KIT ATP-Binding Pocket/Activation Loop Mutations in GI Stromal Tumor: Emerging Mechanisms of Kinase Inhibitor Escape.

PURPOSE: Imatinib resistance in GI stromal tumors (GISTs) is primarily caused by secondary KIT mutations, and clonal heterogeneity of these secondary mutations represents a major treatment obstacle. KIT inhibitors used after imatinib have clinical activity, albeit with limited benefit. Ripretinib is a potent inhibitor of secondary KIT mutations in the activation loop (AL). However, clinical benefit in fourth line remains limited and the molecular mechanisms of ripretinib resistance are largely unknown. PATIENTS AND METHODS: Progressing lesions of 25 patients with GISTs refractory to ripretinib were sequenced for KIT resistance mutations. Resistant genotypes were validated and characterized using novel cell line models and in silico modeling. RESULTS: GISTs progressing on ripretinib were enriched for secondary mutations in the ATP-binding pocket (AP), which frequently occur in cis with preexisting AL mutations, resulting in highly resistant AP/AL genotypes. AP/AL mutations were rarely observed in a cohort of progressing GIST samples from the preripretinib era but represented 50% of secondary KIT mutations in patients with tumors resistant to ripretinib. In GIST cell lines harboring secondary KIT AL mutations, the sole genomic escape mechanisms during ripretinib drug selection were AP/AL mutations. Ripretinib and sunitinib synergize against mixed clones with secondary AP or AL mutants but do not suppress clones with AP/AL genotypes. CONCLUSION: Our findings underscore that KIT remains the central oncogenic driver even in late lines of GIST therapy. KIT-inhibitor combinations may suppress resistance because of secondary KIT mutations. However, the emergence of KIT AP/AL mutations after ripretinib treatment calls for new strategies in the development of next-generation KIT inhibitors.

Smartphone survey data reveal the timecourse of changes in mood outcomes following vitamin C or kiwifruit intervention in adults with low vitamin C.

Vitamin C-rich foods can improve mood; however, the timecourse of these benefits is unknown. This study utilised intensive longitudinal smartphone surveys from a three-armed placebo-controlled trial to determine mood-related changes following supplementation with vitamin C (250 mg tablet/d), kiwifruit (2 SunGold™ kiwifruit/d) or a placebo (1 tablet/d). Secondary data were analysed from the KiwiC for Vitality trial (Trial ID: ACTRN12617001031358). Adults (n 155, 63 % female, aged 18-35 years) with low plasma vitamin C (<40 µmol/l) completed a 14-d lead-in, 28-d intervention and 14-d washout. Participants self-reported vitality (SF-36), mood (POMS total mood disturbance), flourishing (flourishing scale), sleep quality, sleep quantity and physical activity every second day using smartphone surveys. Plasma vitamin C, measured fortnightly, reached saturation after 2 weeks of vitamin C or kiwifruit supplementation. Kiwifruit supplementation improved vitality and mood within 4 days, peaking around 14-16 days, and improved flourishing from day 14. Vitamin C marginally improved mood until day 12. Incremental AUC analyses revealed significant overall effects of kiwifruit consumption on vitality and mood compared with placebo, which were stronger than effects for vitamin C tablets, but attenuated when adjusting for covariates. Sensitivity analyses of participants with low baseline vitamin C status revealed improved mood (vitamin C and kiwifruit) and flourishing (kiwifruit only). This is the first study to use intensive smartphone surveys to model the day-to-day timecourse of mood-related states following vitamin C intervention and highlights the value of using smartphone surveys to reveal the temporal changes in mood-related outcomes following nutrient supplementation.

Plasma Sequencing for Patients with GIST-Limitations and Opportunities in an Academic Setting.

