-based health systems in California. Each system serves 40,000 to 180,000 culturally and linguistically diverse patients across 4 to 19 primary care locations. Study design We interviewed leaders whose systems received grant funding between 2015 and 2017 to plan and implement e-consult. Interviews discussed platform selection, electronic health record (EHR) compatibility, PCC and specialist opinions, and project governance. We also collected implementing systems' platform operations metrics. Methods Mixed methods, including semistructured interviews and quantitative platform metrics. Interviews were analyzed in alignment with the Consolidated Framework for Implementation Research inner setting domain. Results Three of the 5 systems successfully implemented e-consults. System 1 sustained implementation across 27 specialties, system 2 achieved fragmented implementation, and system 3 reported early-stage implementation. Existing PCC-specialist relationships emerged as the strongest facilitator. E-consult-EHR technology integration was also important, although an add-on platform enabled e-consult expansion in system 2. Although all systems faced challenges, such as project management resourcing, systems 4 and 5 abandoned implementation amid compound climate and readiness barriers. Conclusions Successful e-consult implementations in public delivery systems leveraged (1) prior primary care and specialty care clinician relationships and (2) integrated EHR and e-consult platforms. This contrasts with common expectations that new technology will overcome care delivery gaps. Findings add to existing e-consult implementation literature that emphasizes reimbursement and leadership champions.

Older people do not want to be called 'elderly' (Falconer et al. in BMJ 334: 75-88, 2007). The UN Committee on Economic, Social and Cultural Rights of Older Persons agreed in 1995 that the term 'older persons' is preferred over 'elderly' 'seniors' and 'the aged'. Medical literature may lag behind this trend and continued to refer to older adults by nomenclature that they find stigmatising. We examined the use of stigmatising language in two medical journals. METHODS: All articles published by Age and Ageing and European Geriatric Medicine from January 2018 to December 2020 were reviewed. The articles were searched for the use of the words 'elderly', 'senior', and 'the aged' as well as 'older'.383 articles were published in the EGM and 511 in Age and Ageing. In the EGM, 80 articles (20.8%) used stigmatising language. In Age and Ageing, 90 (17.6%) used stigmatising language.While progress has been made in reframing the language used in journal articles compared to previous studies (Lundebjerg et al. in J Am Geriatr Soc 65: 1386-1388, 2017), more can be done to ensure our compliance with addressing older adults by their preferred terminology.

Background Sleepiness associated with night shift working (NSW) is known to adversely affect workers’ health and well-being. It has been associated with adverse safety outcomes and is a recognized workplace hazard among healthcare workers. Aims This study was aimed to assess the prevalence of self-reported sleepiness in NSW nurses and midwives. This study also explored the consequences of sleepiness on safety at work and driving. Methods A cross-sectional study of NSW nurses and midwives was conducted at an National Health Service (NHS) hospital trust from 16 March 2020 to 1 June 2020. Data were collected by online questionnaire and included information on demographics, shift work and safety aspects. Sleepiness was assessed with the Epworth Sleepiness Scale (ESS). Results Data collection coincided with the first coronavirus pandemic peak in England. Out of 1985 eligible NSW nurses and midwives, 229 participated in the study, with a response rate of 12%. The prevalence of sleepiness was 28%. Following a night shift, 49% of nurses reported nodding off at the wheel and 44% reported a near-miss car accident in past 12 months. An abnormal ESS score was significantly associated with near-miss car accidents (odds ratio [OR] 2.75, 95% confidence interval [CI] 1.31–5.77) and with low confidence in undertaking complex tasks at night (OR 2.64, 95% CI 1.20–5.84). Conclusions More than a quarter of NSW nurses and midwives reported excessive daytime sleepiness although, due to the low response rate, this may not be representative. Adverse driving events were common. Elevated ESS scores correlated well with safety issues relating to work and driving.

Compassion is fundamental to the delivery of quality nursing care and is an expected core competency that students must achieve to become a registered nurse. Nurse educators have a role in teaching compassion and in cultivating compassionate behaviours, among students, thus this novel study explores the student nurse's experience and understanding of compassion within the academic setting. A qualitative descriptive study using digitally recorded focus group interviews was undertaken with student nurses (n = 32) to explore their experiences of compassion in an academic setting. Data analysis was performed based on Braun and Clarke's framework of thematic analysis. Three themes were identified: students understanding of compassion, students experience of compassion within the academic setting and supporting compassion in an academic space. Student nurses reported their experiences of compassion as predominantly positive. They advocated for further 'space' within the curriculum for more formalised approaches to foster supportive relationships and to improve their experience of compassion within the academic setting. It is important to understand students' perspectives as this can guide teaching practice, organisational policy reform, and future research.

Background: Outcomes after hematopoietic cell transplantation (HCT) for acute myeloid leukemia (AML) are better when HCT is performed during first complete remission (CR1). This study aimed to identify and address knowledge gaps that affect the timely referral of patients for HCT consultation. Methods: A mixed-methods educational needs assessment included a national survey and focus groups consisting of hematologists/oncologists. An educational intervention of 3 webinars addressed identified knowledge gaps. Results: A total of 150 hematologists/oncologists were recruited for the survey, of whom 20 participated in focus groups. Physicians in practice 0 to 10 years were 4.2 times more likely to refer for HCT consultation in CR1 than those with >10 years in practice (P=.0027). Physicians seeing ≤10 patients with AML in the past year were 3.7 times more likely to refer for HCT consultation in CR1 than those seeing >10 patients (P=.0028). Knowledge gaps included (1) improper classification of molecular/cytogenetic results for risk stratification, (2) lack of understanding that disease stage impacts outcomes, and (3) use of chronologic age alone for referral decision-making. Combined attendance for the webinars was 1,098 clinicians; >74% of participants indicated that they would apply the knowledge they gained in clinical practice. Trends were observed toward improvement in identifying favorable-risk AML, from 48% to 60% (n=85; P=.12); improvement in identifying 2 poor-risk cytogenetic/molecular abnormalities, with the percentage of respondents indicating chromosome 7 deletion increasing from 51% to 70% (n=53; P=.05) and that of respondents indicating TP53 mutation increasing from 42% to 62% (n=62; P=.03); and improvement in identifying which patients with AML aged >60 years were most likely to benefit from HCT based on cytogenetic/molecular features, with the percentage of correct responses increasing from 66% to 81% (n=62; P=.07). Conclusions: The webinars met the educational needs of learners and improved knowledge gaps. This study provided novel insights into the learning needs of clinicians who care for patients with AML and a roadmap for future educational interventions.

