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.

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.

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.

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.

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.

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].

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.

Macrofilaricidal Benzimidazole-Benzoxaborole Hybrids as an Approach to the Treatment of River Blindness: Part 2. Ketone Linked Analogs.

The optimization of a series of benzimidazole-benzoxaborole hybrid molecules linked via a ketone that exhibit good activity against Onchocerca volvulus, a filarial nematode responsible for the disease onchocerciasis, also known as river blindness, is described. The lead identified in this series, 21 (AN15470), was found to have acceptable pharmacokinetic properties to enable an evaluation following oral dosing in an animal model of onchocerciasis. Compound 21was effective in killing worms implanted in Mongolian gerbils when dosed orally as a suspension at 100 mg/kg/day for 14 days but not when dosed orally at 100 mg/kg/day for 7 days.

Macrofilaricidal Benzimidazole-Benzoxaborole Hybrids as an Approach to the Treatment of River Blindness: Part 1. Amide Linked Analogs.

A series of benzimidazole-benzoxaborole hybrid molecules linked via an amide linker are described that exhibit good in vitro activity against Onchocerca volvulus, a filarial nematode responsible for the disease onchocerciasis, also known as river blindness. The lead identified in this series, 8a (AN8799), was found to have acceptable pharmacokinetic properties to enable evaluation in animal models of human filariasis. Compound 8a was effective in killing Brugia malayi, B. pahangi, and Litomosoides sigmodontis worms present in Mongolian gerbils when dosed subcutaneously as a suspension at 100 mg/kg/day for 14 days but not when dosed orally at 100 mg/kg/day for 28 days. The measurement of plasma levels of 8a at the end of the dosing period and at the time of sacrifice revealed an interesting dependence of activity on the extended exposure for both 8a and the positive control, flubendazole.

Identification of a potent benzoxaborole drug candidate for treating cryptosporidiosis.

Cryptosporidiosis is a leading cause of life-threatening diarrhea in young children and causes chronic diarrhea in AIDS patients, but the only approved treatment is ineffective in malnourished children and immunocompromised people. We here use a drug repositioning strategy and identify a promising anticryptosporidial drug candidate. Screening a library of benzoxaboroles comprised of analogs to four antiprotozoal chemical scaffolds under pre-clinical development for neglected tropical diseases for Cryptosporidium growth inhibitors identifies the 6-carboxamide benzoxaborole AN7973. AN7973 blocks intracellular parasite development, appears to be parasiticidal, and potently inhibits the two Cryptosporidium species most relevant to human health, C. parvum and C. hominis. It is efficacious in murine models of both acute and established infection, and in a neonatal dairy calf model of cryptosporidiosis. AN7973 also possesses favorable safety, stability, and PK parameters, and therefore, is an exciting drug candidate for treating cryptosporidiosis.

Boron-Pleuromutilins as Anti- Wolbachia Agents with Potential for Treatment of Onchocerciasis and Lymphatic Filariasis.

A series of pleuromutilins modified by introduction of a boron-containing heterocycle on C(14) of the polycyclic core are described. These analogs were found to be potent anti- Wolbachia antibiotics and, as such, may be useful in the treatment of filarial infections caused by Onchocerca volvulus, resulting in Onchocerciasis or river blindness, or Wuchereria bancrofti and Brugia malayi and related parasitic nematodes resulting in lymphatic filariasis. These two important neglected tropical diseases disproportionately impact patients in the developing world. The lead preclinical candidate compound containing 7-fluoro-6-oxybenzoxaborole (15, AN11251) was shown to have good in vitro anti- Wolbachia activity and physicochemical and pharmacokinetic properties providing high exposure in plasma. The lead was effective in reducing the Wolbachia load in filarial worms following oral administration to mice.

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.

Long-Term Impact of Belimumab on Health-Related Quality of Life and Fatigue in Patients With Systemic Lupus Erythematosus: Six Years of Treatment.