Circulating tumor DNA (ctDNA) from circulating free DNA (cfDNA) in GIST is of interest for the detection of heterogeneous resistance mutations and treatment monitoring. However, methodologies for use in a local setting are not standardized and are error-prone and difficult to interpret. We established a workflow to evaluate routine tumor tissue NGS (Illumina-based next generation sequencing) panels and pipelines for ctDNA sequencing in an academic setting. Regular blood collection (Sarstedt) EDTA tubes were sufficient for direct processing whereas specialized tubes (STRECK) were better for transportation. Mutation detection rate was higher in automatically extracted (AE) than manually extracted (ME) samples. Sensitivity and specificity for specific mutation detection was higher using digital droplet (dd)PCR compared to NGS. In a retrospective analysis of NGS and clinical data (133 samples from 38 patients), cfDNA concentration correlated with tumor load and mutation detection. A clinical routine pipeline and a novel research pipeline yielded different results, but known and resistance-mediating mutations were detected by both and correlated with the resistance spectrum of TKIs used. In conclusion, NGS routine panel analysis was not sensitive and specific enough to replace solid biopsies in GIST. However, more precise methods (hybridization capture NGS, ddPCR) may comprise important research tools to investigate resistance. Future clinical trials need to compare methodology and protocols.

Reply to Vorland et al. Mixed Random and Nonrandom Allocation, and Group Randomization Have Been Mislabeled and Misanalysed, Necessitating Reanalysis. Comment on "Conner et al. KiwiC for Vitality: Results of a Randomized Placebo-Controlled Trial Testing the Effects of Kiwifruit or Vitamin C Tablets on Vitality in Adults with Low Vitamin C Levels. Nutrients 2020, 12, 2898".

We have read the Comment article by Vorland et al. [...].

Correction: Conner et al. KiwiC for Vitality: Results of a Placebo-Controlled Trial Testing the Effects of Kiwifruit or Vitamin C Tablets on Vitality in Adults with Low Vitamin C Levels. Nutrients 2020, 12, 2898.

In the original publication title [...].

Symptom burden and health-related quality of life in chronic kidney disease: A global systematic review and meta-analysis.

BACKGROUND: The importance of patient-reported outcome measurement in chronic kidney disease (CKD) populations has been established. However, there remains a lack of research that has synthesised data around CKD-specific symptom and health-related quality of life (HRQOL) burden globally, to inform focused measurement of the most relevant patient-important information in a way that minimises patient burden. The aim of this review was to synthesise symptom prevalence/severity and HRQOL data across the following CKD clinical groups globally: (1) stage 1-5 and not on renal replacement therapy (RRT), (2) receiving dialysis, or (3) in receipt of a kidney transplant. METHODS AND FINDINGS: MEDLINE, PsycINFO, and CINAHL were searched for English-language cross-sectional/longitudinal studies reporting prevalence and/or severity of symptoms and/or HRQOL in CKD, published between January 2000 and September 2021, including adult patients with CKD, and measuring symptom prevalence/severity and/or HRQOL using a patient-reported outcome measure (PROM). Random effects meta-analyses were used to pool data, stratified by CKD group: not on RRT, receiving dialysis, or in receipt of a kidney transplant. Methodological quality of included studies was assessed using the Joanna Briggs Institute Critical Appraisal Checklist for Studies Reporting Prevalence Data, and an exploration of publication bias performed. The search identified 1,529 studies, of which 449, with 199,147 participants from 62 countries, were included in the analysis. Studies used 67 different symptom and HRQOL outcome measures, which provided data on 68 reported symptoms. Random effects meta-analyses highlighted the considerable symptom and HRQOL burden associated with CKD, with fatigue particularly prevalent, both in patients not on RRT (14 studies, 4,139 participants: 70%, 95% CI 60%-79%) and those receiving dialysis (21 studies, 2,943 participants: 70%, 95% CI 64%-76%). A number of symptoms were significantly (p < 0.05 after adjustment for multiple testing) less prevalent and/or less severe within the post-transplantation population, which may suggest attribution to CKD (fatigue, depression, itching, poor mobility, poor sleep, and dry mouth). Quality of life was commonly lower in patients on dialysis (36-Item Short Form Health Survey [SF-36] Mental Component Summary [MCS] 45.7 [95% CI 45.5-45.8]; SF-36 Physical Component Summary [PCS] 35.5 [95% CI 35.3-35.6]; 91 studies, 32,105 participants for MCS and PCS) than in other CKD populations (patients not on RRT: SF-36 MCS 66.6 [95% CI 66.5-66.6], p = 0.002; PCS 66.3 [95% CI 66.2-66.4], p = 0.002; 39 studies, 24,600 participants; transplant: MCS 50.0 [95% CI 49.9-50.1], p = 0.002; PCS 48.0 [95% CI 47.9-48.1], p = 0.002; 39 studies, 9,664 participants). Limitations of the analysis are the relatively few studies contributing to symptom severity estimates and inconsistent use of PROMs (different measures and time points) across the included literature, which hindered interpretation. CONCLUSIONS: The main findings highlight the considerable symptom and HRQOL burden associated with CKD. The synthesis provides a detailed overview of the symptom/HRQOL profile across clinical groups, which may support healthcare professionals when discussing, measuring, and managing the potential treatment burden associated with CKD. PROTOCOL REGISTRATION: PROSPERO CRD42020164737.

