Clinic vs Home Spirometry for Monitoring Lung Function in Patients With Asthma.

BACKGROUND: Studies examining agreement between home and clinic spirometry in patients with asthma are limited, with conflicting results. Understanding the strengths and limitations of telehealth and home spirometry is particularly important considering the SARS-CoV-2 pandemic. RESEARCH QUESTION: How well do home and clinic measurements of trough FEV1 agree in patients with uncontrolled asthma? STUDY DESIGN AND METHODS: This post hoc analysis used trough FEV1 data from the randomized double-anonymized parallel-group phase 3A CAPTAIN (205715; NCT02924688) and phase 2B 205832 (NCT03012061) trials in patients with uncontrolled asthma. CAPTAIN evaluated the impact of adding umeclidinium to fluticasone furoate/vilanterol via a single inhaler; the 205832 trial investigated adding umeclidinium to fluticasone furoate vs placebo. Trough FEV1 measurements were collected via home spirometry and supervised in-person spirometry in the research clinic. To compare home and clinic spirometry, we examined the time-course analyses of home and clinic trough FEV1, and generated post hoc Bland-Altman plots to assess agreement between home and clinic spirometry. RESULTS: Data from 2,436 patients (CAPTAIN trial) and 421 patients (205832 trial) were analyzed. Treatment-related improvements in FEV1 were observed in both trials, using home and clinic spirometry. Improvements measured by home spirometry were of lower magnitude and less consistent than clinic measurements. Bland-Altman plots suggested poor agreement between home and clinic trough FEV1 at baseline and week 24. INTERPRETATION: This post hoc comparison of home and clinic spirometry is the largest conducted in asthma. Results showed that home spirometry was less consistent than and lacked agreement with clinic spirometry, suggesting that unsupervised home readings are not interchangeable with clinic measurements. However, these findings may only be applicable to home spirometry using the specific device and coaching methods employed in these studies. Postpandemic, further research to optimize home spirometry use is needed. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov; Nos.: NCT03012061 and NCT02924688; URL: www. CLINICALTRIALS: gov.

Suboptimally controlled asthma in patients treated with inhaled ICS/LABA: prevalence, risk factors, and outcomes.

This observational claims-linked survey study assessed the prevalence of and risk factors for suboptimal asthma control and healthcare utilization in adults with asthma receiving fixed-dose combination (FDC) inhaled corticosteroid/long-acting ß2-agonist (ICS/LABA). Commercially insured adults from the Optum Research Database were invited to complete the Asthma Control Test (ACT) and Asthma Control Questionnaire-6 (ACQ-6). Among participants (N = 428), 36.4% (ACT-assessed) and 55.6% (ACQ-6-assessed) had inadequately controlled asthma. Asthma-related quality of life was worse and asthma-related healthcare resource utilization was higher in poorly controlled asthma. Factors associated with ACT-defined suboptimal asthma control in multivariate analysis included: frequent short-acting ß2-agonist (SABA) use, asthma-related outpatient visits, lower treatment adherence, and lower education levels. During follow-up, factors associated with asthma exacerbations and/or high SABA use included: inadequately controlled asthma (ACT-assessed), body mass index ≥30 kg/m2, and high-dose ICS/LABA. Approximately 35-55% of adults with asthma were inadequately controlled despite FDC ICS/LABA; poor control was associated with worse disease outcomes.

Pharmacogenomic Profiling of Pediatric Patients on Psychotropic Medications in an Emergency Department.