OBJECTIVE: To report long-term health-related quality of life (HRQoL) and fatigue outcomes in patients with systemic lupus erythematosus (SLE) receiving belimumab. METHODS: Patients with SLE who completed the Study of Belimumab in Subjects with SLE 76-week trial (BLISS-76) were enrolled in this continuation study (BEL112233 [ClinicalTrials.gov identifier: NCT00724867]). The belimumab groups continued to receive the same dose (1 mg/kg or 10 mg/kg) intravenously. After March 2011, all patients received belimumab 10 mg/kg every 28 days plus standard therapy. The placebo group switched to belimumab 10 mg/kg. HRQoL and fatigue assessments included the Short Form 36 (SF-36) health survey and the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue subscale. Post hoc subgroup analyses (BEL206350) assessed clinical characteristics associated with improved HRQoL and fatigue. RESULTS: Of the 268 patients enrolled, 140 completed the study. Patients receiving long-term belimumab treatment reported continued improvements in HRQoL and fatigue. At study year 6, the mean ± SD SF-36 physical component summary (PCS) score and the mental component summary (MCS) score increased from 37.0 ± 9.9 at baseline to 41.7 ± 10.0 (mean ± SD change 4.8 ± 9.4) and from 44.3 ± 11.3 to 47.0 ± 11.6 (mean ± SD change 2.7 ± 11.3) for the PCS and MCS, respectively, exceeding the minimum clinically important difference (MCID) for improvement (2.5 units). The mean ± SD FACIT-Fatigue score exceeded the MCID of 4 at study years 1-5; at study year 6, the mean ± SD change was 3.7 ± 11.8. Statistically significant associations were observed between parent trial treatment groups and change from baseline in PCS, MCS, and FACIT-Fatigue scores (P < 0.01). CONCLUSION: Long-term control of SLE disease activity with belimumab plus standard therapy translates into meaningful improvements in patient-reported fatigue and HRQoL.

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.

Discovery of a cofactor-independent inhibitor of Mycobacterium tuberculosis InhA.

New antitubercular agents are needed to combat the spread of multidrug- and extensively drug-resistant strains of Mycobacterium tuberculosis. The frontline antitubercular drug isoniazid (INH) targets the mycobacterial enoyl-ACP reductase, InhA. Resistance to INH is predominantly through mutations affecting the prodrug-activating enzyme KatG. Here, we report the identification of the diazaborines as a new class of direct InhA inhibitors. The lead compound, AN12855, exhibited in vitro bactericidal activity against replicating bacteria and was active against several drug-resistant clinical isolates. Biophysical and structural investigations revealed that AN12855 binds to and inhibits the substrate-binding site of InhA in a cofactor-independent manner. AN12855 showed good drug exposure after i.v. and oral delivery, with 53% oral bioavailability. Delivered orally, AN12855 exhibited dose-dependent efficacy in both an acute and chronic murine model of tuberculosis infection that was comparable with INH. Combined, AN12855 is a promising candidate for the development of new antitubercular agents.

Using a ResearchKit Smartphone App to Collect Rheumatoid Arthritis Symptoms From Real-World Participants: Feasibility Study.

BACKGROUND: Using smartphones to enroll, obtain consent, and gather self-reported data from patients has the potential to enhance our understanding of disease burden and quantify physiological impact in the real world. It may also be possible to harness integral smartphone sensors to facilitate remote collection of clinically relevant data. OBJECTIVE: We conducted the Patient Rheumatoid Arthritis Data From the Real World (PARADE) observational study using a customized ResearchKit app with a bring-your-own-device approach. Our objective was to assess the feasibility of using an entirely digital approach (social media and smartphone app) to conduct a real-world observational study of patients with rheumatoid arthritis. METHODS: We conducted this observational study using a customized ResearchKit app with a bring-your-own-device approach. To recruit patients, the PARADE app, designed to guide patients through a series of tasks, was publicized via social media platforms and made available for patients in the United States to download from the Apple App Store. We collected patient-reported data, such as medical history, rheumatoid arthritis-related medications (past and present), and a range of patient-reported outcome measures. We included in the assessment a joint-pain map and a novel objective assessment of wrist range of movement, measured by the smartphone-embedded gyroscope and accelerometer. RESULTS: Within 1 month of recruitment via social media campaigns, 399 participants self-enrolled, self-consented, and provided complete demographic data. Joint pain was the most frequently reported rheumatoid arthritis symptom to bother study participants (344/393, 87.5%). Severe patient-reported wrist pain appeared to be inversely linked with the range of wrist movement measured objectively by the app. At study entry, 292 of 399 participants (73.2%) indicated a preference for participating in a mobile app-based study. The number of participants in the study declined to 45 of 399 (11.3%) at week 12. CONCLUSIONS: Despite the declining number of participants over time, the combination of social media and smartphone app with sensor integration was a feasible and cost-effective approach for the collection of patient-reported data in rheumatoid arthritis. Integral sensors within smartphones can be harnessed to provide novel end points, and the novel wrist range of movement test warrants further clinical validation.