Fears about COVID-19 and perceived risk among people with rheumatoid arthritis or ankylosing spondylitis following the initial lockdown in Aotearoa New Zealand.

BACKGROUND: The COVID-19 pandemic has disrupted all aspects of life and may raise particular fears for people with rheumatic disease. There is a need for research on fears and perceived risk of SARS-CoV-2 so as to understand the impact on wellbeing and inform service provision. OBJECTIVES: The aim of this study was to examine the correlates of COVID-19 fears and perceived risk of SARS-CoV-2 among people with rheumatoid arthritis or ankylosing spondylitis. DESIGN: A cross-sectional survey design was applied in Aotearoa New Zealand in the period after initial nationwide lockdowns. METHOD: An online survey was completed from July to September 2020 by 126 individuals with rheumatoid arthritis (n = 96) or ankylosing spondylitis (n = 30) who had previously been recruited to the Patient Opinion Real-Time Anonymous Liaison (PORTAL) study in 2015 or 2018. The survey included demographics and health information as well as measures of COVID-19 fears and experiences, functional disability and fatigue-related disability. RESULTS: Fears about COVID-19 were higher among younger participants, those who had been tested for SARS-CoV-2, and those who experienced more flares over the initial lockdown. Perceived risk of SARS-CoV-2 infection was also higher among individual who had been tested for SARS-CoV-2 and those taking biologic medications. CONCLUSION: Fears about COVID-19 and perceived risk of infection are related to age, health and medications among individuals with rheumatoid arthritis or ankylosing spondylitis. These findings inform how health professionals can help address the concerns of particular groups of people with rheumatic disease by providing relevant information about the ongoing effects of the pandemic.

Mental health and quality of life for people with rheumatoid arthritis or ankylosing spondylitis in Aotearoa New Zealand following the COVID-19 national lockdown.

The aim of this study was to investigate the effects of lockdown on the mental health (anxiety and depression) and quality of life (QOL) of people with rheumatoid arthritis (RA) and ankylosing spondylitis (AS) in the context of the COVID-19 pandemic and public health measures instituted at a national level by the New Zealand Government. The present cohort was 104 individuals with RA (73.1%) and AS (26.9%) who had previously completed surveys for the Patient Opinion Real-Time Anonymous Liaison (PORTAL) project in 2018. Participants completed an online survey between July and September 2020 assessing their experiences over the first national COVID-19 lockdown in New Zealand (March-May, 2020). Fear of SARS-CoV-2 infection, baseline anxiety, and being younger in age were all predictors of participants' current anxiety levels. Current QOL scores were significantly lower than prior to lockdown and were predicted by baseline QOL and current depression. No variables predicted current depression other than baseline levels. The COVID-19 pandemic appears to have had an impact on QOL and anxiety levels, but not depression for people with RA and AS in New Zealand. These novel findings imply that appropriate screening of mental health issues should be included in planning within the ongoing COVID-19 pandemic and for future pandemics to optimise the wellbeing of people with RA and AS.

