Compensatory coping and depression in women with interstitial cystitis/bladder pain syndrome.

INTRODUCTION: Women with genitourinary pain, a hallmark symptom of interstitial cystitis/bladder pain syndrome (IC/BPS), are at a two- to four-fold risk for depression as compared to women without genitourinary pain. Despite the pervasive impact of IC/BPS on psychological health, there is a paucity of empirical research on understanding the relation between IC/BPS and psychological distress. It has been previously reported that women with overactive bladder use increased compensatory coping and these behaviors are associated with heightened anxiety and stress. However, it is unknown whether a similar pattern emerges in IC/BPS populations, as ICBPS and OAB share many similar urinary symptoms. The current study examined the relationship between compensatory coping behaviors and symptoms of psychological distress in a sample of women with IC/BPS to inform understanding of risk and potential mechanisms for intervention. METHOD: This was a secondary analysis of an observational cohort of women with bladder symptoms. Fifty-five adult women with IC/BPS completed validated assessments of genitourinary symptoms, emotional distress, and bladder coping behaviors. Five compensatory coping behaviors were summed to create a total Bladder Coping Score. Linear regression examined associations between individual coping behaviors, total compensatory coping scores, and other risk variables. RESULTS: Most (93%) participants reported use of at least one compensatory coping behavior. Age, education level, history of vaginal birth, and symptom severity were all associated with greater compensatory coping scores, and anxiety was not. Beyond the influence of symptom severity, higher levels of depression were significantly associated with higher compensatory coping scores. DISCUSSION: Greater compensatory coping was associated with increased depression but not anxiety, suggesting different profiles of coping and psychological distress may exist among different types of bladder dysfunction.

Clinical hypnosis can reduce lower urinary tract symptoms in individuals with chronic pain.

STUDY PURPOSE: Lower urinary tract symptoms (LUTS) can occur in chronic pain populations at high rates and drastically affect quality of life. Hypnosis is a nonpharmacological treatment used in chronic pain known to have beneficial implications to health outside of pain reduction. This study evaluated the potential for hypnosis to reduce LUTS in a sample of individuals with chronic pain, if baseline LUTS severity affected outcomes, and specific LUTS that may respond to hypnosis. METHODS: Sixty-four adults with chronic pain and LUTS at a level of detectable symptom change (American Urological Association Symptom Index, AUASI 3) participated in an 8-week group hypnosis protocol. Participants completed validated assessments of LUTS, pain, and overall functioning before, after, 3- and 6-months posttreatment. Linear mixed effects models assessed improvement in LUTS over time while accounting for known factors associated with outcome (e.g., age, gender). The interaction of baseline symptom severity and treatment assessed the potential effect of baseline symptoms on change scores. RESULTS: Participants experienced significant and meaningful improvements in LUTS following group hypnosis (p = 0.006). There was a significant interaction between baseline symptom severity and treatment (p < 0.001), such that those with severe symptoms experienced the most pronounced gains over time (e.g., an 8.8 point reduction). Gains increased over time for those with moderate and severe symptoms. Changes in LUT symptoms occurred independently of pain relief. CONCLUSIONS: This pilot study suggests hypnosis has the potential to drastically improve LUTS in individuals with chronic pain, even when pain reduction does not occur. Results provide initial evidence for the treatment potential of hypnosis in urologic pain (and possibly non-pain/benign) populations, with randomized trials needed for definitive outcomes.

Time to deterioration of patient-reported outcomes in non-small cell lung cancer: exploring different definitions.

