Phase 3, multicentre, randomised, placebo-controlled study evaluating the efficacy and safety of ustekinumab in patients with systemic lupus erythematosus.

OBJECTIVE: Evaluate the efficacy and safety of ustekinumab, an anti-interleukin-12/23 p40 antibody, in a phase 3, randomised, placebo-controlled study of patients with active systemic lupus erythematosus (SLE) despite receiving standard-of-care. METHODS: Active SLE patients (SLE Disease Activity Index 2000 (SLEDAI-2K) ≥6 during screening and SLEDAI-2K ≥4 for clinical features at week 0) despite receiving oral glucocorticoids, antimalarials, or immunomodulatory drugs were randomised (3:2) to receive ustekinumab (intravenous infusion ~6 mg/kg at week 0, followed by subcutaneous injections of ustekinumab 90 mg at week 8 and every 8 weeks) or placebo through week 48. The primary endpoint was SLE Responder Index (SRI)-4 at week 52, and major secondary endpoints included time to flare through week 52 and SRI-4 at week 24. RESULTS: At baseline, 516 patients were randomised to placebo (n=208) or ustekinumab (n=308). Following the planned interim analysis, the sponsor discontinued the study due to lack of efficacy but no safety concerns. Efficacy analyses included 289 patients (placebo, n=116; ustekinumab, n=173) who completed or would have had a week 52 visit at study discontinuation. At week 52, 44% of ustekinumab patients and 56% of placebo patients had an SRI-4 response; there were no appreciable differences between the treatment groups in the major secondary endpoints. Through week 52, 28% of ustekinumab patients and 32% of placebo patients had a British Isles Lupus Assessment Group flare, with a mean time to first flare of 204.7 and 200.4 days, respectively. Through week 52, 70% of ustekinumab patients and 74% of placebo patients had ≥1 adverse event. CONCLUSIONS: Ustekinumab did not demonstrate superiority over placebo in this population of adults with active SLE; adverse events were consistent with the known safety profile of ustekinumab. TRIAL REGISTRATION NUMBER: NCT03517722.

Real-world impact of flaring on patient-reported outcomes and healthcare resource utilisation in systemic lupus erythematosus.

OBJECTIVES: We investigated the association of SLE flares with patient-reported outcomes (PRO) and healthcare resource utilisation (HCRU) using real-world data. METHODS: Rheumatologists from the USA, France, Germany, Spain, Italy provided demographic, clinical, and HCRU data for patients with SLE, who provided PRO data. "Flaring" was defined as ≥1 rheumatologist-reported flare in the past 12 months. Demographic/clinical data were analysed descriptively, and findings compared statistically by flaring status. Logistic regression estimated a propensity score for flaring based on ethnicity, disease duration, and severity at diagnosis. Propensity score-matched flaring and non-flaring patients were compared for their HCRU, PROs, income loss and treatment satisfaction. RESULTS: Physicians (n=263) provided data for 1,278 patients (408 flaring/870 non-flaring); 729 patients (241 flaring/488 non-flaring) provided matched patient data. Patients had a mean 2.1 flares in the previous 12 months. Propensity score matched analyses indicated worse outcomes and greater HCRU in the past 12 months in flaring than non-flaring patients: EuroQoL 5D-3L Utility Index: 0.72 vs. 0.83; Functional Assessment of Chronic Illness Therapy-Fatigue scale: 30.06 vs. 36.48; Work Productivity and Activity Impairment Index: absenteeism 5.87% vs. 2.53% / presenteeism 33.44% vs. 19.16% / overall work impairment 35.98% vs. 20.66% / total activity impairment 42.47% vs. 30.23%; healthcare consultations (8.10 vs. 6.41), hospitalisations (24.26 vs. 7.63), emergency department visits (20.83 vs. 4.19), tests (46.59 vs. 38.90); current medications (2.76 vs. 2.19) (all p<0.001 except absenteeism, p=0.004). CONCLUSIONS: Similar flaring SLE patients had worse PROs and higher HCRU than non-flaring patients, underscoring the need for more effective strategies and treatments to alleviate or prevent flaring.

Pazopanib may reduce bleeding in hereditary hemorrhagic telangiectasia.

