The Health-Related Quality of Life, Work Productivity, Healthcare Resource Utilization, and Economic Burden Associated with Levels of Suicidal Ideation Among Patients Self-Reporting Moderately Severe or Severe Major Depressive Disorder in a National Survey.

Background: Suicidal ideation (SI) is a cardinal aspect of major depressive disorder (MDD); however, patient-reported outcomes data from large-scale surveys are limited concerning SI in the context of MDD. This study aims to understand the association between varying levels of SI and health-related quality of life (HRQoL), work productivity, healthcare resource utilization (HRU), and associated costs in patients with moderately severe/severe MDD. Methods: This was a retrospective, cross-sectional analysis of 2013 national survey data. Patients who self-reported moderately severe or severe MDD and completed the Short Form Survey Version 2 (SF-36v2), Work Productivity Loss and Activity Impairment questionnaire (WPAI), and questions related to HRU were analyzed. Direct and indirect costs were calculated. Patients were categorized and analyzed by the level of SI (no SI, low, moderate, and high) based on their response to Item 9 of the Patient Health Questionnaire-9. Results: Among 75,000 respondents, 15.3% self-reported receiving a physician diagnosis of moderately severe or severe MDD and 2.8% of the total sample endorsed some level of SI. Patients with high SI showed a higher burden than patients with no SI, reporting lower mean SF-36v2 mental component summary scores ( Conclusion: Higher levels of SI were associated with lower HRQoL, greater HRU, and more work impairment resulting in higher direct and indirect costs compared with patients with MDD but no SI. These results highlight the need to implement effective treatment models and interventions in the employed population

Continuous improvement through differential trajectories of individual minimal disease activity criteria with guselkumab in active psoriatic arthritis: post hoc analysis of a phase 3, randomized, double-blind, placebo-controlled study

Background To explore the trajectory of, and factors contributing to, achievement of individual criteria of minimal disease activity (MDA) in patients with active psoriatic arthritis (PsA) treated with guselkumab. Methods The Phase 3, randomized, placebo-controlled DISCOVER-2 study enrolled adults (N = 739) with active PsA despite standard therapies who were biologic/Janus kinase inhibitor-naive. Patients were randomized 1:1:1 to guselkumab 100 mg every 4 weeks; guselkumab 100 mg at week 0, week 4, then every 8 weeks; or placebo. In this post hoc analysis, patients randomized to guselkumab were included and pooled (N = 493). Longitudinal trajectories of achieving each MDA criterion through week 100 were derived using non-responder imputation. Time to achieve each criterion was estimated with Kaplan-Meier analysis. Multivariate regression for time to achieve each criterion (Cox regression) and achievement at week 100 (logistic regression) was used to identify contributing factors. Results Continuous improvement across all MDA domains was shown over time. ~70% of patients achieved near remission in swollen joint count (SJC), Psoriasis Area and Severity Index (PASI), and enthesitis through week 100. Median times to achieve individual criteria differed significantly (p Conclusions Substantial proportions of guselkumab-treated patients achieved individual MDA criteria, each showing continuous improvement through week 100, although with distinct trajectories. Median times to achieve physician-assessed MDA criteria were significantly faster compared with patient-driven criteria. Identification of modifiable factors affecting the time to achieve patient-reported criteria has the potential to optimize the achievement and sustainability of MDA in the clinic via a multidisciplinary approach to managing PsA, involving both medical and lifestyle interventions. Trial registration number NCT03158285. Trial registration date May 16, 2017

Guselkumab provides durable improvement across psoriatic arthritis disease domains: post hoc analysis of a phase 3, randomised, double-blind, placebo-controlled study