PURPOSE: The clinical relevance of different time-to-deterioration (TTD) definitions for patient-reported outcomes were explored. METHODS: TTD definitions differing by reference score and deterioration event were used to analyse data from the phase 3 FLAURA trial of first-line osimertinib versus erlotinib or gefitinib in patients with EGFR-mutated advanced non-small cell lung cancer. Pre-specified key symptoms were fatigue, appetite loss, cough, chest pain and dyspnoea, scored using the European Organisation for Research and Treatment of Cancer QLQ-C30 and QLQ-LC13 questionnaires (≥ 10-point difference = clinically relevant). RESULTS: No significant treatment differences in TTD (distributions) were observed using definitions based on transient or definitive deterioration alone. TTD definitions based on definitive, sustained deterioration, with death not included as an event, yielded a significant treatment difference for dyspnoea (hazard ratio [HR] 0.71; P = 0.034) when baseline was the reference, and for cough (HR 0.70; P = 0.009) and dyspnoea (HR 0.71; P = 0.004) when best previous score was the reference. With death included as an event, treatment differences were significant for dyspnoea (HR 0.70; P = 0.025) when baseline was the reference, and for cough (HR 0.70; P = 0.011), dyspnoea (HR 0.71; P = 0.003) and chest pain (HR 0.71; P = 0.038) when best previous score was the reference. Irrespective of definition, TTD for appetite loss and fatigue did not differ significantly between arms. CONCLUSION: This exploratory work showed that different TTD definitions yield different magnitudes of treatment difference, highlighting the importance of pre-specifying TTD definitions upfront in clinical trials. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT02296125.

Willingness to report treatment-related symptoms of immunotherapy among patients with non-small cell lung cancer.

PURPOSE: Immunotherapy is an evolving therapeutic approach for non-small cell lung cancer (NSCLC). This study explored factors involved in patients' perceptions about reporting or not reporting treatment-related symptoms experienced while undergoing immunotherapy. METHODS: Patients receiving immunotherapy for NSCLC were recruited in the USA and Europe. Qualitative interviews were conducted to elicit treatment-related symptoms and explore patients' reasons and motivations for either reporting or not reporting these to their medical teams. Interviews were audio-recorded, transcribed, and coded for qualitative analysis. RESULTS: Sixty-six patients were interviewed (mean age: 62 years; 55% male; 91% with stage IV NSCLC). The most frequent symptoms that patients experienced but did not report were gastrointestinal (23% of patients), respiratory (17%), and energy related (12%). The most common reasons for not reporting symptoms included a perception that they were not severe enough, being unsure whether the experiences were side effects, and deciding that the experiences were expected and could be managed without assistance. Fear of having treatment discontinued was also mentioned but was not a prominent reason. The most common reasons for reporting symptoms were to ascertain if these were normal and expected, and to let the medical team know. Patients emphasized the importance of survival over treatment burden when balancing symptoms with treatment benefits. CONCLUSION: Patients have a range of reasons for not reporting their treatment-related symptoms when undergoing immunotherapy for NSCLC. Reasons are more strongly related to determination of the severity versus manageability of patients' experiences of symptoms than they are to the fear of having treatment discontinued.

How patients being treated for non-small cell lung cancer value treatment benefit despite side effects.

PURPOSE: To describe symptoms and side effects experienced by patients with advanced non-small cell lung cancer (NSCLC), assess how patients allocate sensations (i.e. symptoms or side effects) to either the disease or its treatment, and evaluate how patients balance side effects with treatment benefits. METHODS: Qualitative sub-studies were conducted as part of two clinical trials in patients treated for advanced NSCLC (AURA [NCT01802632]; ARCTIC [NCT02352948]). RESULTS: Interviews were conducted with 23 patients and 19 patients in the AURA and ARCTIC sub-studies, respectively. The most commonly experienced symptoms/side effects were respiratory (81% of patients), digestive (76%), pain and discomfort (76%), energy-related (71%), and sensory (62%). Patients identified a sensation as a treatment side effect if they had not experienced it before, if there was a temporal link between the sensation and receipt of treatment, and/or if their doctors consistently told or asked them about it in relation to side effects. Themes that emerged when patients talked about their cancer treatment and its side effects related to the serious nature of their advanced disease and their treatment expectations. Patients focused on treatment benefits, wanting a better quality of life, being hopeful, not really having a choice, and not thinking about side effects. CONCLUSIONS: In these two qualitative sub-studies, patients with advanced NSCLC valued the benefits of their treatment regardless of side effects that they experienced. Patients weighed their options against the seriousness of their disease and expressed their willingness to tolerate their side effects in return for receiving continued treatment benefits.