Pazopanib (Votrient) is an orally administered tyrosine kinase inhibitor that blocks VEGF receptors potentially serving as anti-angiogenic treatment for hereditary hemorrhagic telangiectasia (HHT). We report a prospective, multi-center, open-label, dose-escalating study [50 mg, 100 mg, 200 mg, and 400 mg], designed as a proof-of-concept study to demonstrate efficacy of pazopanib on HHT-related bleeding, and to measure safety. Patients, recruited at 5 HHT Centers, required ≥ 2 Curacao criteria AND [anemia OR severe epistaxis with iron deficiency]. Co-primary outcomes, hemoglobin (Hgb) and epistaxis severity, were measured during and after treatment, and compared to baseline. Safety monitoring occurred every 1.5 weeks. Seven patients were treated with 50 mg pazopanib daily. Six/seven showed at least 50% decrease in epistaxis duration relative to baseline at some point during study; 3 showed at least 50% decrease in duration during Weeks 11 and 12. Six patients showed a decrease in ESS of > 0.71 (MID) relative to baseline at some point during study; 3/6 showed a sustained improvement. Four patients showed > 2 gm improvement in Hgb relative to baseline at one or more points during study. Health-related QOL scores improved on all SF-36 domains at Week 6 and/or Week 12, except general health (unchanged). There were 19 adverse events (AE) including one severe AE (elevated LFTs, withdrawn from dosing at 43 days); with no serious AE. In conclusion, we observed an improvement in Hgb and/or epistaxis in all treated patients. This occurred at a dose much lower than typically used for oncologic indications, with no serious AE. Further studies of pazopanib efficacy are warranted.

Efficacy and Improved Resistance Potential of a Cofactor-Independent InhA Inhibitor of Mycobacterium tuberculosis in the C3HeB/FeJ Mouse Model.

AN12855 is a direct, cofactor-independent inhibitor of InhA in Mycobacterium tuberculosis In the C3HeB/FeJ mouse model with caseous necrotic lung lesions, AN12855 proved efficacious with a significantly lower resistance frequency than isoniazid. AN12855 drug levels were better retained in necrotic lesions and caseum where the majority of hard to treat, extracellular bacilli reside. Owing to these combined attributes, AN12855 represents a promising alternative to the frontline antituberculosis agent isoniazid.

Identification of a 4-fluorobenzyl l-valinate amide benzoxaborole (AN11736) as a potential development candidate for the treatment of Animal African Trypanosomiasis (AAT).

Novel l-valinate amide benzoxaboroles and analogues were designed and synthesized for a structure-activity-relationship (SAR) investigation to optimize the growth inhibitory activity against Trypanosoma congolense (T. congolense) and Trypanosoma vivax (T. vivax) parasites. The study identified 4-fluorobenzyl (1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbonyl)-l-valinate (5, AN11736), which showed IC50 values of 0.15 nM against T. congolense and 1.3 nM against T. vivax, and demonstrated 100% efficacy with a single dose of 10 mg/kg against both T. congolense and T. vivax in mouse models of infection (IP dosing) and in the target animal, cattle, dosed intramuscularly. AN11736 has been advanced to early development studies.

Development of the Systemic Lupus Erythematosus Steroid Questionnaire (SSQ): a novel patient-reported outcome tool to assess the impact of oral steroid treatment.

BACKGROUND: Oral glucocorticoids (steroids) are the mainstay of treatment for systemic lupus erythematosus (SLE), but their use is often associated with short- and long-term side effects. Following a literature review and discussions with patients with SLE, clinicians, and payers, a need was identified for a comprehensive SLE-specific tool that can be used to evaluate the side effects and benefits of steroids over time from a patient perspective. The objective of this study was to develop a patient-reported outcome (PRO) measure to assess general impact (baseline burden), benefits, side effects, and impacts associated with the use of oral steroids in patients with SLE. METHODS: A qualitative research protocol was developed in which adults with SLE currently receiving or who had received steroids in the past year were recruited from six US rheumatology practices to participate in concept elicitation (CE) interviews. The SLE Steroid Questionnaire (SSQ) was developed based on CE interview results and clinical input. Cognitive debriefing interviews with a second group of patients with SLE evaluated the content, clarity, and relevance of the items. The SSQ was refined using patient feedback, clinician review, and a translatability assessment. The protocol received central independent review board approval. RESULTS: Thirty-three patients (52% moderate disease severity; 58% currently receiving steroids, mean dose 8.7 mg/day) completed CE interviews. Patients reported benefits, side effects, and impacts from steroids. The refined SSQ contains 50 items assessing steroid dose/duration (4 items), general impact (baseline burden; 19 items), benefits (7 items), work/productivity (3 items), side effects (10 items), emotions (6 items), and overall satisfaction (1 item). CONCLUSION: The SSQ is a unique PRO, developed using robust scientific methodology in accordance with the Food and Drug Administration PRO Guidance. It was designed to comprehensively assess the patient experience with steroid therapy and better understand the benefits and burden of steroids for patients with SLE.