Objective Evaluate long-term guselkumab effectiveness across Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA)-recognised domains/related conditions of psoriatic arthritis (PsA). Methods Post hoc analyses used data from DISCOVER-2 (NCT03158285) biologic/Janus-kinase inhibitor-naïve participants with active PsA (≥5 swollen/≥5 tender joints, C-reactive protein ≥0.6 mg/dL), randomised (1:1:1) to guselkumab every 4 or 8 weeks (Q4W/Q8W) or placebo with crossover to guselkumab. Outcomes aligned with key GRAPPA-recognised domains of overall disease activity, peripheral arthritis, axial disease, enthesitis/dactylitis and skin psoriasis (nail psoriasis was not evaluated). PsA-related conditions (inflammatory bowel disease (IBD)/uveitis) were assessed via adverse events through W112. Least squares mean changes from baseline through W100 in continuous outcomes employed repeated measures mixed-effects models adjusting for baseline scores. Binary measure response rates were determined with non-responder imputation for missing data. Results 442/493 (90%) of guselkumab-randomised patients completed treatment through W100. Following early reductions in disease activity with guselkumab, durable improvements were observed across key PsA domains (swollen/tender joints, psoriasis, spinal pain, enthesitis/dactylitis) through W100. Response rates of therapeutically relevant targets generally increased through W100 with guselkumab Q4W/Q8W: Disease Activity Index for PsA low disease activity (LDA) 62%/59%, enthesitis resolution 61%/70%, dactylitis resolution 72%/83%, 100% improvement in Psoriasis Area and Severity Index 59%/53%, Psoriatic Arthritis Disease Activity Score LDA 51%/49% and minimal disease activity 38%/40%. Through W112, no cases of IBD developed among guselkumab-randomised patients and one case of uveitis was reported. Conclusion In biologic-naïve patients with active PsA, guselkumab provided early and durable improvements in key GRAPPA-recognised domains through 2 years, with substantial proportions achieving important treatment targets

The Effect of Guselkumab on Work Productivity in Biologic-Naïve Patients with Active Psoriatic Arthritis Through Week 52 of the Phase 3, Randomized, Placebo-Controlled DISCOVER-2 Trial

Introduction: The phase 3 DISCOVER-2 trial evaluated the effect of guselkumab on impaired work productivity and nonwork activity in biologic-naïve patients with psoriatic arthritis (PsA). Methods: Adults with active PsA were randomized (1:1:1) to guselkumab 100 mg every 4 weeks (Q4W), guselkumab 100 mg at weeks 0 and 4 and then every 8 weeks (Q8W), or placebo (with crossover to guselkumab Q4W at week 24). Least squares mean change from baseline in Work Productivity and Activity Impairment Questionnaire for PsA (WPAI-PsA) domains and employment were assessed by treatment group. Multivariate analysis of data from weeks 0 through 24 assessed independent associations between PsA clinical features and WPAI-PsA domains. Results: In total, 738 patients were evaluated (guselkumab Q4W n = 245; guselkumab Q8W n = 248; placebo n = 245). At week 24, improvements (reduced impairment) in presenteeism (Q4W −20.1%, Q8W −19.6%, placebo −10.5%), work productivity (Q4W −20.1%, Q8W −19.2%, placebo −10.6%), and nonwork activity (Q4W −20.5%, Q8W −21.2%, placebo −9.9%) were greater in guselkumab-treated versus placebo-treated patients. At week 52, following placebo crossover at week 24, improvements were similar among groups. Baseline absenteeism was minimal and did not change in any group. By week 52, 23.1–25.9% of guselkumab-treated patients who were unemployed at baseline were employed. All WPAI-PsA domains were positively associated with C-reactive protein level, fatigue, and pain. All domains except absenteeism were positively associated with enthesitis and Psoriasis Area and Severity Index score. Age was negatively associated with presenteeism and work productivity loss, female sex and tender joint count were positively associated with nonwork activity impairment, and dactylitis was positively associated with presenteeism. Conclusion: Both guselkumab regimens reduced work productivity loss and nonwork activity impairment in patients with active PsA. Association of work productivity loss and nonwork activity impairment with PsA joint and skin features suggests that improvement in both features is beneficial for optimizing improved work productivity loss and nonwork activity impairment. Trial registration: ClinicalTrials.gov identifier, NCT03158285

Association between enthesitis/dactylitis resolution and patient-reported outcomes in guselkumab-treated patients with psoriatic arthritis