Nosebleeds in hereditary hemorrhagic telangiectasia: Development of a patient-completed daily eDiary.

OBJECTIVE: A prospective, qualitative study was conducted to develop a patient-reported outcome measure (PROM) for daily administration via electronic diary (eDiary) to assess the severity of nosebleeds in patients with hereditary hemorrhagic telangiectasia (HHT), in accordance with Food and Drug Administration (FDA) PROM guidance criteria. METHODS: Three expert clinicians who treat patients with HHT provided input during instrument development, which comprised: 1) Peer-reviewed literature and instrument review; 2) Development of draft Nosebleed Diary items; 3a) Three rounds of qualitative interviews (two with a paper-based diary, one with an eDiary) with patients with documented severe epistaxis related to HHT, for concept elicitation and cognitive debriefing; 3b) Face validity and translatability assessment; 3c) Patient evaluation of the usability and acceptability of the eDiary device; and 4) Preparation of the final Nosebleed eDiary and conceptual framework. RESULTS: No existing instruments were identified that evaluate HHT-related nosebleed severity daily and meet FDA PROM guidance criteria. Frequency, duration, and/or speed of flow (i.e., intensity) were reported by most participants with HHT when asked to describe their nosebleed severity. The Nosebleed eDiary was refined based on 17 patient interviews, clinical expert input and the face validity and translatability assessment. The final four-item eDiary was acceptable to patients with HHT. CONCLUSION: The Nosebleed eDiary is "fit for purpose" to assess the severity of HHT-related nosebleeds, and has established face and content validity. Further adaptation may be required for use in mild or moderate HHT populations. Psychometric testing to evaluate construct validity and reliability are recommended next steps. LEVEL OF EVIDENCE: 2c "Outcomes research".

Patient Evaluation of Satisfaction and Outcomes with an Autoinjector for Self-Administration of Subcutaneous Belimumab in Patients with Systemic Lupus Erythematosus.

OBJECTIVE: This study assessed patient experiences of using an autoinjector device to self-administer subcutaneous belimumab for the treatment of systemic lupus erythematosus (SLE). Satisfaction, ease and convenience of use, and confidence with the device were assessed, in addition to overall experience with belimumab. METHODS: This cross-sectional study was conducted among patients who completed a phase IIb open-label, multi-dose usability, tolerability, and safety study of subcutaneous belimumab (NCT02124798), in which patients receiving intravenous belimumab or subcutaneous belimumab using a prefilled syringe were switched to eight weekly self-administered doses of subcutaneous belimumab using the autoinjector. This follow-up study comprised an online/paper questionnaire and qualitative telephone interviews. RESULTS: In total, 43 patients receiving belimumab completed the questionnaire, 21 of whom also completed a follow-up telephone interview. Qualitative interviews indicated that 17 of 21 (81%) patients had a positive experience using the autoinjector; all patients considered the autoinjector to be convenient. Of the 42 patients who switched from intravenous belimumab to the autoinjector, 32 (76%) expressed a preference for the autoinjector over intravenous administration; reasons included convenience, time saved, cost, and reduced injection pain. The most commonly reported disadvantage of the autoinjector was injection discomfort (n = 5 [24%]; qualitative interview). Compared with intravenous administration, the autoinjector improved ability to work (17 of 29 [59%] of those employed) and carry out daily activities (40%). CONCLUSION: Patients with SLE reported high levels of satisfaction with the belimumab autoinjector and preferred the autoinjector to intravenous administration, citing advantages such as time saved, cost, and improved ability to work and carry out daily activities.

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.

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.