Understanding the patient experience of chronic kidney disease stages 2-3b: a qualitative interview study with Kidney Disease Quality of Life (KDQOL-36) debrief.

BACKGROUND: Qualitative patient interviews and patient-reported outcome instruments are important tools to understand the patient experience of disease. The aim of this study was to use patient interviews to identify concepts relevant and important to patients living with chronic kidney disease (CKD) stages 2-3b, develop a comprehensive conceptual model of the patient experience and debrief the Kidney Disease Quality of Life 36-item instrument (KDQOL-36) for patients with CKD stages 2-3b. METHODS: Concept elicitation interviews were conducted with patients with CKD stages 2-3b to identify signs/symptoms and impacts most relevant and important to patients (i.e., 'salient' concepts) and develop a conceptual model for the disease. Based on the salient concepts identified in the interviews, new items were proposed to supplement the KDQOL-36. Cognitive debriefing was performed to evaluate the KDQOL-36 and the additional items. RESULTS: A total of 31 patients were interviewed in this study (22 for concept elicitation and 15 for cognitive debriefing). The interviews identified 56 concepts (33 signs/symptoms and 23 impacts), 17 of which had not been identified in a previous literature review. Four signs/symptoms ('fatigue/lack of energy/tiredness', 'sleep problems', 'increased urination [including nocturia]' and 'swelling in legs/ankles/feet') and two impacts ('anxiety/worry' and 'general negative emotional/mental impact') were identified as salient. Of the salient signs/symptoms, three were not covered by the KDQOL-36 (sleep problems, increased urination and swelling in legs/ankles/feet) and were represented during cognitive debriefing interviews through four additional items (trouble falling asleep, trouble staying asleep, increased urination [including nocturia] and swelling in legs/ankles/feet) generated in the style of the KDQOL-36. All patients found the KDQOL-36 plus the four additional items relevant, and the majority found them clear. CONCLUSIONS: By identifying previously unknown concepts and augmenting the understanding of which are most important to patients, a comprehensive conceptual model was developed for patients who have CKD stages 2-3b. This study also demonstrates the suitability of the KDQOL-36 for patients who have CKD stages 2-3b and provides suggestions for how the instrument could be further developed to more comprehensively capture patient experience.

Patient-reported outcomes with durvalumab by PD-L1 expression and prior chemoradiotherapy-related variables in unresectable stage III non-small-cell lung cancer.

Aim: We retrospectively investigated the impact of tumor PD-L1 expression and prior chemoradiotherapy (CRT)-related variables on patient-reported outcomes (PROs) from PACIFIC. Patients & methods: PACIFIC was a Phase III study of durvalumab versus placebo after CRT in patients with unresectable, stage III non-small-cell lung cancer. If available, pre-CRT tumor tissue was tested for PD-L1 tumor-cell expression, scored at prespecified (25%) and post-hoc (1%) cut-offs. PROs were assessed using EORTC QLQ C30/-LC13. Results: Similar to the intent-to-treat (ITT) population, most PROs remained stable over time across PD-L1 and CRT subgroups, with few clinically relevant differences between treatment arms. Time to deterioration was generally similar to the ITT population. Conclusion: Neither PD-L1 expression nor prior CRT-related variables influenced PROs with durvalumab therapy. Clinical trial registration: NCT02125461 (ClinicalTrials.gov).

Development of a preliminary conceptual model of the patient experience of chronic kidney disease: a targeted literature review and analysis.