Objectives To evaluate the association between enthesitis resolution (ER) and dactylitis resolution (DR) and meaningful improvements in patient-reported outcomes (PROs) among biologic-naïve patients with PsA receiving guselkumab in the DISCOVER-2 study. Methods Enthesitis and dactylitis, characteristic lesions of PsA, were evaluated by independent assessors using the Leeds Enthesitis Index (range, 0–6) and Dactylitis Severity Score (range, 0–60). Proportions of patients with ER or DR (score = 0) among those with score > 0 at baseline were determined at weeks 24, 52, and 100. PROs included: fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue [FACIT-Fatigue]), pain (0–100 visual analog scale), physical function (Health Assessment Questionnaire-Disability Index [HAQ-DI]), and health-related quality of life (36-item Short-Form Health Survey physical/mental component summary [SF-36 PCS/MCS]). Meaningful responses were defined as: improvements of ≥ 4 for FACIT-Fatigue, ≥ 0.35 for HAQ-DI, and ≥ 5 for SF-36 PCS/MCS and absolute scores of ≤ 15 for minimal pain and ≤ 0.5 for normalized HAQ-DI. Associations between ER/DR status and PRO response status were tested using a Chi-square test. Results Guselkumab-treated patients with ER were more likely than those without ER to achieve minimal pain (p < 0.001), normalized HAQ-DI (p < 0.001), and PCS response (p < 0.05) at weeks 24, 52, and 100. Patients with DR were more likely than those without DR to achieve FACIT-Fatigue response at week 24 and week 52 (both p ≤ 0.01) and minimal pain at week 24 and normalized HAQ-DI at week 52 (both p ≤ 0.03). Conclusion In biologic-naïve patients with active PsA treated with guselkumab, achieving ER or DR was associated with durable improvements in selected PROs, including those of high importance to patients

Resolution of enthesitis by guselkumab and relationships to disease burden: 1-year results of two phase 3 psoriatic arthritis studies

Objective: To further characterize the effect of guselkumab, a selective IL-23p19-subunit inhibitor approved for PsA, on enthesitis and assess relationships between enthesitis resolution and patient status/outcomes. Methods: Adults with active PsA despite standard therapies in the phase 3 DISCOVER-1 and DISCOVER-2 studies were randomized 1:1:1 to guselkumab 100 mg every 4 weeks (Q4W); guselkumab 100 mg at week 0, week 4, Q8W; or placebo through week 20 followed by guselkumab 100 mg Q4W. Independent assessors evaluated enthesitis using the Leeds Enthesitis Index (LEI; total score 0–6). Enthesitis findings through week 24 were pre-specified to be pooled across studies; post hoc and week 52 analyses also employed pooled data. Results: Among 1118 randomized, treated patients in DISCOVER-1 and 2 who had ≥1 LEI site evaluated, 65% had enthesitis at baseline. These patients exhibited numerically more swollen and tender joints, systemic inflammation and impaired physical function than patients without enthesitis. Guselkumab Q4W and Q8W were superior to placebo in resolving pre-existing enthesitis at week 24 (45 and 50% vs 29%; both adjusted P = 0.0301). Enthesitis resolution rates continued to rise; 58% of guselkumab-randomized patients achieved resolution at week 52, including patients with mild (LEI = 1; 70–75%), moderate (LEI = 2; 69–73%) or severe (LEI = 3–6; 42–44%) enthesitis at baseline. Among guselkumab-randomized patients with resolved enthesitis at week 24, 42% achieved minimal disease activity at week 52, vs 17% of patients with unresolved enthesitis. Conclusion: Guselkumab resulted in higher proportions of PsA patients with resolved enthesitis by week 24, with maintenance of resolution rates through 1 year. As enthesitis confers greater disease burden, sustained resolution could portend better patient outcomes. Clinical trial registration: DISCOVER 1 (NCT03162796) and DISCOVER 2 (NCT03158285)

Pooled safety results through 1 year of 2 phase iii trials of guselkumab in patients with psoriatic arthritis