OBJECTIVE: The aim of the study was to evaluate the ability of a combinatorial pharmacogenomic test to predict medication blood levels and relative clinical improvements in a selected pediatric population. METHODS: This study enrolled patients between ages 3 to 18 years who presented to a pediatric emergency department with acute psychiatric, behavioral, or mental health crisis and/or concerns, and had previously been prescribed psychotropic medications. Patients received combinatorial pharmacogenomic testing with medications categorized according to gene-drug interactions (GDIs); medications with a GDI were considered "incongruent," and medications without a GDI were considered "congruent." Blood levels for escitalopram, fluoxetine, aripiprazole, and clonidine were evaluated according to level of GDI. Relative clinical improvements in response to the prescribed psychotropic medications were measured using a parent-rated Clinical Global Impression of Improvement (CGI-I) assessment, where lower scores corresponded with greater improvement. RESULTS: Of the 100 patients enrolled, 73% reported taking ≥1 incongruent medication. There was no significant difference in CGI-I scores between patients prescribed congruent versus incongruent medications (3.37 vs 3.68, P = 0.343). Among patients who presented for depression or suicidal ideation, those prescribed congruent medications had significantly lower CGI-I scores compared with those taking incongruent medications ( P = 0.036 for depression, P = 0.018 for suicidal ideation). There was a significant association between medication GDI and blood levels for aripiprazole (n = 15, P = 0.01) and escitalopram (n = 10, P = 0.01). CONCLUSIONS: Our preliminary findings suggest that combinatorial pharmacogenomic testing can predict medication blood levels and relative outcomes based on medication congruency in children presenting to an emergency department with acute psychiatric/behavioral crises. Additional studies will be needed to confirm these findings.

Study to Explore the Association of the Renin-Angiotensin System and Right Ventricular Function in Mechanically Ventilated Patients.

BACKGROUND: Right ventricular (RV) dysfunction is associated with pulmonary vasoconstriction in mechanically ventilated patients. Enhancing the activity of angiotensin-converting enzyme 2 (ACE2), a key enzyme of the renin-angiotensin system (RAS), using recombinant human ACE2 (rhACE2) could alleviate RAS-mediated vasoconstriction and vascular remodeling. METHODS: This prospective observational study investigated the association between concentrations of RAS peptides (Ang II or Ang(1-7)) and markers of RV function, as assessed by echocardiography (ratio of RV to left ventricular end-diastolic area, interventricular septal motion, and pulmonary arterial systolic pressure (PASP)). RESULTS: Fifty-seven mechanically ventilated patients were enrolled. Incidence rates of acute cor pulmonale (ACP) and pulmonary circulatory dysfunction (PCD) were consistent with previous studies. In the 45 evaluable participants, no notable or consistent changes in RAS peptides concentration were observed over the observation period, and there was no correlation between Ang II concentration and either PASP or RV size. The model of the predicted posterior distributions for the pre- and post-dose values of Ang II demonstrated no change in the likelihood of PCD after hypothetical dosing with rhACE2, thus meeting the futility criteria. Similar results were observed with the other RAS peptides evaluated. CONCLUSIONS: Pre-defined success criteria for an association between PCD and the plasma RAS peptides were not met in the mechanically ventilated unselected patients.

Assessment of Pediatric Residents' Comfort Level With CellScope Oto to Examine Pediatric Ear Exams.

Examining a child's tympanic membrane (TM) is challenging, but crucial for proper management of acute otitis media (AOM). CellScope Oto (CSO) is an attachment that turns a smartphone into an otoscope. We aimed to assess pediatric resident comfort level with ear exams using CSO to see whether comfort level and accuracy of diagnosis of AOM improved. A pre-post study of pediatric residents in a freestanding Pediatric Emergency Department was conducted to assess their comfort level of traditional otoscope and CSO via a Likert scale. Ear exams were recorded and rated by 2 faculty for accuracy of AOM diagnosis. A total of 18 pediatric residents participated, and 308 exams were collected, with 2% diagnosed as AOM. The median change in comfort level increased by +1.0 for interns and third years but remained unchanged for second years. There was substantial agreement by faculty raters of video ear exams. Overall, comfort level increased with accuracy of diagnosis of AOM.

Blue light phones as potential locations for deploying public access naloxone kits on a college campus.