The relationship between duration and quality of sleep and upper respiratory tract infections: a systematic review.

BACKGROUND: Upper respiratory tract infections (URTIs) are common, mostly self-limiting, but result in inappropriate antibiotic prescriptions. Poor sleep is cited as a factor predisposing to URTIs, but the evidence is unclear. OBJECTIVE: To systematically review whether sleep duration and quality influence the frequency and duration of URTIs. METHODS: Three databases and bibliographies of included papers were searched for studies assessing associations between sleep duration or quality and URTIs. We performed dual title and abstract selection, discussed full-text exclusion decisions and completed 50% of data extraction in duplicate. The Newcastle-Ottawa Quality Assessment Scale assessed study quality and we estimated odds ratios (ORs) using random effects meta-analysis. RESULTS: Searches identified 5146 papers. Eleven met inclusion criteria, with nine included in meta-analyses: four good, two fair and five poor for risk of bias. Compared to study defined 'normal' sleep duration, shorter sleep was associated with increased URTIs (OR: 1.30, 95% confidence interval [CI]: 1.19-1.42, I2: 11%, P < 0.001) and longer sleep was not significantly associated (OR: 1.11 95% CI: 0.99-1.23, I2: 0%, P = 0.070). Sensitivity analyses using a 7- to 9-hour baseline found that sleeping shorter than 7-9 hours was associated with increased URTIs (OR: 1.31, 95% CI: 1.22-1.41, I2: 0%, P < 0.001). Sleeping longer than 7-9 hours was non-significantly associated with increased URTIs (OR: 1.15, 95% CI: 1.00-1.33, I2: 0%, P = 0.050, respectively). We were unable to pool sleep quality studies. No studies reported on sleep duration and URTI severity or duration. CONCLUSIONS: Reduced sleep, particularly shorter than 7-9 hours, is associated with increased URTIs. Strategies improving sleep should be explored to prevent URTIs.

It is widely believed that poor sleep increases people's chances of catching coughs, colds and other upper airway infections. UK government advice states that poor sleep and catching a cold or the flu could be related and suggests most individuals need 8 hours sleep a night. Studies have helped to explain the link between sleep and infections by showing that shortened sleep reduces the body's ability to fight infections. Studies in humans that look at the link between sleep and catching a cold or other airway infection have mostly been small and have conclusions that differ. We set out to investigate whether the quality of sleep (how 'well' you sleep) and the quantity of sleep (how 'long' you sleep) influence a person's likelihood of getting an upper airway infection. We found that shorter sleep than normal resulted in increased chances of having an upper airway infection, whereas longer sleep did not. We also found that sleeping for shorter or longer than 7­9 hours per night increased the likelihood of having an upper airway infection. Our results are important for informing conversations between patients and doctors around sleep and for encouraging the investigation of the impact of sleep on more serious infections.

Initial Evidence of Variation by Ethnicity in the Relationship between Vitamin C Status and Mental States in Young Adults.

Higher fruit and vegetable intake has been associated with improved mood, greater vitality, and lower stress. Although the nutrients driving these benefits are not specifically identified, one potentially important micronutrient is vitamin C, an important co-factor for the production of peptide hormones, carnitine and neurotransmitters that are involved in regulation of physical energy and mood. The aim of our study was to investigate the cross-sectional relationship between blood plasma vitamin C status and mood, vitality and perceived stress. A sample of 419 university students (aged 18 to 35; 67.8% female) of various ethnicities (49.2% European, 16.2% East Asian, 8.1% Southeast/Other Asian, 9.1% Maori/Pasifika, 11.5% Other) provided a fasting blood sample to determine vitamin C status and completed psychological measures consisting of the Profile of Mood States Short Form (POMS-SF), the vitality subscale of the Rand 36-Item Short Form (SF-36), and the Perceived Stress Scale (PSS). Participants were screened for prescription medication, smoking history, vitamin C supplementation, fruit/juice and vegetable consumption, kiwifruit allergies, excessive alcohol consumption and serious health issues, and provided age, gender, ethnicity, and socioeconomic status information, which served as covariates. There were no significant associations between vitamin C status and the psychological measures for the sample overall. However, associations varied by ethnicity. Among Maori/Pasifika participants, higher vitamin C was associated with greater vitality and lower stress, whereas among Southeast Asian participants, higher vitamin C was associated with greater confusion on the POMS-SF subscale. These novel findings demonstrate potential ethnicity-linked differences in the relationship between vitamin C and mental states. Further research is required to determine whether genetic variation or cultural factors are driving these ethnicity differences.