BACKGROUND: Patient-reported outcome (PRO) instruments should capture the experiences of disease and treatment that patients consider most important in order to inform patient-centred care and product development. The aim of this study was to develop a preliminary conceptual model of patient experience in chronic kidney disease (CKD) based on a targeted literature review and to characterize existing PRO instruments used in CKD. METHODS: PubMed, EMBASE and Cochrane databases and recent society meetings were searched for publications reporting signs/symptoms and life impacts of CKD. Concepts identified in the literature review were used to develop a preliminary conceptual model of patient experience of CKD, overall, and within patient subpopulations of differing CKD causes, severities and complications. PRO instruments, identified from PRO databases, CKD literature and CKD clinical trials, were assessed for content validity, psychometric strength and coverage of concepts in the literature review. RESULTS: In total, 100 publications met criteria for analysis; 56 signs/symptoms and 37 life impacts of CKD were identified from these sources. The most frequently mentioned signs/symptoms were pain/discomfort (57% of publications) and tiredness/low energy/lethargy/fatigue (42%); the most commonly reported life impacts were anxiety/depression (49%) and decrements in physical functioning (43%). Signs/symptoms and life impacts varied across the subpopulations and were more frequent at advanced CKD stages. The preliminary conceptual model grouped signs/symptoms into seven domains (pain/discomfort; energy/fatigue; sleep-related; gastrointestinal-related; urinary-related; skin-/hair-/nails-related; and other) and life impacts into six domains (psychological/emotional strain; cognitive impairment; dietary habit disruption; physical function decrements; interference with social relationships; and other). Eleven PRO instruments were considered to be promising for use in CKD; all had limitations. CONCLUSIONS: Although preliminary, the proposed conceptual model highlights key PROs for people with CKD and is intended to spur development of more tailored PRO instruments to assess these concepts.

Patient-reported outcomes with durvalumab after chemoradiotherapy in stage III, unresectable non-small-cell lung cancer (PACIFIC): a randomised, controlled, phase 3 study.

BACKGROUND: In the ongoing, phase 3 PACIFIC trial, durvalumab improved the primary endpoints of progression-free survival and overall survival compared with that for placebo, with similar safety, in patients with unresectable, stage III non-small-cell lung cancer. In this analysis, we aimed to evaluate one of the secondary endpoints, patient-reported outcomes (PROs). METHODS: PACIFIC is an ongoing, international, multicentre, double-blind, randomised, controlled, phase 3 trial. Eligible patients were aged at least 18 years, had a WHO performance status of 0 or 1, with histologically or cytologically documented stage III, unresectable non-small-cell lung cancer, for which they had received at least two cycles of platinum-based chemoradiotherapy, with no disease progression after this treatment. We randomly assigned patients (2:1) using an interactive voice response system and a blocked design (block size=3) stratified by age, sex, and smoking history to receive 10 mg/kg intravenous durvalumab or matching placebo 1-42 days after concurrent chemoradiotherapy, then every 2 weeks up to 12 months. The primary endpoints of progression-free survival and overall survival have been reported previously. PROs were a prespecified secondary outcome. We assessed PRO symptoms, functioning, and global health status or quality of life in the intention-to-treat population with the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) version 3 and its lung cancer module, the Quality of Life Questionnaire-Lung Cancer 13 (QLQ-LC13) at the time of random allocation to groups, at weeks 4 and 8, every 8 weeks until week 48, and then every 12 weeks until progression. Changes from baseline to 12 month in key symptoms were analysed with mixed model for repeated measures (MMRM) and time-to-event analyses. A 10-point or greater change from baseline (deterioration or improvement) was deemed clinically relevant. This study is registered with ClinicalTrials.gov, NCT02125461, and EudraCT, 2014-000336-42. FINDINGS: Between May 9, 2014, and April 22, 2016, 476 patients were assigned to receive durvalumab, and 237 patients were assigned to receive placebo. As of March 22, 2018, the median follow-up was 25·2 months (IQR 14·1-29·5). More than 79% of patients given durvalumab and more than 82% of patients given placebo completed questionnaires up to week 48. Between baseline and 12 months, the prespecified longitudinal PROs of interest, cough (MMRM-adjusted mean change 1·8 [95% CI 0·06 to 3·54] in the durvalumab group vs 0·7 [-1·91 to 3·30] in the placebo group), dyspnoea (3·1 [1·75 to 4·36] vs 1·4 [-0·51 to 3·34]), chest pain (-3·1 [-4·57 to -1·60] vs -3·5 [-5·68 to -1·29]), fatigue (-3·0 [-4·53 to -1·50] vs -5·2 [-7·45 to -2·98]), appetite loss (-5·8 [-7·28 to -4·36] vs -7·0 [-9·17 to -4·87]), physical functioning (0·1 [-1·10 to 1·28] vs 2·0 [0·22 to 3·73]), and global health status or quality of life (2·6 [1·21 to 3·94] vs 1·8 [-0·25 to 3·81]) remained stable with both treatments, with no clinically relevant changes from baseline. The between-group differences in changes from baseline to 12 months in cough (difference in adjusted mean changes 1·1, 95% CI -1·89 to 4·11), dyspnoea (1·6, -0·58 to 3·87), chest pain (0·4, -2·13 to 2·93), fatigue (2·2, -0·38 to 4·78), appetite loss (1·2, -1·27 to 3·67), physical functioning (-1·9, -3·91 to 0·15), or global health status or quality of life (0·8, -1·55 to 3·14) were not clinically relevant. Generally, there were no clinically important between-group differences in time to deterioration of prespecified key PRO endpoints. INTERPRETATION: Our findings suggest that a clinical benefit with durvalumab can be attained without compromising PROs. This result is of note because the previous standard of care was observation alone, with no presumed detriment to PROs. FUNDING: AstraZeneca.