Allogeneic hematopoietic cell transplantation (alloHCT) is a highly specialized procedure. We surveyed adult transplant centers in the United States (US) and then used data reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) (2008–2010) to evaluate associations of center volume, infrastructure, and care delivery models with survival post alloHCT. Based on their 2010 alloHCT volume, centers were categorized as low-volume (≤40 alloHCTs; N = 42 centers, 1900 recipients) or high-volume (>40 alloHCTs; N = 41 centers, 9637 recipients). 100-day survival was 86% (95% CI, 85–87%) in high-volume compared with 83% (95% CI, 81–85%) in low-volume centers (difference 3%; P

OBJECTIVE This study determined whether 1 health system's frontline nursing model redesign to integrate clinical nurse leaders (CNLs) improved care quality and outcome score consistency. METHODS Interrupted time-series design was used to measure patient satisfaction with 7 metrics before and after formally integrating CNLs into a Michigan healthcare system. Analysis generated estimates of quality outcome: a) change point; b) level change; and c) variance, pre-post implementation. RESULTS The lowest-performing unit showed significant increases in quality scores, but there were no significant increases at the hospital level. Quality metric consistency increased significantly for every indicator at the hospital and unit level. CONCLUSIONS To our knowledge, this is the 1st study quantifying quality outcome consistency before and after nursing care delivery redesign with CNLs. The significant improvement suggests the CNL care model is associated with production of stable clinical microsystem practices that help to reduce clinical variability, thus improving care quality.

Survivorship Care Plans (SCPs) may facilitate long-term care for cancer survivors, but their effectiveness has not been established in hematopoietic cell transplantation recipients. We evaluated the impact of individualized SCPs on patient-reported outcomes among transplant survivors. Adult (≥18 years at transplant) survivors who were 1-5 years post transplantation, proficient in English, and without relapse or secondary cancers were eligible for this multicenter randomized trial. SCPs were developed based on risk-factors and treatment exposures using patient data routinely submitted by transplant centers to the Center for International Blood and Marrow Transplant Research and published guidelines for long-term follow up of transplant survivors. Phone surveys assessing patient-reported outcomes were conducted at baseline and at 6 months. The primary end point was confidence in survivorship information, and secondary end points included cancer and treatment distress, knowledge of transplant exposures, health care utilization, and health-related quality of life. Of 495 patients enrolled, 458 completed a baseline survey and were randomized (care plan=231, standard care=227); 200 (87%) and 199 (88%) completed the 6-month assessments, respectively. Patients’ characteristics were similar in the two arms. Participants on the care plan arm reported significantly lower distress scores at 6 months and an increase in the Mental Component Summary quality of life score assessed by the Short Form 12 (SF-12) instrument. No effect was observed on the end point of confidence in survivorship information or other secondary outcomes. Provision of individualized SCPs generated using registry data was associated with reduced distress and improved mental domain of quality of life among 1-5 year hematopoietic cell transplantation survivors. Trial registered at clinicaltrials.gov 02200133.

Confocal microscopy

Summary Optical methods for measuring intracellular ions including Ca2+ revolutionized our understanding of signal transduction. However, these methods are not extensively applied to intact organs due to issues including inner filter effects, motion, and available probes. Mitochondrial Ca2+ is postulated to regulate cell energetics and death pathways that are best studied in an intact organ. Here, we develop a method to optically measure mitochondrial Ca2+ and demonstrate its validity for mitochondrial Ca2+ and metabolism using hearts from wild-type mice and mice with germline knockout of the mitochondria calcium uniporter (MCU-KO). We previously reported that germline MCU-KO hearts do not show an impaired response to adrenergic stimulation. We find that these MCU-KO hearts do not take up Ca2+, consistent with no alternative Ca2+ uptake mechanisms in the absence of MCU. This approach can address the role of mitochondrial Ca2+ to the myriad of functions attributed to alterations in mitochondrial Ca2+.

Empathy, when demonstrated by health care providers, results in improved patient compliance and enhanced patient outcomes. Yet, self-reported empathy has been shown to decrease in health care professional students during their course of study. Possible reasons for this decrease in empathy have included the type of curriculum of the professional program, participation in clinical experiences, the movement from idealism to realism, and student distress. This current study using the Jefferson Scale of Empathy-Health Professions Student Version (JSE-HPS) demonstrated that Doctor of Physical Therapy (DPT) students, from two DPT programs, showed an increase in their self-reported levels of empathy over the course of their professional education. These students were surveyed before and after clinical experiences and represented two pedagogically different DPT programs. These data suggest that DPT students may differ from the trends found in other healthcare domains. Instead of developing interventions to improve student empathy, as has been suggested, educational time may be better spent helping these DPT students protect and utilize their current levels of empathy.

The increased prevalence of obese, pregnant women who have a higher risk of glucose intolerance warrants the need for nutritional interventions to improve maternal glucose homeostasis. In this study, the effect of a low-glycemic load (GL) (n = 28) was compared to a high-GL (n = 34) dietary intervention during the second half of pregnancy in obese women (body mass index (BMI) &gt, 30 or a body fat &gt, 35%). Anthropometric and metabolic parameters were assessed at baseline (20 week) and at 28 and 34 weeks gestation. For the primary outcome 3h-glucose-iAUC (3h-incremental area under the curve), mean between-group differences were non-significant at every study timepoint (p = 0.6, 0.3, and 0.8 at 20, 28, and 34 weeks, respectively) and also assessing the mean change over the study period (p = 0.6). Furthermore, there was no statistically significant difference between the two intervention groups for any of the other examined outcomes (p ³ 0.07). In the pooled cohort, there was no significant effect of dietary GL on any metabolic or anthropometric outcome (p ³ 0.2). A post hoc analysis comparing the study women to a cohort of overweight or obese pregnant women who received only routine care showed that the non-study women were more likely to gain excess weight (p = 0.046) and to deliver large-for-gestational-age (LGA) (p = 0.01) or macrosomic (p = 0.006) infants. Thus, a low-GL diet consumed during the last half of pregnancy did not improve pregnancy outcomes in obese women, but in comparison to non-study women, dietary counseling reduced the risk of adverse outcomes.