Objective: Evaluate the safety of guselkumab (monoclonal antibody targeting interleukin [IL]-23p19) in patients with psoriatic arthritis (PsA) through 1 year (1Y) of the phase III DISCOVER-1 and DISCOVER-2 trials. Methods: Patients with active PsA (n = 1120; biologic-naïve except 118 patients treated with tumor necrosis factor inhibitors in DISCOVER-1) were randomized to subcutaneous guselkumab 100 mg every 4 weeks (Q4W) or at Week 0, Week 4, then every 8 weeks (Q8W); or placebo. At Week 24, patients in the placebo group switched to guselkumab 100 mg Q4W. Treatment continued through 1Y and 2 years for DISCOVER-1 and DISCOVER-2, respectively. In this pooled analysis, patients with ≥ 1 adverse event (AE) through 1Y were standardized for 100 patient-years [100 PYs] of follow-up. Results: Through Week 24, adverse events (AEs) were consistent between patients treated with placebo and guselkumab (Q4W + Q8W). AEs were 142.8/100 PYs and 150.6/100 PYs, serious AEs were 7.1/100 PYs and 4.4/100 PYs, and AEs leading to study agent discontinuation were 4.1/100 PYs and 3.8/100 PYs, respectively. Through 1Y in patients treated with guselkumab, no uveitis, active tuberculosis, opportunistic infections, or inflammatory bowel disease were observed, and low rates of malignancy and major adverse cardiovascular (CV) events were observed. Injection-site reactions occurred in 1.7%, and antibodies to guselkumab in 4.5% of patients treated with guselkumab through 1Y; the vast majority of antibodies to guselkumab were nonneutralizing. Serum hepatic transaminase elevations (more common with Q4W than Q8W dosing) and decreased neutrophil counts were generally mild, transient, and did not require treatment discontinuation, with minimal change from Week 24 to 1Y. Conclusion: Guselkumab 100 mg Q4W and Q8W were well tolerated in patients with PsA, with no new safety concerns through 1Y of the phase III DISCOVER trials. Guselkumab safety through 1Y in patients with PsA is consistent with that established in patients with psoriasis who were treated with guselkumab. [ClinicalTrials.gov: NCT03162796 and NCT03158285]

Psychometric properties of the Adverse Childhood Experiences Abuse Short Form (ACE-ASF) among Romanian high school students

Objective: Child abuse is a major public health problem. In order to establish the prevalence of abuse exposure among children, measures need to be age appropriate, sensitive, reliable and valid. This study aimed to investigate the psychometric properties of the Adverse Childhood Experiences Questionnaire Abuse Short Form (ACE-ASF). Methods: The ACE-ASF is an 8-item retrospective self-report questionnaire measuring lifetime physical, emotional and sexual abuse. Data from a nationally representative sample of 15-year-old school-going adolescents (n=1733, 55.5% female) from the Romanian Health Behavior in School-based Children Study 2014 (HBSC) was analyzed. The factorial structure of the ACE-ASF was tested with Exploratory Factor Analysis (EFA) and confirmed using Confirmatory Factor Analysis (CFA). Measurement invariance was examined across boys and girls and internal reliability and concurrent criterion validity were established. Results: Violence exposure was high: 39.7% physical, 32.2% emotional and 13.1% sexual abuse. EFA established a two factor structure: physical/emotional abuse and sexual abuse. CFA confirmed this model fitted the data well [χ 2 (df)=60.526(19); RMSEA=.036; CFI/TLI=.990/.986]. Metric invariance was supported across genders. Internal consistency was good (.83) for the sexual abuse scale and poor (.57) for the physical/emotional abuse scale. Concurrent criterion validity confirmed hypothesized relationships between childhood abuse and health-related quality of life, life satisfaction, self-perceived health, bullying victimization and perpetration, externalizing and internalizing behaviors and multiple health complaints. Conclusions: Results support the ACE-ASF as a valid measure of physical, emotional and sexual abuse in school-aged adolescents. Future research is needed to replicate findings in other youth populations and across different age groups

Telomerase and telomere regulation by associated proteins and in primary malignant lymphocytes