Informing the Tolerability of Cancer Treatments Using Patient-Reported Outcome Measures: Summary of an FDA and Critical Path Institute Workshop.

The US Food and Drug Administration and the Critical Path Institute's Patient-Reported Outcome (PRO) Consortium convened a cosponsored workshop on the use of PRO measures to inform the assessment of safety and tolerability in cancer clinical trials. A broad array of international stakeholders involved in oncology drug development and PRO measurement science provided perspectives on the role of PRO measures to provide complementary clinical data on the symptomatic side effects of anticancer agents. Speakers and panelists explored the utility of information derived from existing and emerging PRO measures, focusing on the PRO version of the National Cancer Institute's Common Terminology Criteria for Adverse Events. Panelists and speakers discussed potential ways to improve the collection, analysis, and presentation of PRO data describing symptomatic adverse events to support drug development and better inform regulatory and treatment decisions. Workshop participants concluded the day with a discussion of possible approaches to the patient-reported assessment of an investigational drug's overall side effect burden as a potential clinical trial end point. The Food and Drug Administration reiterated its commitment to collaborate with international drug development stakeholders to identify rigorous methods to incorporate the patient perspective into the development of cancer therapeutics.

Anti-IL-21 monoclonal antibody combined with liraglutide effectively reverses established hyperglycemia in mouse models of type 1 diabetes.

Immunotherapy for type 1 diabetes (T1D) has previously focused on suppressing the autoimmune response against pancreatic beta cells to preserve endogenous insulin production and regulate glucose levels. With increased attention toward combination therapy strategies, studies indicate the multifunctional cytokine interleukin-21 (IL-21) may be a suitable target as an immuno-modulatory arm, while glucagon-like peptide-1 receptor (GLP-1R) agonists may be appropriate as a beta cell protective arm in combination therapy for T1D. We report here that treatment with anti-IL-21 monoclonal antibody delays diabetes onset in the spontaneous non-obese diabetic (NOD) and NOD.scid adoptive transfer models, while its effect in reversing recent-onset hyperglycemia is limited. However, the combination of anti-IL-21 plus the GLP-1R agonist liraglutide is effective in reversing established disease compared to either monotherapy in both the NOD and rat insulin promotor-lymphocytic choriomeningitis virus glycoprotein (RIP-LCMV-GP) models of autoimmune diabetes. Enhanced efficacy is particularly evident in severely hyperglycemic mice, with return to normoglycemia remaining stable for the majority of mice even after therapy is withdrawn. Importantly, increased beta cell proliferation does not appear to be the predominant mechanism. In conclusion, combination therapy with anti-IL-21 and liraglutide is able to consistently reverse disease in mouse models of T1D. The observed effects rival the most effective experimental disease-modifying treatments tested in preclinical studies.