This is a pre-copyedited, author-produced version of an article accepted for publication in Cardiovascular Research (CVR) following peer review. The version of record Perrino, Ferdinandy, Bøtker, Brundel, Collins, Davidson, Den Ruijter, Engel, Gerdts, Girao, Gyöngyösi, Hausenloy, Lecour, Madonna, Marber, Murphy, Pesce, Regitz-Zagrosek, Sluijter, Steffens, Gollmann-Tepeköylü, Van Laake, Van Linthout, Schulz, Ytrehus. Improving translational research in sex-specific effects of comorbidities and risk factors in ischaemic heart disease and cardioprotection: Position paper and recommendations of the ESC Working Group on Cellular Biology of the Heart. Cardiovascular Research (CVR). 2021;117(2):367-385, is available online at: https://doi.org/10.1093/cvr/cvaa155. Ischaemic heart disease (IHD) is a complex disorder and a leading cause of death and morbidity in both men and women. Sex, however, affects several aspects of IHD, including pathophysiology, incidence, clinical presentation, diagnosis as well as treatment and outcome. Several diseases or risk factors frequently associated with IHD can modify cellular signalling cascades, thus affecting ischaemia/reperfusion injury as well as responses to cardioprotective interventions. Importantly, the prevalence and impact of risk factors and several comorbidities differ between males and females, and their effects on IHD development and prognosis might differ according to sex. The cellular and molecular mechanisms underlying these differences are still poorly understood, and their identification might have important translational implications in the prediction or prevention of risk of IHD in men and women. Despite this, most experimental studies on IHD are still undertaken in animal models in the absence of risk factors and comorbidities, and assessment of potential sex-specific differences are largely missing. This ESC WG Position Paper will discuss: (i) the importance of sex as a biological variable in cardiovascular research, (ii) major biological mechanisms underlying sex-related differences relevant to IHD risk factors and comorbidities, (iii) prospects and pitfalls of preclinical models to investigate these associations, and finally (iv) will provide recommendations to guide future research. Although gender differences also affect IHD risk in the clinical setting, they will not be discussed in detail here.

Background Cryptococcal meningoencephalitis (CM) is a major cause of mortality in immunosuppressed patients and previously healthy individuals. In the latter, a post-infectious inflammatory response syndrome (PIIRS) is associated with poor clinical response despite antifungal therapy and negative cerebrospinal fluid (CSF) cultures. Data on effective treatment are limited. Methods Between March 2015 and March 2020, 15 consecutive previously healthy patients with CM and PIIRS were treated with adjunctive pulse corticosteroid taper therapy (PCT) consisting of intravenous methylprednisolone 1 gm daily for 1 week followed by oral prednisone 1 mg/kg/day, tapered based on clinical and radiological response plus oral fluconazole. Montreal cognitive assessments (MOCA), Karnofsky performance scores, magnetic resonance imaging (MRI) brain scanning, ophthalmic and audiologic exams, and CSF parameters including cellular and soluble immune responses were compared at PIIRS diagnosis and after methylprednisolone completion. Results The median time from antifungal treatment to steroid initiation was 6 weeks. The most common symptoms at PIIRS diagnosis were altered mental status and vision changes. All patients demonstrated significant improvements in MOCA and Karnofsky scores at 1 month (P Conclusions PCT in this small cohort of PIIRS was associated with improvements in CM-related complications with minimal toxicity in the acute setting.

Mitochondria are responsible for ATP production but are also known as regulators of cell death, and mitochondrial matrix Ca

Objective To identify possible differences in baseline characteristics, initial treatment and treatment response between RA patient subgroups based on age at disease onset. Methods Daily practice data from the worldwide METEOR registry were used. Patients (7912) were stratified into three age-groups (age at disease diagnosis 65 years). Initial treatment was compared between the different age-groups. With Cox regression analyses the effect of age-group on time-to-switch from first to second treatment was investigated, and with linear mixed models differences in response to treatment (DAS and HAQ) between the age-groups were assessed, after correction for potential confounders. Results The >65 years age-group included more men, and more seronegative RA with somewhat higher inflammatory markers. Initial treatment choices differed only slightly between the age-groups, and the time-to-switch from initial treatment to the next was similar. DAS and HAQ improvement were dependent on the age-group, reflected by a significant interaction between age-group and outcome. The stratified analysis showed a difference of −0.02 and −0.05 DAS points and, −0.01 and 0.02 HAQ points per month in the 65 year age group, a difference that did not seem clinically relevant. Conclusion In this international study on worldwide clinical practice, patients with RA onset >65 years include more men and seronegative arthritis, and were initially treated slightly differently than younger patients. We observed no clinically relevant differences in timing of a next treatment step, or response to treatment measured by DAS and HAQ.