Objective Opioid use and the risk of opioid overdose are growing public health concerns for college-aged adults. Naloxone can temporarily reverse opioid overdoses, but only if easily accessible. On most college campuses, "blue light" phones (BLPs)-call boxes topped with a blue light-offer visible access to emergency services. We hypothesized that BLPs would provide potential naloxone access points. Participants: A major university campus in Los Angeles, CA. Methods: BLP locations were obtained using Google Maps, and the area of campus within a set distance to each BLP calculated. To model effects of loss or diversion, we simulated the random loss of various BLPs. Results: Placing naloxone kits at the 59 BLP locations could provide access within 100 m to 91.5% of the campus. With loss of half of the BLPs, campus access remained above 70%. Conclusions: Naloxone at BLP locations could be accessed from almost all campus areas.

Measuring respiratory symptoms in moderate/severe asthma: evaluation of a respiratory symptom tool, the E-RS®: COPD in asthma populations.

BACKGROUND: Symptom constructs included in the Evaluating Respiratory Symptoms in Chronic Obstructive Pulmonary Disease (E-RS®: COPD) tool may be relevant to patients with asthma. The purpose of this study was to evaluate content validity and psychometric performance of the E-RS: COPD in moderate/severe asthma patients. METHODS: Content validity of the E-RS: COPD was evaluated in patients with moderate/severe asthma using concept elicitation and cognitive debriefing interviews. Secondary analyses using data from two clinical trials in patients with moderate/severe asthma evaluated the factor structure of the E-RS: COPD plus two supplementary items (wheeze; shortness of breath with strenuous physical activity) and assessed psychometric properties of the tool, which will be referred to as E-RS®: Asthma when used in asthma populations. RESULTS: Qualitative interviews (N = 25) achieved concept saturation for asthma respiratory symptoms. Concepts in the E-RS: COPD were relevant to patients and instructions were understood. Most patients (19/25; 76%) reported experiencing all concepts in the E-RS: COPD; no patients indicated missing symptoms. Secondary analyses of clinical trial data supported the original factor structure (RS-Total and three symptom-specific subscales). The two supplemental items did not fit with this factor structure and were not retained. RS-Total and subscale score reliability was high (internal consistency [α] > 0.70). Validity was demonstrated through significant (P < 0.0001) relationships with the St George's Respiratory Questionnaire (SGRQ) and Asthma Symptom Severity scale. E-RS: Asthma was responsive to change when evaluated using SGRQ, Patient Global Impression of Change and Asthma Quality of Life Questionnaire as anchors (P < 0.0001). Clinically meaningful change thresholds were also identified (RS-Total: - 2.0 units). CONCLUSIONS: The E-RS: Asthma is reliable and responsive for evaluating respiratory symptoms in patients with moderate/severe asthma.

MatOrtho Proximal Interphalangeal Joint Arthroplasty via Lateral Approach: Minimum 2-Year Follow-Up.

Background: The MatOrtho implant is a cementless, mobile-bearing surface arthroplasty with a cobalt-chromium metal-on polyethylene articulation designed to treat osteoarthritis of the PIP joint. Early results for the prosthesis inserted through a dorsal approach have demonstrated good pain relief but no significant improvement in range of motion. In an attempt to improve the range of motion the senior author has changed his surgical practice to inserting the MatOrtho implant via a lateral approach. The purpose of this study is to assess the outcome of this change of surgical technique. Methods: Consecutive patients with osteoarthritis who underwent PIPJ replacement surgery via the lateral approach at a single institution, with a minimum follow-up period of 2 years were identified. A visual analogue score was used to assess pain. Grip strength, range of motion and functional outcomes scores were collected. Results: A total of 46 PIP joint arthroplasties were performed in 29 patients. Ten patients were lost to follow-up resulting in 33 PIP joint arthroplasties reviewed in 19 patients. Six implants failed. The mean follow-up time at the final follow-up for the remaining 25 prosthesis was 34.2 months (range 24-52). Range of motion improved from a mean of 37.2 preoperatively to a mean of 57.9 postoperatively. This was statistically significant (p = 0.0007). There was also a significant improvement in pain and functional outcome scores but not for grip strength. Conclusions: The MatOrtho PIPJ replacement delivers significant improvements in pain relief and functional outcome scores, as well as increased range of motion when the surgical procedure is performed through a lateral approach. There are, however, limitations to the use of this implant. Currently we do not consider this implant when there is instability or deformity of the PIP joint preoperatively.