Surface water retention systems for cattail production as a biofuel.

Surface water retention systems act to reduce nutrient pollution by collecting excess nutrients within a watershed via runoff. Harvesting aquatic biomass, such as the invasive cattail, from retention systems removes nutrients absorbed by the plant from the ecosystem permanently. Harvested biomass can be used as a renewable energy source in place of fossil fuels, offsetting carbon emissions. The purpose of this research was to simulate cattail harvest from surface water retention systems to determine their ability to provide suitable growing conditions with annual fluctuations in water availability. The economic and environmental benefits associated with nutrient removal and carbon offsets were also calculated and monetized. A proposed upstream and existing downstream water retention system in southern Manitoba were modelled using a system dynamics model with streamflow inputs provided by a physical hydrologic model, Modélisation Environmentale Communautaire - Surface and Hydrology (MESH). Harvesting cattail and other unconventional feedstocks, such as reeds, sedges, and grasses, from retention systems provided a viable revenue stream for landowners over a ten-year period. This practice generates income for landowners via biomass and carbon credit production on otherwise underutilized marginal cropland invaded with cattail. The economic benefits promote wetland habitat restoration while managing cattail growth to maintain biodiversity. Excess nitrogen and phosphorus are also removed from the ecosystem, reducing downstream nutrient loading. Utilizing surface water retention systems for cattail harvest is a best management strategy for nutrient retention on the landscape and improving agricultural resilience.

Treatment Satisfaction in Systemic Lupus Erythematosus: Development of a Patient-Reported Outcome Measure.

OBJECTIVE: The aim of this study was to develop a patient-reported outcome measure specific for systemic lupus erythematosus (SLE) to assess patient satisfaction with treatment, treatment options, and medical care. METHODS: Patients with SLE were recruited from four US rheumatology practices. Concept elicitation interviews identified aspects that patients considered important and relevant regarding satisfaction with treatment and medical care. Concept elicitation interviews and clinical input were used to draft the Lupus Satisfaction Questionnaire (LSQ). A second cohort of patients with SLE participated in combined concept elicitation/cognitive debriefing interviews, after which the LSQ was revised. RESULTS: Fourteen patients completed concept elicitation interviews: 93% were female, 57% were white, and 85% had moderate/severe SLE. Current treatments included hydroxychloroquine (93%), steroids (79%), and belimumab (57%), and 43% were biologic naive. Patients were generally satisfied with their treatment and medical care; however, they were dissatisfied with treatment adverse effects and the number of available treatment options. Cognitive debriefing interviews (n = 8) demonstrated that the LSQ was comprehensive, clear, and relevant; therefore, only minor revisions were made to the questionnaire. The LSQ assesses satisfaction with current SLE treatments (25 items), medical care (11 items), and insurance coverage (3 items). The draft LSQ was evaluated in 195 adults with SLE. Fifty-eight percent of patients reported that they were "somewhat satisfied" with their SLE treatment. CONCLUSIONS: The LSQ has been developed to assess treatment satisfaction among patients with SLE. Following further testing to support its validity and reliability, it will provide a useful tool to facilitate assessment of satisfaction with treatments for SLE and help inform treatment decisions.

Stapled α-helical peptide drug development: a potent dual inhibitor of MDM2 and MDMX for p53-dependent cancer therapy.