Background Evidence for the effectiveness of treatments in early-onset psychosis is sparse. Current guidance for the treatment of early-onset psychosis is mostly extrapolated from trials in adult populations. The UK National Institute for Health and Care Excellence has recommended evaluation of the clinical effectiveness and cost-effectiveness of antipsychotic drugs versus psychological intervention (cognitive behavioural therapy [CBT] and family intervention) versus the combination of these treatments for early-onset psychosis. The aim of this study was to establish the feasibility of a randomised controlled trial of antipsychotic monotherapy, psychological intervention monotherapy, and antipsychotics plus psychological intervention in adolescents with first-episode psychosis. Methods We did a multicentre pilot and feasibility trial according to a randomised, single-blind, three-arm, controlled design. We recruited participants from seven UK National Health Service Trust sites. Participants were aged 14–18 years; help-seeking; had presented with first-episode psychosis in the past year; were under the care of a psychiatrist; were showing current psychotic symptoms; and met ICD-10 criteria for schizophrenia, schizoaffective disorder, or delusional disorder, or met the entry criteria for an early intervention for psychosis service. Participants were assigned (1:1:1) to antipsychotics, psychological intervention (CBT with optional family intervention), or antipsychotics plus psychological intervention. Randomisation was via a web-based randomisation system, with permuted blocks of random size, stratified by centre and family contact. CBT incorporated up to 26 sessions over 6 months plus up to four booster sessions, and family intervention incorporated up to six sessions over 6 months. Choice and dose of antipsychotic were at the discretion of the treating consultant psychiatrist. Participants were followed up for a maximum of 12 months. The primary outcome was feasibility (ie, data on trial referral and recruitment, session attendance or medication adherence, retention, and treatment acceptability) and the proposed primary efficacy outcome was total score on the Positive and Negative Syndrome Scale (PANSS) at 6 months. Primary outcomes were analysed by intention to treat. Safety outcomes were reported according to as-treated status, for all patients who had received at least one session of CBT or family intervention, or at least one dose of antipsychotics. The study was prospectively registered with ISRCTN, ISRCTN80567433. Findings Of 101 patients referred to the study, 61 patients (mean age 16·3 years [SD 1·3]) were recruited from April 10, 2017, to Oct 31, 2018, 18 of whom were randomly assigned to psychological intervention, 22 to antipsychotics, and 21 to antipsychotics plus psychological intervention. The trial recruitment rate was 68% of our target sample size of 90 participants. The study had a low referral to recruitment ratio (around 2:1), a high rate of retention (51 [84%] participants retained at the 6-month primary endpoint), a high rate of adherence to psychological intervention (defined as six or more sessions of CBT; in 32 [82%] of 39 participants in the monotherapy and combined groups), and a moderate rate of adherence to antipsychotic medication (defined as at least 6 consecutive weeks of exposure to antipsychotics; in 28 [65%] of 43 participants in the monotherapy and combined groups). Mean scores for PANSS total at the 6-month primary endpoint were 68·6 (SD 17·3) for antipsychotic monotherapy (6·2 points lower than at randomisation), 59·8 (13·7) for psychological intervention (13·1 points lower than at randomisation), and 62·0 (15·9) for antipsychotics plus psychological intervention (13·9 points lower than at randomisation). A good clinical response at 6 months (defined as ≥50% improvement in PANSS total score) was achieved in four (22%) of 18 patients receiving antipsychotic monotherapy, five (31%) of 16 receiving psychological intervention, and five (29%) of 17 receiving antipsychotics plus psychological intervention. In as-treated groups, serious adverse events occurred in eight [35%] of 23 patients in the combined group, two [13%] of 15 in the antipsychotics group, four [24%] of 17 in the psychological intervention group, and four [80%] of five who did not receive any treatment. No serious adverse events were considered to be related to participation in the trial. Interpretation This trial is the first to show that a head-to-head clinical trial comparing psychological intervention, antipsychotics, and their combination is safe in young people with first-episode psychosis. However, the feasibility of a larger trial is unclear because of site-specific recruitment challenges, and amendments to trial design would be needed for an adequately powered clinical and cost-effectiveness trial that provides robust evidence. Funding National Institute for Health Research.

Background Evidence regarding stress, team structure and decision-making has been used to inform efficacious team composition and deployment. There have been limited attempts to establish the relationship between psychological stress with physiological data within professional environments. The current study explored measures of psychological and physiological stress in Australian emergency practitioners. Methods Thirty-seven staff in an Australian emergency department completed an online survey assessing freedom to make decisions, social support, and psychological job demands. Seven participants provided saliva samples three times daily for seven days (valid n = 141 samples). Cortisol levels of the samples were analysed using competitive enzyme immunoassay kits, and α-amylase using kinetic enzyme assay kits. Results Years of emergency experience was positively associated with freedom to make decisions, and social support was negatively correlated with psychological demand. No consistent pattern was observed between cortisol level and reported psychological demand, decision freedom or social support. Physical activity was not reflected in elevated α-amylase. Diurnal variation of cortisol and α-amylase was not affected by shiftwork. Conclusions The data supports the case for using multiple assessments to measure stress. While the psychological data is consistent with previous findings, there are possible disparities between psychological reports and physical indicators of stress.

Background Coronavirus disease 2019 (COVID-19) is a disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), first detected in China in December, 2019. In January, 2020, state, local, and federal public health agencies investigated the first case of COVID-19 in Illinois, USA. Methods Patients with confirmed COVID-19 were defined as those with a positive SARS-CoV-2 test. Contacts were people with exposure to a patient with COVID-19 on or after the patient's symptom onset date. Contacts underwent active symptom monitoring for 14 days following their last exposure. Contacts who developed fever, cough, or shortness of breath became persons under investigation and were tested for SARS-CoV-2. A convenience sample of 32 asymptomatic health-care personnel contacts were also tested. Findings Patient 1-a woman in her 60s-returned from China in mid-January, 2020. One week later, she was hospitalised with pneumonia and tested positive for SARS-CoV-2. Her husband (Patient 2) did not travel but had frequent close contact with his wife. He was admitted 8 days later and tested positive for SARS-CoV-2. Overall, 372 contacts of both cases were identified; 347 underwent active symptom monitoring, including 152 community contacts and 195 health-care personnel. Of monitored contacts, 43 became persons under investigation, in addition to Patient 2. These 43 persons under investigation and all 32 asymptomatic health-care personnel tested negative for SARS-CoV-2. Interpretation Person-to-person transmission of SARS-CoV-2 occurred between two people with prolonged, unprotected exposure while Patient 1 was symptomatic. Despite active symptom monitoring and testing of symptomatic and some asymptomatic contacts, no further transmission was detected. Funding None.