Interruption of the Ascending Aorta-Biventricular Surgical Repair.

Interruption of the ascending aorta is an extremely rare anomaly defined by a point of interruption between the intrapericardial and extrapericardial aorta and can be explained by developmental errors proximal to the embryologic right aortic sac. Herein, we present a case of interruption of the ascending aorta and describe a successful biventricular surgical repair of this unique anomaly.

Annual dynamics of antimicrobials and resistance determinants in flocculent and aerobic granular sludge treatment systems.

The occurrence and removal patterns of 24 antimicrobial agents and antimicrobial resistant determinants namely 6 antibiotic resistance genes (ARGs) and 2 mobile genetic elements (MGEs), and the fecal indicator E. coli were investigated in three full-scale wastewater treatment plants. Their waterlines and biosolids lines (including secondary treatment based on both granular and activated sludge) were sampled monthly throughout one year. Samples were analyzed by means of LC-MS/MS, qPCR and cell enumeration, respectively. The influence of rainfall, temperature, and turbidity on the occurrence and removal of the aforementioned agents was assessed through statistical linear mixed models. Ten of the antimicrobial agents (macrolides, fluoroquinolones, tetracyclines, and sulfonamides) were commonly found in influent in concentrations of 0.1-2 µg L-1, and the predominant ARGs were ermB and sul1 (6.4 and 5.9 log10 mL-1 respectively). Warmer temperatures slightly reduced gene concentrations in influent whilst increasing that of E. coli and produced an uneven effect on the antimicrobial concentrations across plants. Rainfall diluted both E. coli (-0.25 logs, p < 0.001) and antimicrobials but not genes. The wastewater treatment reduced the absolute abundance of both genes (1.86 logs on average) and E. coli (2.31 logs on average). The antimicrobials agents were also partly removed, but 8 of them were still detectable after treatment, and 6 accumulated in the biosolids. ARGs were also found in biosolids with patterns resembling those of influent. No significant differences in the removal of antimicrobials, genes and E. coli were observed when comparing conventional activated sludge with aerobic granular sludge. Irrespective of the type of sludge treatment, the removal of genes was significantly reduced with increasing hydraulic loads caused by rainfall (-0.35 logs per ∆ average daily flow p < 0.01), and slightly decreased with increasing turbidity (-0.02 logs per ∆1 nephelometric turbidy unit p < 0.05) .

Revisiting Risk and Benefit in Early Oncology Trials in the Era of Precision Medicine: A Systematic Review and Meta-Analysis of Phase I Trials of Targeted Single-Agent Anticancer Therapies.