Stapled α-helical peptides have emerged as a promising new modality for a wide range of therapeutic targets. Here, we report a potent and selective dual inhibitor of MDM2 and MDMX, ATSP-7041, which effectively activates the p53 pathway in tumors in vitro and in vivo. Specifically, ATSP-7041 binds both MDM2 and MDMX with nanomolar affinities, shows submicromolar cellular activities in cancer cell lines in the presence of serum, and demonstrates highly specific, on-target mechanism of action. A high resolution (1.7-Å) X-ray crystal structure reveals its molecular interactions with the target protein MDMX, including multiple contacts with key amino acids as well as a role for the hydrocarbon staple itself in target engagement. Most importantly, ATSP-7041 demonstrates robust p53-dependent tumor growth suppression in MDM2/MDMX-overexpressing xenograft cancer models, with a high correlation to on-target pharmacodynamic activity, and possesses favorable pharmacokinetic and tissue distribution properties. Overall, ATSP-7041 demonstrates in vitro and in vivo proof-of-concept that stapled peptides can be developed as therapeutically relevant inhibitors of protein-protein interaction and may offer a viable modality for cancer therapy.

Patient-reported outcomes and healthcare resource utilization in systemic lupus erythematosus: impact of disease activity.

BACKGROUND: Limited real-world data exists on clinical outcomes in systemic lupus erythematosus (SLE) patients by SLE Disease Activity Index 2000 (SLEDAI-2 K), hereafter, SLEDAI. We aimed to examine the association between SLEDAI score and clinical, patient-reported and economic outcomes in patients with SLE. METHODS: Rheumatologists from the United States of America and Europe provided real-world demographic, clinical, and healthcare resource utilization (HCRU) data for SLE patients. Patients provided self-reported outcome data, capturing their general health status using the EuroQol 5-dimension 3-level questionnaire (EQ-5D-3 L), health-related quality of life using the Functional Assessment of Chronic Illness Therapy (FACIT) and work productivity using the Work Productivity and Activity Impairment questionnaire (WPAI). Low disease activity was defined as SLEDAI score ≤ 4 and ≤ 7.5 mg/day glucocorticoids; patients not meeting these criteria were considered to have "higher" active disease. Data were compared between patients with low and higher disease activity. Logistic regression estimated a propensity score for SLE based on demographic and clinical characteristics. Propensity score matched analyses compared HCRU, patient-reported outcomes, income loss and treatment satisfaction in patients with low disease activity versus higher active disease. RESULTS: Data from 296 physicians reporting on 730 patients (46 low disease activity, 684 higher active disease), and from 377 patients' self-reported questionnaires (24 low disease activity, 353 higher active disease) were analyzed. Flaring in the previous 12 months was 2.6-fold more common among patients with higher versus low active disease. Equation 5D-3 L utility index was 0.79 and 0.88 and FACIT-Fatigue scores were 34.78 and 39.79 in low versus higher active disease patients, respectively, indicating better health and less fatigue, among patients with low versus higher active disease. Absenteeism, presenteeism, overall work impairment, and total activity impairment were 47.0-, 2.0-, 2.6- and 1.5-fold greater in patients with higher versus low disease activity. In the previous 12 months there were 28% more healthcare consultations and 3.4-fold more patients hospitalized in patients with higher versus low disease activity. CONCLUSION: Compared to SLE patients with higher active disease, patients with low disease activity experienced better health status, lower HCRU, less fatigue, and lower work productivity impairment, with work absenteeism being substantially lower in these patients.

First-in-Human Gene Therapy Trial of AAV8-hCARp.hCNGB3 in Adults and Children With CNGB3-associated Achromatopsia.

PURPOSE: To assess the safety and efficacy of AAV8-hCARp.hCNGB3 in participants with CNGB3-associated achromatopsia (ACHM). DESIGN: Prospective, phase 1/2 (NCT03001310), open-label, nonrandomized clinical trial. METHODS: The study enrolled 23 adults and children with CNGB3-associated ACHM. In the dose-escalation phase, adult participants were administered 1 of 3 AAV8-hCARp.hCNGB3 dose levels in the worse-seeing eye (up to 0.5 mL). After a maximum tolerated dose was established in adults, an expansion phase was conducted in children ≥3 years old. All participants received topical and oral corticosteroids. Safety and efficacy parameters, including treatment-related adverse events and visual acuity, retinal sensitivity, color vision, and light sensitivity, were assessed for 6 months. RESULTS: AAV8-hCARp.hCNGB3 (11 adults, 12 children) was safe and generally well tolerated. Intraocular inflammation occurred in 9 of 23 participants and was mainly mild or moderate in severity. Severe cases occurred primarily at the highest dose. Two events were considered serious and dose limiting. All intraocular inflammation resolved following topical and systemic steroids. There was no consistent pattern of change from baseline to week 24 for any efficacy assessment. However, favorable changes were observed for individual participants across several assessments, including color vision (n = 6/23), photoaversion (n = 11/20), and vision-related quality-of-life questionnaires (n = 21/23). CONCLUSIONS: AAV8-hCARp.hCNGB3 for CNGB3-associated ACHM demonstrated an acceptable safety and tolerability profile. Improvements in several efficacy parameters indicate that AAV8-hCARp.hCNGB3 gene therapy may provide benefit. These findings, with the development of additional sensitive and quantitative end points, support continued investigation.