Adult cardiomyocytes are postmitotic cells that undergo very limited cell division. Thus, cardiomyocyte death as occurs during myocardial infarction has very detrimental consequences for the heart. Mitochondria have emerged as an important regulator of cardiovascular health and disease. Mitochondria are well established as bioenergetic hubs for generating ATP but have also been shown to regulate cell death pathways. Indeed many of the same signals used to regulate metabolism and ATP production, such as calcium and reactive oxygen species, are also key regulators of mitochondrial cell death pathways. It is widely hypothesized that an increase in calcium and reactive oxygen species activate a large conductance channel in the inner mitochondrial membrane known as the PTP (permeability transition pore) and that opening of this pore leads to necroptosis, a regulated form of necrotic cell death. Strategies to reduce PTP opening either by inhibition of PTP or inhibiting the rise in mitochondrial calcium or reactive oxygen species that activate PTP have been proposed. A major limitation of inhibiting the PTP is the lack of knowledge about the identity of the protein(s) that form the PTP and how they are activated by calcium and reactive oxygen species. This review will critically evaluate the candidates for the pore-forming unit of the PTP and discuss recent data suggesting that assumption that the PTP is formed by a single molecular identity may need to be reconsidered.

AIMS: Knockout (KO) of the mitochondrial Ca(2+) uniporter (MCU) in mice abrogates mitochondrial Ca(2+) uptake and permeability transition pore (PTP) opening. However, hearts from global MCU-KO mice are not protected from ischaemic injury. We aimed to investigate whether adaptive alterations occur in cell death signalling pathways in the hearts of global MCU-KO mice. METHODS AND RESULTS: First, we examined whether cell death may occur via an upregulation in necroptosis in MCU-KO mice. However, our results show that neither RIP1 inhibition nor RIP3 knockout afford protection against ischaemia-reperfusion injury in MCU-KO as in wildtype (WT) hearts, indicating that the lack of protection cannot be explained by upregulation of necroptosis. Instead, we have identified alterations in cyclophilin D (CypD) signalling in MCU-KO hearts. In the presence of a calcium ionophore, MCU-KO mitochondria take up calcium and do undergo PTP opening. Furthermore, PTP opening in MCU-KO mitochondria has a lower calcium retention capacity (CRC), suggesting that the calcium sensitivity of PTP is higher. Phosphoproteomics identified an increase in phosphorylation of CypD-S42 in MCU-KO. We investigated the interaction of CypD with the putative PTP component ATP synthase and identified an approximately 50% increase in this interaction in MCU-KO cardiac mitochondria. Mutation of the novel CypD phosphorylation site S42 to a phosphomimic reduced CRC, increased CypD-ATP synthase interaction by approximately 50%, and increased cell death in comparison to a phospho-resistant mutant. CONCLUSION: Taken together these data suggest that MCU-KO mitochondria exhibit an increase in phosphorylation of CypD-S42 which decreases PTP calcium sensitivity thus allowing activation of PTP in the absence of an MCU-mediated increase in matrix calcium.

Blood or marrow transplant (BMT) is a potentially curative treatment for numerous cancers and non-malignant disorders. BMT is a resource-intense treatment process, requiring patients to comprehend difficult health information and navigate a complex healthcare system. Linguistic and cultural barriers create additional challenges for patients with limited English proficiency (LEP) who may need translated information and interpretive services to make an informed decision about treatment. To identify information needs and gaps in language services for BMT patients with LEP, the National Marrow Donor Program® (NMDP)/Be The Match® administered a cross-sectional, web-based survey to 139 transplant centers (TCs) across the United States (U.S.). The survey yielded a 59% response rate. Findings show a significant need for translated patient education materials, especially in Spanish, Chinese, and Arabic, and practice gaps in the use of appropriate interpreters. Nearly one third of respondents indicated using family and friends to interpret for patients. The inability to locate educational resources in a specific language, lack of available bilingual staff, lack of a formal, centralized tracking system, and outdated tracking systems also pose significant barriers to meeting the language needs of BMT patients with LEP.

Objective.To assess differences in initial treatment and treatment response in male and female patients with rheumatoid arthritis (RA) in daily clinical practice.Methods.The proportion of patients with RA starting different antirheumatic treatments (disease-modifying antirheumatic drugs; DMARD) and the response to treatment were compared in the international, observational METEOR register. All visits from start of the first DMARD until the first DMARD switch or the end of followup were selected. The effect of sex on time to switch from first to second treatment was calculated using Cox regression. Linear mixed model analyses were performed to assess whether men and women responded differently to treatments, as measured by Disease Activity Score (DAS) or Health Assessment Questionnaire.Results.Women (n = 4393) more often started treatment with hydroxychloroquine, as monotherapy or in combination with methotrexate (MTX) or a glucocorticoid, and men (n = 1142) more often started treatment with MTX and/or sulfasalazine. Time to switch DMARD was shorter for women than for men. Women had a statistically significantly higher DAS over time than men (DAS improvement per year β −0.69, 95% CI −0.75 to −0.62 for men and −0.58, 95% CI −0.62 to −0.55 for women). Subanalyses per DMARD group showed for the conventional synthetic DMARD combination therapy a slightly greater decrease in DAS over time in men (−0.89, 95% CI −1.07 to −0.71) compared to women (−0.59, 95% CI −0.67 to −0.51), but these difference between the sexes were clinically negligible.Conclusion.This worldwide observational study suggests that in daily practice, men and women with RA are prescribed different initial treatments, but there were no differences in response to treatment between the sexes.

Clinical social workers are psychosocial care experts who provide interventions that aim to address the emotional, relational, financial, and logistical challenges that arise throughout the hematopoietic cell transplantation (HCT) treatment and recovery process. Interventions that contribute to better patient outcomes can include cognitive behavioral therapy and counseling for adaptation to illness, family planning for 24/7 caregiver availability and strategies to support patient activities of daily living, instruction on guided imagery and relaxation techniques for symptom management and to decrease anxiety, psychoeducation on the treatment trajectory, and linkage with financial resources. A Social Work Workforce Group (SWG) was established through the System Capacity Initiative, led by the National Marrow Donor Program/Be The Match, to characterize the current social work workforce capacity and challenges. The SWG conducted a web-based survey of HCT clinical social workers in the United States. The response rate was 57% (n = 90), representing 76 transplant centers. Survey results indicated that the clinical social worker role and scope of practice varies significantly between centers; less than half of respondents reported that their clinical social work expertise was used to its fullest potential. With an estimated 3-fold increase in HCT patient volume by 2020, the need for specialized psychosocial health services will increase. The SWG makes recommendations to build capacity for the psychosocial care of HCT patients and to more fully integrate the social worker as a core member of the HCT team. The SWG created a Blood and Marrow Transplant (BMT) Clinical Social Worker role description that can be used by transplant centers to educate healthcare professionals, benchmark utilization of clinical social workers, and improve comprehensive psychosocial health programs.