Development and Validation of the AFImpact: An Atrial Fibrillation-Specific Measure of Patient-Reported Health-Related Quality of Life.

BACKGROUND: Improvement in health-related quality of life is a key therapeutic goal of disease management in atrial fibrillation (AF). OBJECTIVES: To describe the development of the AFImpact, an AF-specific health-related quality-of-life patient-reported outcome measure. METHODS: Development and validation of the AFImpact comprised a qualitative stage, consisting of a literature review and concept elicitation interviews (91 patients with AF), item generation, and cognitive debriefing (30 patients with AF), and a quantitative stage, consisting of evaluation of the instrument's psychometric properties (313 patients with AF). Preliminary responsiveness to change was assessed in 118 patients undergoing cardioversion. RESULTS: On the basis of the literature review and concept elicitation interviews, 75 items were generated. Factor analyses guided a reduction to 18 items. Three domains were confirmed: vitality (7 items), emotional distress (8 items), and sleep (3 items). The 18-item AFImpact demonstrated high item convergent and discriminant validity. Cronbach α coefficients showed high internal consistency reliability. Test-retest reliability of individual items in stable patients (n = 33) was satisfactory, with intraclass correlation coefficients ranging from 0.61 to 0.86. All three AFImpact domain scores differentiated patients who reported different levels of overall health, thereby supporting known-groups validity. Scores for each item improved after cardioversion, with effect sizes ranging from -0.19 to -0.65. CONCLUSIONS: Psychometric evaluations support the reliability and validity of the AFImpact as a patient-reported outcome instrument to measure the impact of AF, with preliminary results in patients undergoing cardioversion supporting responsiveness to change.

Oral insulin (human, murine, or porcine) does not prevent diabetes in the non-obese diabetic mouse.

Studies have shown oral insulin prevents type 1 diabetes (T1D) in mouse models, however human trials were inconclusive. We tested the ability of different insulins to prevent T1D in non-obese diabetic mice. Mice received oral insulin or PBS twice weekly and disease was monitored. Contrary to previous studies, no insulin tested showed significant ability to prevent T1D, nor did testing of linked suppression in a delayed type hypersensitivity model have reproducible effect. To investigate delivery of antigen within the GI tract, blue dye was fed to mice. Dye traveled 5-8 cm from stomach to small intestine within 10s, suggesting orally administered antigen may not get digested in the stomach in mice. Insulin incubated with jejunum extracts was instantly digested. Thus, in humans large doses of insulin may be required to achieve tolerance as antigen may be more vulnerable to digestion in the stomach even before reaching the small intestine.

Comparison of Daily versus Weekly Recording of Gastroesophageal Reflux Disease Symptoms in Patients with a Partial Response to Proton Pump Inhibitor Therapy.

BACKGROUND: The Reflux Symptom Questionnaire electronic Diary (RESQ-eD) and the Reflux Symptom Questionnaire 7-day recall (RESQ-7) are versions of a patient-reported outcome instrument that was developed and validated for measuring the frequency and intensity of symptoms in patients with gastroesophageal reflux disease (GERD) who have a partial response to proton pump inhibitor (PPI) therapy. OBJECTIVE: The aim of these analyses was to assess the ability of the RESQ-7 to reproduce findings based on RESQ-eD reports of the same symptoms. METHODS: These analyses are based on data from patients with GERD with a partial response to PPI (ClinicalTrials.gov identifier: NCT00703534). Participants completed the RESQ-eD twice daily for 7 days and the RESQ-7 on day 7. RESULTS: Data from 446 patients were available for these analyses. Symptom-level analyses showed that, for intensity, mean domain scores were higher for the RESQ-7 (range 1.49-2.72) than for the RESQ-eD (range 1.45-2.57); for frequency, scores were lower for the RESQ-7 (range 2.58-4.82) than for the RESQ-eD (range 4.22-6.24). Correspondence analyses of RESQ-7 and RESQ-eD mean domain scores indicated excellent agreement for intensity (correlation-concordance coefficient 0.77-0.83) and fair agreement for frequency (correlation-concordance coefficient 0.40-0.58). Mean RESQ-eD subscale intensity scores for GERD symptoms were higher for symptoms experienced during the daytime than for those occurring at nighttime. Symptom recall was not associated with peak or recency effects. CONCLUSIONS: Patients with GERD slightly overestimated the intensity of their reflux symptoms and markedly underestimated the frequency on weekly recall compared with twice-daily reporting.