Development of the Shortness of Breath with Daily Activities questionnaire (SOBDA).

OBJECTIVES: Based on qualitative research of patients with chronic obstructive pulmonary disease (COPD), the Shortness of Breath (SOB) with Daily Activities (SOBDA) questionnaire was developed as a patient-reported outcome instrument to evaluate the impact of therapy on SOB and assess how SOB affects daily activities. METHODS: Development of the SOBDA questionnaire consisted of three components. First, focus groups of patients with COPD were asked to describe their experiences of SOB with daily activities. A pool of items was drafted on the basis of information from the focus groups and literature reviews, and then discussed among instrument development and clinical experts. Cognitive debriefing interviews of patients were conducted to assess the draft item pool, and their feedback was used to develop newer versions of the questionnaire. Input was also sought from the Food and Drug Administration, patients, and clinicians. RESULTS: Forty patients participated in seven focus groups. The terms most often used to describe SOB were "short of breath" or "difficulty breathing." Patients were clearly able to distinguish SOB from chest congestion and wheezing, other common symptoms associated with COPD. The resulting item pool contained 37 items to assess SOB associated with everyday activities, and concept saturation was reached. Thirty-seven patients participated in the subsequent cognitive debriefing interviews. Patients found the items clear and easy to understand with relevance to their everyday experiences, and easy to use in an electronic format. CONCLUSIONS: Instructions and response options to the SOBDA questionnaire were well understood by patients with COPD, and item relevance was confirmed. Prospective validation and item reduction studies are highly anticipated.

Systemic Lupus Erythematosus Symptom Clusters and Their Association With Patient-Reported Outcomes and Treatment: Analysis of Real-World Data.

OBJECTIVE: To identify discrete clusters of systemic lupus erythematosus (SLE) patients based on symptoms and investigate differences across clusters. METHODS: Data were collected in the US and 5 European countries via the Adelphi Real World Lupus Disease Specific Programme, a cross-sectional survey. Rheumatologists provided data for 5 consecutively consulting adult patients with SLE, who were invited to participate. Identified SLE symptoms were reduced to factors based on commonly concurrent symptoms, using principal-component factor analysis. Factors were used as covariates in a latent-class cluster analysis to identify discrete patient clusters. Patient-reported outcomes and physician-reported data were compared across clusters. RESULTS: Among 1,376 patients, 87% were female and 74% were White. We identified 4 patient clusters (very mild, mild, moderate, and severe) based on 39 signs/symptoms. Physician-reported symptom burden, organ involvement, disease activity, and the number of flares increased with increasing cluster severity (P < 0.0001). Patient-reported impact (health status, fatigue, work productivity impairment, anxiety/depression, and emotional impact) increased with increasing cluster severity (P < 0.0001). Glucocorticoid and immunosuppressant use increased, and antimalarial use decreased, with increasing cluster severity. In all clusters, <20% of patients received biologics; >15% of patients not receiving biologics were considered eligible for treatment by their physician. The proportion of physicians and patients satisfied with treatment decreased with increasing cluster severity (P < 0.0001). CONCLUSION: Our large, international, real-world survey of SLE patients and physicians demonstrated strong associations between increased impairment, organ involvement, and humanistic burden in SLE, highlighting an unmet need for effective treatment options in patients with high disease activity.

Efficacy and Safety of Ustekinumab in Patients With Active Systemic Lupus Erythematosus: Results of a Phase II Open-label Extension Study.