Safety of Once-Daily Single-Inhaler Triple Therapy with Fluticasone Furoate/Umeclidinium/Vilanterol in Japanese Patients with Asthma: A Long-Term (52-Week) Phase III Open-Label Study.

PURPOSE: The pivotal CAPTAIN study reported a favorable safety profile with once-daily inhaled corticosteroid/long-acting muscarinic antagonist/long-acting ß2-agonist (ICS/LAMA/LABA) triple combination of fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) in patients with inadequately controlled asthma, some of whom were Japanese. Here, we evaluate the long-term (52 weeks) safety of FF/UMEC/VI in Japanese patients with asthma. PATIENTS AND METHODS: This was a Phase III, 52-week, multicenter, non-comparator, non-randomized, open-label study (NCT03184987) in Japanese adults receiving maintenance therapy with ICS/LABA, with or without LAMA. At enrollment, patients were allocated to either FF/UMEC/VI 100/62.5/25mcg (Group 1) or 200/62.5/25mcg (Group 2). Patients in Group 1 could have their treatment stepped up to 200/62.5/25mcg at Week 24 if their Asthma Control Questionnaire (ACQ)-7 score was >0.75. The primary endpoint was the incidence of adverse events (AEs) and serious AEs (SAEs). Secondary endpoints included vital signs, electrocardiogram measurements, and clinical laboratory tests (biochemistry, hematology, urinalysis). Efficacy was assessed as "other" endpoints. RESULTS: A total of 111 Japanese patients were included in the intention-to-treat (ITT) population. Overall, 77 (69%) patients reported ≥1 AE (Group 1: n=30 [64%]; step-up group: n=7 [78%]; Group 2: n=40 [73%]). SAEs were reported for 1 (2.1%) and 2 (3.6%) patients in Groups 1 and 2, respectively. All SAEs were considered unrelated to study treatment. One AE and one SAE led to study withdrawal: oropharyngeal discomfort (Group 1); eosinophilic granulomatosis with polyangiitis (Group 2). No new safety concerns were identified throughout the 52-week treatment period. CONCLUSION: In this uncontrolled open-label study, no new safety concerns were observed with long-term (52 weeks) treatment with once-daily FF/UMEC/VI among 111 Japanese patients with asthma.

Efficacy and safety of once-daily, single-inhaler fluticasone furoate/umeclidinium/vilanterol versus fluticasone furoate/vilanterol in Japanese patients with inadequately controlled asthma: the CAPTAIN study.

OBJECTIVE: In CAPTAIN, a double-blind, parallel-group, Phase IIIA study, fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) improved lung function, symptoms and asthma control versus FF/VI in patients with inadequately controlled asthma. Here, we report efficacy and safety from a Japanese cohort in CAPTAIN. METHODS: Adults with inadequately controlled asthma despite inhaled corticosteroid/long-acting ß2-agonist (ICS/LABA) were randomized (1:1:1:1:1:1) to once-daily FF/VI (100/25 mcg or 200/25 mcg) or FF/UMEC/VI (100/31.25/25 mcg, 100/62.5/25 mcg, 200/31.25/25 mcg, or 200/62.5/25 mcg) for ≥24 weeks. Endpoints included change from baseline in clinic trough FEV1 (primary), annualized rate of moderate/severe asthma exacerbations (key secondary), clinic FEV1 3 h post-dose, and Asthma Control Questionnaire (ACQ)-7, St George's Respiratory Questionnaire (SGRQ) (all Week 24), Evaluating Respiratory Symptoms (E-RS): Asthma total scores (Weeks 21-24) (all secondary). Adverse events and adverse events of special interest were monitored. Clinical trials.gov registry no: NCT02924688. RESULTS: Overall, 229 of 2436 patients in the intention-to-treat (ITT) population were from Japan. In this cohort, change from baseline in trough FEV1 for FF/UMEC/VI 100/62.5/25 mcg versus FF/VI 100/25 mcg was 105 mL (95% confidence interval -5, 216) and 69 mL (-42, 179) for 200/62.5/25 mcg versus 200/25 mcg. These observations were supported by clinic FEV1 at 3 h post-dose. Moderate/severe exacerbation incidence was low and similar across pooled treatment groups (FF/VI, FF/UMEC 31.25 mcg/VI, FF/UMEC 62.5 mcg/VI). All pooled groups demonstrated clinically important improvements from baseline in ACQ-7, SGRQ and E-RS: Asthma total scores. Safety profiles were consistent with the overall ITT population, with no new safety concerns. CONCLUSION: FF/UMEC/VI is an effective option with a favorable risk-benefit profile in Japanese patients with uncontrolled moderate or severe asthma on ICS/LABA.