General immune dampening is associated with disturbed metabolism at diagnosis of type 1 diabetes.

BACKGROUND: Type 1 diabetes (T1D) is a serious diagnosis with the prospect of grave short- and long-term complications and even death if poorly managed. An attempt has been made to describe how clinical and immunological deviations might influence each other close to the diagnosis of T1D. METHODS: Sixty-nine newly diagnosed T1D children were studied together with a reference group of 30 healthy children. Cytokines (interleukin (IL)-6, IL-10, IL-13, IL-17, interferon-γ, and tumor necrosis factor-α) were detected in in vitro culture by multiplex fluorochrome technique. Information of clinical status of the patients such as BMI, weight loss, pubertal stage, duration of symptoms, previous and/or ongoing infections, insulin requirement, and ketoacidosis were gathered together with the analysis of C-peptide and glycosylated hemoglobin (HbA1c). RESULTS: In general, low cytokine secretion was found at diagnosis of T1D. However, high C-peptide, short duration of symptoms, or an infection prior to diagnosis was associated with increased immune activity including proinflammatory, Th2-associated, and Tr1-associated cytokines. In contrast, ketoacidosis and later pubertal stage at onset of disease were more related to a Th1-prone response. CONCLUSION: There is a general immune dampening at diagnosis of T1D, which appears to be related to the metabolic state close to diagnosis.

Symptom profile in partial responders to a proton pump inhibitor compared with treatment-naïve patients with gastroesophageal reflux disease: a post hoc analysis of two study populations.

BACKGROUND: Partial response to proton pump inhibitor (PPI) therapy poses a healthcare challenge. This study aimed to compare symptom profiles in partial PPI responders and treatment-naïve patients with gastroesophageal reflux disease (GERD). METHODS: A post hoc analysis of data from two studies was performed. Partial PPI responders with GERD (n = 580; NCT00703534) had frequent (≥ 3 days/week) heartburn and/or regurgitation despite PPI therapy; patients with no improvement were excluded. Treatment-naïve patients with GERD (diagnosed by endoscopy and pH-metry; n = 203; NCT00291746) had frequent (≥ 3 days/week) upper gastrointestinal symptoms. The Gastrointestinal Symptom Rating Scale (GSRS) was completed by all patients at study entry and by treatment-naïve patients after PPI therapy. RESULTS: The highest (mean [95% confidence interval]) discomfort scores were reported in the Reflux (heartburn, regurgitation), Indigestion, and Abdominal pain domains of the GSRS, both in partial PPI responders (4.3 [4.2-4.4], 3.7 [3.6-3.8], and 3.4 [3.3-3.5], respectively) and in treatment-naïve patients (3.5 [3.3-3.7], 3.6 [3.4-3.7], and 3.1 [3.0-3.3], respectively). Partial PPI responders reported more discomfort than treatment-naïve patients in the Reflux, Abdominal pain, and Constipation domains (4.3 [4.2-4.4] vs. 3.5 [3.3-3.7], 3.4 [3.3-3.5] vs. 3.1 [3.0-3.3], and 2.5 [2.4-2.6] vs. 2.1 [1.9-2.2], respectively). All GSRS domain scores improved in treatment-naïve patients following PPI therapy. CONCLUSIONS: Symptom patterns in partial PPI responders were similar to those in treatment-naïve patients with GERD, but partial PPI responders experienced more severe reflux, abdominal pain, and constipation than did treatment-naïve patients.

Poly(ADP-ribosylation) regulates chromatin organization through histone H3 modification and DNA methylation of the first cell cycle of mouse embryos.