OBJECTIVE: To evaluate the long-term efficacy and safety of ustekinumab through 2 years in patients with active systemic lupus erythematosus (SLE). METHODS: This was a placebo-controlled (week 24), phase II study in 102 patients with seropositive active SLE. Patients were randomized to ustekinumab (approximately 6 mg/kg single intravenous infusion, then subcutaneous [SC] injections of 90 mg every 8 weeks) or placebo, added to background therapy. Placebo patients initiated ustekinumab (90 mg SC every 8 weeks) at week 24. Patients could enter an optional open-label study extension after week 40 (final ustekinumab administration at week 104). Efficacy assessments included Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K), SLEDAI-2K Responder Index-4 (SRI-4), physician global assessment (PGA), and Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI). Observed data are reported for the extension period. The final efficacy assessment was at week 112; safety was monitored through week 120. RESULTS: In this subset of patients who entered the study extension, 24 in the ustekinumab group and 14 in the placebo crossover group completed study treatment. At week 112, 79% and 92%, respectively, had an SRI-4 response; 92% in both groups had ≥ 4-point improvement from baseline in SLEDAI-2K score; 79% and 93%, respectively, had ≥ 30% improvement from baseline in PGA; 86% and 91%, respectively, had ≥ 50% improvement in active joint (pain and inflammation) count; and 79% and 100%, respectively, had ≥ 50% improvement in CLASI Activity Score. No deaths, malignancies, opportunistic infections, or tuberculosis cases occurred. Safety events were consistent with the known ustekinumab safety profile. CONCLUSION: Of the 46 patients who entered the voluntary extension of this phase II study, clinical benefit in global and organ-specific SLE activity measures was observed with ustekinumab through 2 years with no new or unexpected safety findings. [ClinicalTrials.gov: NCT02349061].

Generation of evidence supporting the content validity of SF-36, FACIT-F, and LupusQoL, and novel patient-reported symptom items for use in patients with systemic lupus erythematosus (SLE) and SLE with lupus nephritis (LN).

OBJECTIVE: SLE and lupus nephritis (LN) have significant impacts on the health-related quality of life of patients living with the condition, which are important to capture from the patient's perspective using patient-reported outcomes (PROs). The objectives of this study were to evaluate the content validity of PROs commonly used in SLE and LN (36-Item Short Form Health Survey (SF-36), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) and Lupus Quality of Life (LupusQoL), as well as novel PRO symptom severity items measuring skin rash, joint pain, joint stiffness and swelling of the legs and/or feet, in both populations. METHODS: Qualitative, semi-structured, cognitive interviews were conducted with 48 participants (SLE=28, LN=20). Understanding and relevance of symptom and impact PRO concepts from existing PROs were assessed, alongside novel PRO symptom severity items with different recall periods (24 hours vs 7 days) and response scales (Numerical Rating Scale (NRS) vs Verbal Rating Scale). Interviews were conducted in multiple rounds to allow for modifications to the novel PRO items. Analysis of verbatim interview transcripts was performed. RESULTS: Symptom and impact concepts assessed by the SF-36, FACIT-F, and LupusQoL were well understood by both participants with SLE and LN (≥90.0%), with most considered relevant by over half of the participants asked (≥51.9%). All participants asked (100%) understood the novel PRO symptom severity items, and the majority (≥90.0%) considered the symptoms relevant. Minor modifications to the novel PRO items were made between rounds to improve clarity based on participant feedback. The selected 7-day recall period and NRS in the final iteration of the PRO items were understood and relevant. No differences in interview findings between the SLE and LN samples were identified. CONCLUSIONS: Findings provide evidence of content validity for concepts assessed by the SF-36, FACIT-F, LupusQoL and the novel PRO symptom severity items, supporting use of these PROs to comprehensively assess disease impact in future SLE and LN clinical trials.

Diagnosing delirium in critically ill children: Validity and reliability of the Pediatric Confusion Assessment Method for the Intensive Care Unit.