Summary Energy metabolism is a key aspect of cardiomyocyte biology. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are a promising tool for biomedical application, but they are immature and have not undergone metabolic maturation related to early postnatal development. To assess whether cultivation of hiPSC-CMs in 3D engineered heart tissue format leads to maturation of energy metabolism, we analyzed the mitochondrial and metabolic state of 3D hiPSC-CMs and compared it with 2D culture. 3D hiPSC-CMs showed increased mitochondrial mass, DNA content, and protein abundance (proteome). While hiPSC-CMs exhibited the principal ability to use glucose, lactate, and fatty acids as energy substrates irrespective of culture format, hiPSC-CMs in 3D performed more oxidation of glucose, lactate, and fatty acid and less anaerobic glycolysis. The increase in mitochondrial mass and DNA in 3D was diminished by pharmacological reduction of contractile force. In conclusion, contractile work contributes to metabolic maturation of hiPSC-CMs., Graphical Abstract, Highlights • Higher mitochondrial mass, protein, and DNA content in 3D versus 2D hiPSC-CMs • Similarity of mitochondrial proteomes between 3D hiPSC-CMs and adult human heart • Preference for oxidative metabolism in favor of anaerobic glycolysis in 3D hiPSC-CMs, Ulmer et al. show that 3D-cultured human iPSC-derived cardiomyocytes replicate metabolic aspects of developmental hypertrophy, indicating maturation of hiPSC-derived cardiomyocytes.

Through fragment-based drug design focused on engaging the active site of IRAK4 and leveraging three-dimensional topology in a ligand-efficient manner, a micromolar hit identified from a screen of a Pfizer fragment library was optimized to afford IRAK4 inhibitors with nanomolar potency in cellular assays. The medicinal chemistry effort featured the judicious placement of lipophilicity, informed by co-crystal structures with IRAK4 and optimization of ADME properties to deliver clinical candidate PF-06650833 (compound 40). This compound displays a 5-unit increase in lipophilic efficiency from the fragment hit, excellent kinase selectivity, and pharmacokinetic properties suitable for oral administration.

Steroid hormone receptors including estrogen receptors (ER) classically function as ligand-regulated transcription factors. However, estrogens also elicit cellular effects through binding to extra-nuclear ER (ERα, ERβ, and G protein-coupled ER or GPER) that are coupled to kinases. How extra-nuclear ER actions impact cardiac ischemia-reperfusion (I/R) injury is unknown. We treated ovariectomized wild-type female mice with estradiol or an estrogen-dendrimer conjugate (EDC), which selectively activates extra-nuclear ER, or vehicle interventions for two weeks. I/R injury was then evaluated in isolated Langendorff perfused hearts. Two weeks of treatment with estradiol significantly decreased infarct size and improved post-ischemic contractile function. Similarly, EDC treatment significantly decreased infarct size and increased post-ischemic functional recovery compared to vehicle-treated hearts. EDC also caused an increase in myocardial protein S-nitrosylation, consistent with previous studies showing a role for this post-translational modification in cardioprotection. In further support of a role for S-nitrosylation, inhibition of nitric oxide synthase, but not soluble guanylyl cyclase blocked the EDC mediated protection. The administration of ICI182,780, which is an agonist of G-protein coupled estrogen receptor (GPER) and an antagonist of ERα and ERβ, did not result in protection; however, ICI182,780 significantly blocked EDC-mediated cardioprotection, indicating participation of ERα and/or ERβ. In studies determining the specific ER subtype and cellular target involved, EDC decreased infarct size and improved functional recovery in mice lacking ERα in cardiomyocytes. In contrast, protection was lost in mice deficient in endothelial cell ERα. Thus, extra-nuclear ERα activation in endothelium reduces cardiac I/R injury in mice, and this likely entails increased protein S-nitrosylation. Since EDC does not stimulate uterine growth, in the clinical setting EDC-like compounds may provide myocardial protection without undesired uterotrophic and cancer-promoting effects.

The regulatory control of cardiac endoplasmic reticulum (ER) stress is incompletely characterized. As ER stress signaling upregulates the E3-ubiquitin ligase Parkin, we investigated the role of Parkin in cardiac ER stress. Parkin knockout mice exposed to aortic constriction-induced cardiac pressure-overload or in response to systemic tunicamycin (TM) developed adverse ventricular remodeling with excessive levels of the ER regulatory C/EBP homologous protein CHOP. CHOP was identified as a Parkin substrate and its turnover was Parkin-dose and proteasome-dependent. Parkin depletion in cardiac HL-1 cells increased CHOP levels and enhanced susceptibility to TM-induced cell death. Parkin reconstitution rescued this phenotype and the contribution of excess CHOP to this ER stress injury was confirmed by reduction in TM-induced cell death when CHOP was depleted in Parkin knockdown cardiomyocytes. Isogenic Parkin mutant iPSC-derived cardiomyocytes showed exaggerated ER stress induced CHOP and apoptotic signatures and myocardium from subjects with dilated cardiomyopathy showed excessive Parkin and CHOP induction. This study identifies that Parkin functions to blunt excessive CHOP to prevent maladaptive ER stress-induced cell death and adverse cardiac ventricular remodeling. Additionally, Parkin is identified as a novel post-translational regulatory moderator of CHOP stability and uncovers an additional stress-modifying function of this E3-ubiquitin ligase.