PURPOSE: Phase I trials are a crucial step in the evaluation of new cancer therapies. Historically, low rates of response (5%) and comparably high rates of death from toxicities (0.5%) have contributed to debates on the ethics and orientation of these trials. With the introduction of novel targeted therapies, a contemporary estimate is needed. METHODS: We systematically searched PubMed, Embase, and ClinicalTrials.gov for reports of phase I oncology trials of single-agent targeted immunomodulators, molecularly targeted therapies, and antiangiogenic agents, published between January 2015 and July 2018. Adult and pediatric trials of solid and hematological malignancies were eligible. Treatment-related adverse events (grades 3, 4, and 5) and response rates (objective, complete, and partial) were extracted and analyzed. RESULTS: One hundred and fifty-eight trial reports, covering 6,707 patients, were included. The rate of treatment-related deaths was 0.0% (95% CI, 0.0 to 0.1), while 13.2% of patients (9.5 to 17.3) experienced a grade 3 or 4 treatment-related toxicity. The combined objective response rate was 6.4% (4.6 to 8.5). Among trials using tumor biomarkers as eligibility criteria, the objective response rate was higher (12.0% [7.3 to 17.6] compared to 4.9% [2.5 to 5.7], P value < .01). The same was true of trials focusing on a single tumor type (13.4% [8.2 to 19.4]) compared to multiple tumor types (3.8% [2.5 to 5.3], P value < .01). CONCLUSION: Reduced grade 5 risk and improved benefit appears to exist in modern phase I oncology trials, particularly in trials that target single tumor types and integrate biomarkers as eligibility criteria. These findings provide information to support informed consent discussions, highlight the need for improved reporting of phase I oncology trials, and provide direction for optimizing their design.

Understanding Fatigue-Related Disability in Rheumatoid Arthritis and Ankylosing Spondylitis: The Importance of Daily Correlates.

OBJECTIVE: Fatigue is common among people with inflammatory arthritis but is hard to manage. The aim of this study was to investigate how daily fluctuations in psychological variables correspond with changes in fatigue-related disability in the daily lives of people with inflammatory arthritis and to identify factors to target in psychological interventions and routine clinical practice. METHODS: A cohort of 143 patients with rheumatoid arthritis (n = 97) or ankylosing spondylitis (n = 46) participated in a 10-day online diary study. Each evening participants completed a diary questionnaire assessing their fatigue, pain, fatigue-related disability, and 4 components of psychological flexibility (valued activity, mindfulness, cognitive fusion, and fatigue avoidance). RESULTS: On days when participants were more engaged in valued activities or more mindful, they reported less disability due to fatigue, even when controlling for levels of fatigue and pain that day. The daily psychological flexibility variables explained a total of 15.6% of the variance in daily fatigue-related disability. CONCLUSION: Psychological flexibility variables are directly associated with fatigue-related disability in the daily lives of inflammatory arthritis patients. Further research is needed to investigate whether interventions that target psychological flexibility are effective at reducing fatigue-related disability.

KiwiC for Vitality: Results of a Randomized Placebo-Controlled Trial Testing the Effects of Kiwifruit or Vitamin C Tablets on Vitality in Adults with Low Vitamin C Levels.

Consumption of vitamin C-rich fruits and vegetables has been associated with greater feelings of vitality. However, these associations have rarely been tested in experimental trials. The aim of the current study was to test the effects of eating a vitamin C-rich food (kiwifruit) on subjective vitality and whether effects are driven by vitamin C. Young adults (n = 167, 61.1% female, aged 18­35 years) with plasma vitamin C < 40 µmol/L were allocated to three intervention conditions: kiwifruit (2 SunGold™ kiwifruit/day), vitamin C (250 mg tablet/day), placebo (1 tablet/day). The trial consisted of a two-week lead-in, four-week intervention, and two-week washout. Plasma vitamin C and vitality questionnaires (total mood disturbance, fatigue, and well-being) were measured fortnightly. Self-reported sleep quality and physical activity were measured every second day through smartphone surveys. Nutritional confounds were assessed using a three-day food diary during each study phase. Plasma vitamin C reached saturation levels within two weeks for the kiwifruit and vitamin C groups. Participants consuming kiwifruit showed a trend of improvement in mood disturbance, significantly decreased fatigue, and significantly improved well-being after two weeks of the intervention. Improvements in well-being remained elevated through washout. Consumption of vitamin C tablets alone was associated with improved well-being after two weeks, and additionally improved mood and fatigue for participants with consistently low vitamin C levels during lead-in. Diet records showed that participants consuming kiwifruit reduced their fat intake during the intervention period. Intervention effects remained significant when adjusting for condition allocation groupings, age, and ethnicity, and were not explained by sleep quality, physical activity, BMI, or other dietary patterns, including fat intake. There were no changes in plasma vitamin C status or vitality in the placebo group. Whole-food consumption of kiwifruit was associated with improved subjective vitality in adults with low vitamin C status. Similar, but not identical changes were found for vitamin C tablets, suggesting that additional properties of kiwifruit may contribute to improved vitality.