We examined the roles of poly(ADP-ribosylation) in chromatin remodeling during the first cell cycle of mouse embryos. Drug-based inhibition of poly(ADP-ribosylation) by a PARP inhibitor, PJ-34, revealed up-regulation of dimethylation of histone H3 at lysine 4 in male pronuclei and down-regulation of dimethylation of histone H3 at lysine 9 (H3K9) and lysine 27 (H3K27). Association of poly(ADP-ribosylation) with histone modification was suggested to be supported by the interaction of Suz12, a histone methyltransferase in the polycomb complex, with Parp1. PARP activity was suggested to be required for a proper localization and maintenance of Suz12 on chromosomes. Notably, DNA methylation level of female pronuclei in one-cell embryos was robustly decreased by PJ-34. Electron microscopic analysis showed a frequent appearance of unusual electron-dense areas within the female pronuclei, implying the disorganized and hypercondensed chromatin ultrastructure. These results show that poly(ADP-ribosylation) is important for the integrity of non-equivalent epigenetic dynamics of pronuclei during the first cell cycle of mouse embryos.

The metabolite chemotype of Nicotiana benthamiana transiently expressing artemisinin biosynthetic pathway genes is a function of CYP71AV1 type and relative gene dosage.

Artemisia annua, which produces the anti-malaria compound artemisinin, occurs as high-artemisinin production (HAP) and low-artemisinin production (LAP) chemotypes. Understanding the basis of the difference between these chemotypes would assist breeding and optimising artemisinin biosynthesis. Here we present a systematic comparison of artemisinin biosynthesis genes that may be involved in determining the chemotype (CYP71AV1, DBR2 and ALDH1). These genes were isolated from the two chemotypes and characterized using transient expression in planta. The enzyme activity of DBR2 and ALDH1 from the two chemotypes did not differ, but structural differences in CYP71AV1 from LAP and HAP chemotypes (AMOLAP and AMOHAP, respectively) resulted in altered enzyme activity. AMOLAP displays a seven amino acids N-terminal extension compared with AMOHAP. The GFP fusion of both proteins show equal localization to the ER but AMOHAP may have reduced stability. Upon transient expression in Nicotiana benthamiana, AMOLAP displayed a higher enzyme activity than AMOHAP. However, expression in combination with the other pathway genes also resulted in a qualitatively different product profile ('chemotype'); that is, in a shift in the ratio between the unsaturated and saturated (dihydro) branch of the pathway.

Development and validation of a patient-reported outcome instrument in partial responders to proton pump inhibitors.

OBJECTIVE: The Reflux Symptom Questionnaire 7-day recall (RESQ-7) was developed, in line with the US Food and Drug Administration (FDA) guidelines, to address the need for a patient-reported outcome (PRO) instrument assessing symptoms specifically in patients with gastroesophageal reflux disease (GERD) who are only partially responsive to proton pump inhibitor (PPI) therapy. MATERIALS AND METHODS: The RESQ-7 was constructed using patient interviews and expert consensus. The instrument was psychometrically validated in a clinical trial setting in patients with persistent GERD symptoms despite PPI therapy. RESULTS: Evaluation of content validity yielded a 13-item structure for the RESQ-7, incorporating symptoms overlooked by existing GERD questionnaires, such as hoarseness, cough, difficulty swallowing and burping. Principal component analysis suggested a four-domain structure. All domains had a high inter-item correlation (Cronbach's α lower 95% confidence limits: 0.77-0.87 for intensity; 0.72-0.82 for frequency). Test-retest reliability was fair-to-good or excellent (intraclass correlation coefficient lower 95% confidence limits: 0.70-0.78 for intensity; 0.65-0.75 for frequency). Convergent and discriminant validity were confirmed by correlation comparisons with the Gastrointestinal Symptom Rating Scale. DISCUSSION: The RESQ-7 demonstrated good content validity and psychometric properties in patients with GERD and a partial response to PPIs. The weekly recall makes the RESQ-7 appropriate for use in routine clinical care. The authors believe that it is the first instrument to be developed specifically for patients with a partial response to PPI therapy in line with FDA guidelines on PROs (ClinicalTrials.gov identifier: NCT00703534).