Aims and objectives To evaluate the effect of an ‘insulin introduction’ group visit on insulin initiation and A1C in adults with type 2 diabetes. Background The clinical course of type 2 diabetes involves eventual beta-cell failure and the need for insulin therapy. Patient psychological insulin resistance, provider-related delays and system barriers to timely initiation of insulin are common. Group visits are widely accepted by patients and represent a potential strategy for improving insulin initiation. Design A single two-hour group visit in English or Spanish, facilitated by advanced practice nurses, addressed psychological insulin resistance and encouraged mock injections to overcome needle anxiety. Methods A retrospective review of 273 patients referred from 2008–2012, determined characteristics of group attenders, rates of mock self-injection, rates of insulin initiation and changes in A1C from baseline to 2–6 and 7–12 months postgroup. Change in A1C was compared to patients referred to the group who did not attend (‘nonattenders’). Results Of 241 patients eligible for analysis, 87·6% were racial/ethnic minorities with an average A1C of 9·99%. Group attendance rate was 66%; 92% performed a mock injection, 55% subsequently started insulin. By 2–6 months, A1C decreased by 1·37% among group attenders, and by 1·6% in those who did a mock injection and started insulin. Fewer nonattenders started insulin in primary care (40%), experiencing an A1C reduction of 0·56% by 2–6 months. A1C improvements were sustained by 7–12 months among group attenders and nonattenders who started insulin. Relevance to clinical practice Nurses can effectively address patient fears and engage patients in reframing insulin therapy within group visits. Conclusions This one-time nurse-facilitated group visit addressing psychological barriers to insulin in a predominantly minority patient population resulted in increased insulin initiation rates and clinically meaningful A1C reductions.

This study aimed to confirm the factor structure of the Beliefs about Paranoia Scale (BaPS), a self-report measure to assess metacognitive beliefs about paranoia, and to test hypotheses of a metacognitive model. We hypothesised that positive and negative beliefs about paranoia would be associated with severity of suspiciousness, and that the co-occurrence of positive and negative beliefs would be associated with increased suspiciousness. A total of 335 patients meeting criteria for a schizophrenia spectrum disorder completed the BaPS, the Positive and Negative Syndromes Scale (PANSS), and the Psychotic Symptom Rating Scales (PSYRATS). Confirmatory factor analysis verified that the three BaPS subscales (negative beliefs about paranoia, paranoia as a survival strategy, and normalizing beliefs) were an adequate fit of the data. Ordinal regression showed that positive beliefs about paranoia as a survival strategy and negative beliefs were both associated with severity of suspiciousness. This was the first study to show that the co-occurrence of positive and negative beliefs was associated with increased suspiciousness. All hypotheses were confirmed, suggesting that a metacognitive approach has utility for the conceptualization of paranoia. Clinical implications suggest a role for metacognitive therapy, including strategies such as detached mindfulness and worry postponement.

The clinical course of patients with recently diagnosed early stage chronic lymphocytic leukemia (CLL) is highly variable. We examined the relationship between CLL-cell birth rate and treatment-free survival (TFS) in 97 patients with recently diagnosed, Rai stage 0-II CLL in a blinded, prospective study, using in vivo 2H2O labeling. Birth rates ranged from 0.07 to 1.31% new cells per day. With median follow-up of 4.0 years, 33 subjects (34%) required treatment by NCI criteria. High-birth rate was observed in 44% of subjects and was significantly associated with shorter TFS, unmutated IGHV status and expression of ZAP70 and of CD38. In multivariable modeling considering age, gender, Rai stage, expression of ZAP70 or CD38, IGHV mutation status and FISH cytogenetics, only CLL-cell birth rate and IGHV mutation status met criteria for inclusion. Hazard ratios were 3.51 (P=0.002) for high-birth rate and 4.93 (P

Background There is limited research defining the true prevalence of anal incontinence (AI) in women of childbearing age. Understanding the limitations of the current assessment tools in the identification of AI is paramount for identifying the prevalence of AI and improving the care and management for women of childbearing age. The aim of this research was to explore and develop an understanding of women’s experiences in disclosing AI when completing a new bowel-screening questionnaire when compared to two established AI tools. Methods A phenomenological qualitative research study was undertaken in a maternity setting in a large tertiary hospital. Parous women in the first trimester of a subsequent pregnancy were recruited to complete a specifically designed screening tool (BSQ), St Marks Faecal incontinence score (Vaizey) and Cleveland (Wexner) score. Qualitative semi-structured interviews were utilised to identify experiences in disclosing AI. Results Women (n = 16, 22–42 years) with a history of anal incontinence either following the first birth (n = 12) or the second (n = 4) provided differing responses between the three assessment tools. All women answered the BSQ while the Vaizey and Wexner scores were more difficult to complete due to clinical language and participants level of comprehension. Women identified three major themes that were barriers for disclosing incontinence, which included social expectations, trusted space and confusion. Conclusion There are barriers for disclosing AI in the pregnant and post-natal population, which can be improved with the use of an easy assessment tool. The BSQ may facilitate discussion on AI between the patient and health professional leading to earlier identification and improvement in short and long-term health outcomes.

While much work has been done in associating differentially methylated positions (DMPs) to type 2 diabetes (T2D) across different populations, not much attention has been placed on identifying its possible functional consequences. We explored methylation changes in the peripheral blood of Filipinos with T2D and identified 177 associated DMPs. Most of these DMPs were associated with genes involved in metabolism, inflammation and the cell cycle. Three of these DMPs map to the TXNIP gene body, replicating previous findings from epigenome-wide association studies (EWAS) of T2D. The TXNIP downmethylation coincided with increased transcription at the 3’-UTR, H3K36me3 histone markings, and Sp1 binding, suggesting spurious transcription initiation at the TXNIP 3’-UTR as a functional consequence of T2D methylation changes. We also explored potential epigenetic determinants to increased incidence of T2D in Filipino immigrants in the United States and found 3 DMPs associated with the interaction of T2D and immigration. Two of these DMPs were located near MAP 2 K7 and PRMT1, which may point towards dysregulated stress response and inflammation as a contributing factor to T2D among Filipino immigrants.