Immunogenic and inflammatory responses to citrullinated proteins are enhanced following modification with malondialdehyde-acetaldehyde adducts.

BACKGROUND/OBJECTIVE: Malondialdehyde-acetaldehyde adducts (MAA) act as potent immune adjuvants and co-localize with citrullinated antigens in tissues effected by rheumatoid arthritis (RA). We sought to examine the role of MAA-adducts in promoting RA-related autoimmunity and inflammation. METHODS: DBA/J1 mice were immunized with human serum albumin (HSA), HSA-MAA, citrullinated HSA (HSA-Cit), or HSA-MAA-Cit with subsequent measurement of serum anti-citrullinated protein antibody (ACPA) and anti-Cit T cell responses. Cellular binding of the same antigens was examined using THP-1 monocytes and Chinese Hamster Ovary (CHO) cells transfected with specific scavenger receptors (SRs: TLR4, SR-B2, SREC-1). The effects of these antigens on THP-1 activation were then examined by quantifying plate adherence, pro-inflammatory (TNFα, IL-1ß, IL-10) cytokine release, and SR (CD14, SR-B2)/co-stimulatory molecule (CD80, HLA-DR) expression. Comparisons were completed using one-way ANOVA with Tukey's post-hoc test. RESULTS: Mice immunized with co-modified HSA produced significantly higher ACPA concentrations than all other groups whereas T cell responses to citrullinated proteins were highest following immunization with HSA-MAA. Both transfected CHO and THP-1 cells demonstrated significantly higher binding of HSA-MAA-Cit vs. HSA or HSA-Cit. THP-1 cells exposed to HSA-MAA-Cit expressed significantly higher concentrations of TNFα, IL-1ß, and IL-10 vs. all other groups. Furthermore, THP-1 cells demonstrated significantly increased plate adherence and higher expression of CD14, SR-B2, and HLA-DR following incubation with HSA-MAA-Cit vs. HSA or HSA-Cit. CONCLUSION: These studies demonstrate that MAA-adduction of citrullinated antigen greatly enhances immune and cellular responses, potentially acting as a key co-factor in RA pathogenesis.

Acceptance and commitment therapy for people with rheumatic disease: Existing evidence and future directions.

INTRODUCTION: Despite advances in the management of rheumatic diseases, many patients experience persistent pain and fatigue. Psychological interventions are useful adjunctive treatments, but improvements tend to be small, and progress in this area is needed. The aim of this review was to evaluate the effectiveness of acceptance and commitment therapy (ACT) for the treatment of chronic pain and fatigue in patients with rheumatic disease. METHODS: A systematic literature search was conducted in MEDLINE, EMBASE, and PsycINFO for randomised controlled trials (RCTs) of ACT for the treatment of chronic pain and fatigue in patients with rheumatic disease. Ten RCTs that included people with rheumatic disease were identified, rated for risk of bias, and summarised in terms of effects on relevant outcomes (disability, emotional functioning, pain, and quality of life). RESULTS: Treatment with ACT was associated with improvements in physical and emotional functioning, pain, and quality of life in chronic pain patients. The favourable effects of ACT were evident when compared with those of treatment as usual or active control conditions (e.g., pain education and novel medication). There was consistent evidence to show that ACT is beneficial in improving physical and emotional functioning in patients with fibromyalgia but a lack of evidence pertaining to patients with other forms of rheumatic disease. CONCLUSION: ACT provides benefit for fibromyalgia patients. Further high-quality research is needed to develop ACT interventions for people with inflammatory rheumatic diseases and to evaluate their effectiveness for managing the pain and fatigue associated with these conditions.