Population Pharmacokinetic Modeling of Fluticasone Furoate, Umeclidinium Bromide, and Vilanterol in Patients with Asthma, Using Data from a Phase IIIA Study (CAPTAIN).

BACKGROUND: This analysis aimed to characterize the pharmacokinetics (PK) of the inhaled corticosteroid (ICS) fluticasone furoate (FF), the long-acting muscarinic antagonist umeclidinium (UMEC), and the long-acting ß2-agonist (LABA) vilanterol (VI), administered as dual (FF/VI) or triple (FF/UMEC/VI) single-inhaler therapy to patients with asthma, and to identify covariates that may influence the PK of each analyte. METHODS: Blood samples were obtained from the phase IIIA CAPTAIN study (ClinicalTrials.gov: NCT02924688), which evaluated the efficacy and safety of once-daily FF/UMEC/VI versus FF/VI in patients with uncontrolled asthma taking ICS/LABA. Samples were collected at trough (defined as ≥ 20 h after the last dose) from all subjects randomized to the six treatment groups (FF/UMEC/VI 100/31.25/25 µg, 100/62.5/25 µg, 200/31.25/25 µg, 200/62.5/25 µg; FF/VI 100/25 µg, 200/25 µg) at week 24 or the early withdrawal visit. In a subset of patients, PK samples were obtained predose at week 12, and at 5-30 min, 45-90 min, and 2-3 h postdose. For each analyte, a population PK model was developed using non-linear mixed-effects modeling. The maximum likelihood method was utilized to incorporate data below the quantifiable limit (BQL). Final models were used to derive the area under the plasma concentration-time curve and maximum observed concentration at steady-state for each analyte. RESULTS: We obtained 4018, 2695, and 4032 samples from 1891, 1258, and 1891 patients, for FF, UMEC, and VI, respectively; 48%, 49%, and 50% of samples were reported as BQL for each analyte, respectively. The PK were adequately described by a two-compartment model with first-order absorption and elimination for FF, a two-compartment model with intravenous bolus input and first-order elimination for UMEC, and a three-compartment model with zero-order input and first-order elimination for VI. Statistically significant covariates were body weight on apparent inhaled clearance of FF, creatinine clearance on apparent clearance and body weight on apparent inhaled volume of distribution of the central compartment for UMEC, and race (East Asian, Japanese, and South East Asian heritage) on inhaled apparent volume of distribution of the central compartment for VI. However, the overall effects of covariates were marginal and thus do not warrant dose adjustment. Systemic exposures of FF or VI did not differ when administered as a single-inhaler triple (FF/UMEC/VI) or dual combination (FF/VI), and were similar to those reported for patients with chronic obstructive pulmonary disease. CONCLUSION: Only marginal covariate effects were observed, and thus no dose adjustments are deemed necessary for FF, UMEC, or VI. There was no difference in FF or VI systemic exposure in patients with asthma when administered as either triple (FF/UMEC/VI) or dual therapy (FF/VI). Together with efficacy findings from the CAPTAIN study, our data support the use of single-inhaler FF/UMEC/VI triple therapy for patients with uncontrolled asthma currently receiving ICS/LABA.