Telomeres are repeated sequences of DNA at the ends of chromosomes that protect the cell from death. Telomerase is a ribonucleoprotein (RNP), consisting of a catalytic subunit, TERT, and an RNA component, TR, that synthesizes telomeres. Telomerase is active in 85% of cancers, including leukemias. Telomerase is thus a potential pharmacological drug target for cancer therapy, and it is important to understand this enzyme and its regulation by associated proteins. One goal of this thesis was to identify novel telomerase interacting partners that specifically regulate telomerase function and that could serve as potential anticancer targets. Additionally, it is important to understand how telomerase inhibition works in a cancer model. Telomere length is a prognostic factor in chronic lymphocytic leukemia (CLL). Previous reports have assessed Imetelstat, a telomerase inhibitor which targets the human telomerase RNA component hTR, in a phase I-II clinical trial in CLL patients. We further investigated Imetelstat in lymphocytes from CLL patients. We found that telomerase activity was present in 47% of lymphocyte samples from CLL patients and that treatment with Imetelstat alone did not affect the survival of primary CLL lymphocytes in vitro. Nonetheless, Imetelstat increased the sensitivity of CLL lymphocytes to fludarabine, independent of basal telomerase activity. Imetelstat inhibited fludarabine-induced DNA-PK autophosphorylation, a surrogate of DNA-PK activity in CLL lymphocytes, to the same extent as the DNA-PK inhibitor NU7026. The effect of Imetelstat on fludarabine sensitivity was associated with a lower basal expression of the DNA-PK subunit protein Ku80. Our results suggest that Imetelstat can inhibit fludarabine-induced DNA-PK activity in primary CLL lymphocytes. We conclude that there may be a functional interaction between hTR and DNA-PKcs in primary CLL lymphocytes and that Imetelstat in combination with fludarabine may be useful to decrease the tumour burden in CLL. To investigate other telomerase targets, we identified telomerase associated proteins via mass spectrometry. One potential target is NOP17, which could be involved in the early assembly of telomerase. We created a human cell line stably expressing NOP17 fused to a FLAG tag. Telomerase activity was coimmunoprecipitated using an antibody against FLAG. Moreover, downregulating the expression of this Box C/D SnoRNP protein resulted in decreased telomerase activity. Characterization of telomerase-associated proteins is vital to our understanding of how this enzyme contributes to tumorigenesis. Understanding the regulation of telomere length and telomerase function by associated proteins will be important for the discovery of targeted therapeutics in cancers.La télomérase synthétise les séquences télomériques et se compose minimalement d'une sous-unité transcriptase inverse (TERT) et d'un fragment d'ARN (TR). La télomérase est active dans 85% des cancers, y compris la leucémie, elle représente donc une cible pour les thérapies du cancer. Afin de découvrir de meilleures cibles thérapeutiques, il est important de comprendre cette enzyme et sa régulation par des protéines associées. Un des buts de cette thèse est d'identifier de nouvelles protéines interagissant avec la télomérase, pouvant réguler ses fonctions de façon spécifique et ainsi potentiellement devenir des cibles anticancéreuses. De plus, il est important de bien comprendre l'effet de l'inhibition de la télomérase dans un modèle de cancer. Nous avons choisi la leucémie car la taille des télomères est un facteur pronostique de la leucémie lymphoïde chronique (LLC). De précédentes études ont conduit à l'évaluation d'Imetelstat, un inhibiteur de la télomérase qui cible la composant ARN de l'enzyme, présentement en essais cliniques de phases I-II. Nos résultats montrent qu'il y a activité de la télomérase dans 47% des échantillons de lymphocytes de patients atteints de LLC et que le traitement seul d'Imetelstat n'a aucun effet sur la survie des lymphocytes primaires de LLC in vitro. Cependant, Imetelstat augmente la sensibilisation des lymphocytes à la Fludarabine, et ce indépendamment de l'activité basale de la télomérase. Imetelstat inhibe l'autophosphorylation de DNA-PK (l'autophosphorylation de DNA-PK est corrélée à son activité enzymatique dans les lymphocytes de LLC) induite par la fludarabine au même niveau que l'inhibiteur de DNA-PK NU7026. L'effet d'Imetelstat sur la sensibilité à la fludarabine est associé à l'expression basale de la protéine Ku80. Nos résultats suggèrent que l'Imetelstat inhibe l'activité DNA-PK dans les lymphocytes de LLC primaire. Nous pouvons conclure qu'il peut s'agir d'une interaction fonctionnelle entre hTR et DNA-PKcs dans les lymphocytes de LLC et que la combinaison de la fludarabine et d'Imetelstat pourrait être utile afin de diminuer la masse tumorale dans la LLC. Afin de découvrir de nouvelles cibles contre la télomérase, nous avons purifié le complexe de la télomérase par spectrométrie de masse. Cela nous a permis d'identifié une nouvelle protéine associée à la télomerase, NOP17, qui pourrait être impliquée dans l'assemblage de la télomérase. Nous avons créé une lignée cellulaire humaine exprimant de façon stable la protéine NOP17 fusionnée à une étiquette FLAG. L'Immunoprecipitation de NOP17 montre une activité de la télomérase indiquant qu'elle est associée à un complexe actif. Par ailleurs, la régulation négative de l'expression de la boîte C/D SnoRNP de la protéine réduit l'expression et l'activité de la télomérase. La caractérisation des protéines associées à la télomérase est essentielle afin de mieux comprendre le fonctionnement de cette enzyme ainsi que sont implication dans la formation de cancers. De plus, ces protéines associées à la télomérase pourraient également servir de cibles potentielles dans les thérapies contre le cancer