Patient preferences for management of high blood pressure in the UK: a discrete choice experiment.

BACKGROUND: With a variety of potentially effective hypertension management options, it is important to determine how patients value different models of care, and the relative importance of factors in their decision-making process. AIM: To explore patient preferences for the management of hypertension in the UK. DESIGN AND SETTING: Online survey of patients who have hypertension in the UK including an unlabelled discrete choice experiment (DCE). METHOD: A DCE was developed to assess patient preferences for the management of hypertension based on four attributes: model of care, frequency of blood pressure (BP) measurement, reduction in 5-year cardiovascular risk, and costs to the NHS. A mixed logit model was used to estimate preferences, willingness-to-pay was modelled, and a scenario analysis was conducted to evaluate the impact of changes in attribute levels on the uptake of different models of care. RESULTS: One hundred and sixty-seven participants completed the DCE (aged 61.4 years, 45.0% female, 82.0% >5 years since diagnosis). All four attributes were significant in choice (P<0.05). Reduction in 5-year cardiovascular risk was the main driver of patient preference as evidenced in the scenario and willingness-to-pay analyses. GP management was significantly preferred over self-management. Patients preferred scenarios with more frequent BP measurement, and lower costs to the NHS. CONCLUSION: Participants had similar preferences for GP management, pharmacist management, and telehealth, but a negative preference for self-management. When introducing new models of care for hypertension to patients, discussion of the potential benefits in terms of risk reduction should be prioritised to maximise uptake.

Exploring women's preferences for birth settings in England: A discrete choice experiment.

OBJECTIVE: To explore pregnant women's preferences for birth setting in England. DESIGN: Labelled discrete choice experiment (DCE). SETTING: Online survey. SAMPLE: Pregnant women recruited through social media and an online panel. METHODS: We developed a DCE to assess women's preferences for four hypothetical birth settings based on seven attributes: reputation, continuity of care, distance from home, time to see a doctor, partner able to stay overnight, chance of straightforward birth and safety for baby. We used a mixed logit model, with setting modelled as an alternative-specific constant, and conducted a scenario analysis to evaluate the impact of changes in attribute levels on uptake of birth settings. MAIN OUTCOME MEASURES: Women's preferences for birth setting. RESULTS: 257 pregnant women completed the DCE. All birth setting attributes, except 'time to see doctor', were significant in women's choice (p<0.05). There was significant heterogeneity in preferences for some attributes. Changes to levels for 'safety for the baby' and 'partner able to stay overnight' were associated with larger changes from baseline uptake of birth setting. If the preferences identified were translated into the real-world context up to a third of those who reported planning birth in an obstetric unit might choose a midwifery unit assuming universal access to all settings, and knowledge of the differences between settings. CONCLUSIONS: We found that 'safety for the baby', 'chance of a straightforward birth' and 'can the woman's partner stay overnight following birth' were particularly important in women's preferences for hypothetical birth setting. If all birth settings were available to women and they were aware of the differences between them, it is likely that more low risk women who currently plan birth in OUs might choose a midwifery unit.

The peril of self-reported adherence in digital interventions: A brief example.

Adherence is an important predictor of intervention outcomes, but not all measures of adherence are created equally. Here, we analyzed whether there was a discrepancy between self-report adherence and objective adherence in a digital mindfulness meditation randomised, controlled trial. A sample of 174 young adult undergraduate university students trialled either an app-based or email-based mindfulness meditation program (or an app-based attention control). Participants' adherence (number of sessions completed) and mental health was self-reported. Objective adherence data were provided by the owners of the digital mindfulness programs. We found evidence of inflated self-reported adherence to the app-based intervention and argue that the inflation was not explained by social desirability biases because participants were aware we would have access to object data and no remuneration was tied to adherence. We also comment on the different conclusions we would have drawn about the effectiveness of the digital interventions on mental health, had we used the self-reported adherence data rather than the objective adherence data. We use this example to suggest that it may be perilous to rely on self-reported measures of adherence when assessing the effectiveness of digital interventions.