Efficacy and safety of once-daily single-inhaler triple therapy (FF/UMEC/VI) versus FF/VI in patients with inadequately controlled asthma (CAPTAIN): a double-blind, randomised, phase 3A trial.

BACKGROUND: Despite inhaled corticosteroid plus long-acting ß2-agonist (ICS/LABA) therapy, 30-50% of patients with moderate or severe asthma remain inadequately controlled. We investigated the safety and efficacy of single-inhaler fluticasone furoate plus umeclidinium plus vilanterol (FF/UMEC/VI) compared with FF/VI. METHODS: In this double-blind, randomised, parallel-group, phase 3A study (Clinical Study in Asthma Patients Receiving Triple Therapy in a Single Inhaler [CAPTAIN]), participants were recruited from 416 hospitals and primary care centres across 15 countries. Participants were eligible if they were aged 18 years or older, with inadequately controlled asthma (Asthma Control Questionnaire [ACQ]-6 score of ≥1·5) despite ICS/LABA, a documented health-care contact or a documented temporary change in asthma therapy for treatment of acute asthma symptoms in the year before screening, pre-bronchodilator FEV1 between 30% and less than 85% of predicted normal value, and reversibility (defined as an increase in FEV1 of ≥12% and ≥200 mL in the 20-60 min after four inhalations of albuterol or salbutamol) at screening. Participants were randomly assigned (1:1:1:1:1:1), via central based randomisation stratified by pre-study ICS dose at study entry, to once-daily FF/VI (100/25 µg or 200/25 µg) or FF/UMEC/VI (100/31·25/25 µg, 100/62·5/25 µg, 200/31·25/25 µg, or 200/62·5/25 µg) administered via Ellipta dry powder inhaler (Glaxo Operations UK, Hertfordshire, UK). Patients, investigators, and the funder were masked to treatment allocation. Endpoints assessed in the intention-to-treat population were change from baseline in clinic trough FEV1 at week 24 (primary) and annualised moderate and/or severe asthma exacerbation rate (key secondary). Other secondary endpoints were change from baseline in clinic FEV1 at 3 h post-dose, St George's Respiratory Questionnaire (SGRQ) total score, and ACQ-7 total score, all at week 24. Change from baseline in Evaluating Respiratory Symptoms in Asthma total score at weeks 21-24 was also a secondary endpoint but is not reported here. Exploratory analyses of biomarkers of type 2 airway inflammation on treatment response were also done. This study is registered with ClinicalTrials.gov, NCT02924688, and is now complete. FINDINGS: Between Dec 16, 2016, and Aug 31, 2018, 5185 patients were screened and 2439 were recruited and randomly assigned to FF/VI (100/25 µg n=407; 200/25 µg n=406) or FF/UMEC/VI (100/31·25/25 µg n=405; 100/62·5/25 µg n=406; 200/31·25/25 µg n=404; 200/62·5/25 µg n=408), with three patients randomly assigned in error and not included in analyses. In the intention-to-treat population, 922 (38%) patients were men, the mean age was 53·2 years (SD 13·1) and body-mass index was 29·4 (6·6). Baseline demographics were generally similar across all treatment groups. The least squares mean improvement in FEV1 change from baseline for FF/UMEC/VI 100/62·5/25 µg versus FF/VI 100/25 µg was 110 mL (95% CI 66-153; p<0·0001) and for 200/62·5/25 µg versus 200/25 µg was 92 mL (49-135; p<0·0001). Adding UMEC 31·25 µg to FF/VI produced similar improvements (FF/UMEC/VI 100/31·25/25 µg vs FF/VI 100/25 µg: 96 mL [52-139; p<0·0001]; and 200/31·25/25 µg vs 200/25 µg: 82 mL [39-125; p=0·0002]). These results were supported by the analysis of clinic FEV1 at 3 h post-dose. Non-significant reductions in moderate and/or severe exacerbation rates were observed for FF/UMEC 62·5 µg/VI versus FF/VI (pooled analysis), with rates lower in FF 200 µg-containing versus FF 100 µg-containing treatment groups. All pooled treatment groups demonstrated mean improvements (decreases) in SGRQ total score at week 24 compared with baseline in excess of the minimal clinically important difference of 4 points; however, there were no differences between treatment groups. For mean change from baseline to week 24 in asthma control questionnaire-7 score, improvements (decreases) exceeding the minimal clinically important difference of 0·5 points were observed in all pooled treatment groups. Adding UMEC to FF/VI resulted in small, dose-related improvements compared with FF/VI (pooled analysis: FF/UMEC 31·25 µg/VI versus FF/VI, -0·06 (95% CI -0·12 to 0·01; p=0·094) FF/UMEC 62·5 µg/VI versus FF/VI, -0·09 (-0·16 to -0·02, p=0·0084). By contrast with adding UMEC, the effects of higher dose FF on clinic trough FEV1 and annualised moderate and/or severe exacerbation rate were increased in patients with higher baseline blood eosinophil count and exhaled nitric oxide. Occurrence of adverse events was similar across treatment groups (patients with at least one event ranged from 210 [52%] to 258 [63%]), with the most commonly reported adverse events being nasopharyngitis (51 [13%]-63 [15%]), headache (19 [5%]-36 [9%]), and upper respiratory tract infection (13 [3%]-24 [6%]). The incidence of serious adverse events was similar across all groups (range 18 [4%]-25 [6%)). Three deaths occurred, of which one was considered to be related to study drug (pulmonary embolism in a patient in the FF/UMEC/VI 100/31·25/25 µg group). INTERPRETATION: In patients with uncontrolled moderate or severe asthma on ICS/LABA, adding UMEC improved lung function but did not lead to a significant reduction in moderate and/or severe exacerbations. For such patients, single-inhaler FF/UMEC/VI is an effective treatment option with a favourable risk-benefit profile. Higher dose FF primarily reduced the rate of exacerbations, particularly in patients with raised biomarkers of type 2 airway inflammation. Further confirmatory studies into the differentiating effect of type 2 inflammatory biomarkers on treatment outcomes in asthma are required to build on these exploratory findings and further guide clinical practice. FUNDING: GSK.