Objective There is an ongoing debate about excluding patient's global assessment (PtGA) from composite and Boolean-based definitions of rheumatoid arthritis (RA) remission. This study aimed at determining the influence of PtGA on RA disease states, exploring differences across countries, and understanding the association between PtGA, measures of disease impact (symptoms), and markers of disease activity (inflammation). Methods Cross-sectional data from the Measurement of Efficacy of Treatment in the Era of Outcome in Rheumatology international database were used. We calculated the proportion of patients failing American College of Rheumatology/European League Against Rheumatism Boolean-based remission (4-variable remission) solely due to PtGA (PtGA-near-remission) in the overall sample and in the most representative countries (i.e., those with >3,000 patients in the database). Multivariable linear regression models were used to identify the main determinants of PtGA, grouped in predominantly inflammatory impact factors (28 tender joint counts, 28 swollen joint counts, and C-reactive protein level) and disease impact factors (pain and function). Results This study included 27,768 patients. Excluding PtGA from the Boolean-based definition (3-variable remission) increased the remission rate from 5.8% to 15.8%. The rate of PtGA-near-remission varied considerably between countries, from 1.7% in India to 17.9% in Portugal. One-third of the patients in PtGA-near-remission group scored PtGA >4 of 10. Pain and function were the main correlates of PtGA, with inflammation-related variables contributing less to the model (R2 = 0.57). Conclusion PtGA is moderately related to joint inflammation overall, but only weakly so in low levels of disease activity. A considerable proportion of patients otherwise in biologic remission still perceive high PtGA, putting them at risk of excessive immunosuppressive treatment.

Patient, caregiver, and family education and support was 1 of 6 key areas of interest identified by the National Marrow Donor Program/Be The Match 2-year project to prioritize patient-centered outcomes research (PCOR) goals for the blood and marrow transplantation (BMT) community. PCOR focuses on research to help patients and their caregivers make informed decisions about health care. Therefore, each area of interest was assigned to a working group with broad representation, including patients, caregivers, and clinicians. Each working group was charged with identifying gaps in knowledge and making priority recommendations for critical research to fill those gaps. The report from this working group presents a conceptual framework to address gaps in knowledge regarding patient and caregiver education in BMT and recommendations for priority research questions on this topic. ispartof: BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION vol:25 issue:7 pages:1416-1423 ispartof: location:United States status: published

ObjectiveTo investigate associations between baseline presence of erosions and/or anti-citrullinated protein antibodies (ACPA) on functional ability, disease activity and treatment survival over time.MethodsReal life data from newly diagnosed rheumatoid arthritis patients were identified in the international METEOR registry. Patients were grouped according to presence/absence of ACPA and/or erosions at baseline. Associations between the presence of ACPA and/or erosions (four groups) with the change of Disease Activity Score (DAS) and Health Assessment Questionnaire (HAQ) over time were assessed using linear mixed models during maximum 6 or maximum 12 months from baseline. Treatment survival was assessed using multiple failure-times Cox regression.ResultsData were included from 701 ACPA‒/erosions‒, 334 ACPA‒/erosions+, 1585 ACPA+/erosions‒ and 1993 ACPA+/erosions+ patients. We found statistically significant differences in DAS and HAQ change over time between the four groups, both after maximum follow-up durations of 6 and of 12 months, but after stratification differences proved small and not clinically meaningful. Patients in the ACPA‒/erosions‒ group were less likely to switch treatment compared with the ACPA+/erosions‒ reference group (pConclusionsIn this analysis of worldwide real life data, we found statistically significant, but clinically irrelevant differences in treatment response to initial disease modifying anti-rheumatic drug therapies as measured by DAS and HAQ in ACPA‒/erosions‒, ACPA‒/erosions+, ACPA+/erosions‒ and ACPA+/erosions+ rheumatoid arthritis patients. However, after maximum follow-up durations of 6 and 12 months all groups had a similar response to initial treatment, but with a lower likelihood to switch treatment for ACPA‒/erosions‒ patients during the first year of follow-up.

The mechanisms regulating translation and splicing are not well understood. We provide insight into a new regulator of translation, OGFOD1 (2-oxoglutarate and iron dependent oxygenase domain-containing protein 1), which is a prolyl-hydroxylase that catalyzes the posttranslational hydroxylation of Pro-62 in the small ribosomal protein S23. We show that deletion of OGFOD1 in an in vitro model of human cardiomyocytes decreases translation of specific proteins (e.g., RNA-binding proteins) and alters splicing. RNA sequencing showed poor correlation between changes in mRNA and protein synthesis, suggesting that posttranscriptional regulation was the primary cause for the observed differences. We found that loss of OGFOD1 and the resultant alterations in protein translation modulates the cardiac proteome, shifting it towards higher protein amounts of sarcomeric proteins such as cardiac troponins, titin and cardiac myosin binding protein C. Furthermore, we found a decrease of OGFOD1 during cardiomyocyte differentiation. These results suggest that loss of OGFOD1 modulates protein translation and splicing, thereby leading to alterations in the cardiac proteome and highlight the role of altered translation and splicing in regulating the proteome..

Introduction Clinics increasingly screen patients for food insecurity, but little is known about the efficacy of referring food-insecure patients to community-based food resources. Objective To evaluate the implementation of a tailored community food resource referral program in a safety-net diabetes clinic. Methods We conducted semistructured phone interviews with food-insecure patients participating in a screening and referral program in a diabetes clinic affiliated with a safety-net hospital. In this qualitative study, we describe barriers to and facilitators of successful food resource referrals from the patient's perspective. Results The prevalence of food insecurity was high (60%). Provision of written and verbal information alone about community food resources resulted in low linkage rates (0%-4%), even with individually tailored referrals. Misperceptions about eligibility, fears around government program registration, inaccessibility, lack of information retention, competing priorities, an inability to cook, stigma, and a perceived sense of stability with existing food support were major barriers to use. Personnel-guided, in-clinic enrollment to a food resource facilitated a higher connection rate (31%). Discussion Results of this study suggest that screening for food insecurity followed by a list of food resources for those screening positive may not adequately address patient barriers to using community-based food resources. For food insecurity screening programs in the clinical setting to be effective, systems must not only distribute food resource information but also assist patients in enrollment processes.