OBJECTIVE: To validate a diagnostic instrument for pediatric delirium in critically ill children, both ventilated and nonventilated, that uses standardized, developmentally appropriate measurements. DESIGN AND SETTING: A prospective observational cohort study investigating the Pediatric Confusion Assessment Method for Intensive Care Unit (pCAM-ICU) patients in the pediatric medical, surgical, and cardiac intensive care unit of a university-based medical center. PATIENTS: A total of 68 pediatric critically ill patients, at least 5 years of age, were enrolled from July 1, 2008, to March 30, 2009. INTERVENTIONS: None. MEASUREMENTS: Criterion validity including sensitivity and specificity and interrater reliability were determined using daily delirium assessments with the pCAM-ICU by two critical care clinicians compared with delirium diagnosis by pediatric psychiatrists using Diagnostic and Statistical Manual, 4th Edition, Text Revision criteria. RESULTS: A total of 146 paired assessments were completed among 68 enrolled patients with a mean age of 12.2 yrs. Compared with the reference standard for diagnosing delirium, the pCAM-ICU demonstrated a sensitivity of 83% (95% confidence interval, 66-93%), a specificity of 99% (95% confidence interval, 95-100%), and a high interrater reliability (κ = 0.96; 95% confidence interval, 0.74-1.0). CONCLUSIONS: The pCAM-ICU is a highly valid reliable instrument for the diagnosis of pediatric delirium in critically ill children chronologically and developmentally at least 5 yrs of age. Use of the pCAM-ICU may expedite diagnosis and consultation with neuropsychiatry specialists for treatment of pediatric delirium. In addition, the pCAM-ICU may provide a means for delirium monitoring in future epidemiologic and interventional studies in critically ill children.

A qualitative exploration of the patient experience of erosive and non-erosive hand osteoarthritis.

BACKGROUND: Many patients with hand osteoarthritis (HOA) experience reduced health-related quality of life. This study sought to better understand the disease and treatment experience of individuals with HOA, explore any differences in experiences between erosive and non-erosive HOA sub-types, and evaluate content validity of the Michigan Hand Outcomes Questionnaire (MHQ) in HOA. METHODS: Thirty subjects from the United States (n = 15 erosive HOA; n = 15 non-erosive HOA) participated in semi-structured interviews: concept elicitation explored symptoms/impacts important to patients; cognitive interviews assessed understanding and relevance of the MHQ. A sub-sample participated in real-time data capture (RTDC) activities via a smartphone/tablet app over 7 days. Verbatim transcripts were coded using Atlas.ti software and thematically analyzed. Concept saturation and MHQ content validity were evaluated. RESULTS: Most participants reported experiencing pain, swelling and stiffness, symptoms that most commonly had a direct impact on physical functioning. Substantial impacts on activities of daily living, emotional functioning, sleep and work were also reported. RTDC findings corroborated concept elicitation findings. There were no notable differences between erosive and non-erosive HOA, except nodules were reported more frequently in erosive disease. Most participants used analgesic treatments, but effects were short-lived. Pain was the symptom most frequently reported as most bothersome and important to treat. Concept saturation was achieved. MHQ items and instructions were well understood and relevant to most participants; stiffness and swelling were reported as important symptoms not included in the MHQ. CONCLUSIONS: This study characterizes key symptoms of HOA which are burdensome for patients and not well controlled by current therapies, highlighting an unmet treatment need. Although the study is limited by a small sample size that may not be representative of the broader erosive and non-erosive HOA population, concept saturation was achieved, and our findings suggest that disease experience is similar for patients with erosive and non-erosive HOA. Evaluation of stiffness and swelling items in conjunction with the MHQ may enhance relevance and improve measurement precision to assess important domains of HQRoL in an HOA population.

Exploration of a new series of CCR5 antagonists: multi-dimensional optimization of a sub-series containing N-substituted pyrazoles.

The introduction of N-substituted pyrazoles in a new series of CCR5 antagonists was shown to substantially increase antiviral activity.

Evaluation of amide replacements in CCR5 antagonists as a means to increase intrinsic permeability. Part 2: SAR optimization and pharmacokinetic profile of a homologous azacyle series.

Replacement of a secondary amide with a piperidine or azetidine moiety in a series of CCR5 antagonists led to the discovery of compounds with increased intrinsic permeability. This effort led to the identification of a potent CCR5 antagonist which exhibited an improved in vivo pharmacokinetic profile.

Synthesis, SAR and evaluation of [1,4']-bipiperidinyl-4-yl-imidazolidin-2-one derivatives as novel CCR5 antagonists.

Elaboration of our previously disclosed spiropiperidine template led to the development of a series of novel CCR5 antagonists. Results of SAR exploration and preliminary lead characterization are described.