The influence of pre-treatment on biomat development in soil treatment units.

Soil treatment units (STUs) receiving effluent from on-site wastewater treatment systems (OWTSs) rely on the gradual development of a microbial biomat/biozone at the infiltrative surface for optimal effluent distribution and pollutant attenuation. Here, we present the first direct measurement of gradual biomat development in the field in STU trenches receiving either primary (PE) or secondary treated effluent (SE) under identical environmental, hydrological and subsoil conditions. Two domestic OWTSs were constructed in Ireland and monitored over a period of >2 years using an automated, three-dimensional network of buried soil water content sensors tracking water flow and retention within the soil underneath the infiltrative surface. While trenches receiving PE expressed signs of biomat formation along the entire length of STU trenches, biomats in trenches receiving SE were significantly muted and did not extend further than 10 m from the inlet at the end of the study. The presence of a mature biomat helped to retain soil moisture above background levels and made the system more resilient towards drought events and desiccation stress but led, in one case, to effluent ponding within the trenches. A growth-limited non-linear model fit revealed that biomats in SE trenches are expected to remain considerably shorter and will not spread along the entire trench design length, even after 10 years of operation, which is contrary to prevalent design assumptions. Muted biomat growth, on the contrary, might lead to localized hydraulic and pollutant overloading and has been shown previously to negatively affect the ability to attenuate pollutants effectively within the soil profile before the effluent reaches the groundwater.

A phase IIb, randomised, parallel-group study: the efficacy, safety and tolerability of once-daily umeclidinium in patients with asthma receiving inhaled corticosteroids.

BACKGROUND: Patients with asthma uncontrolled on inhaled corticosteroids may benefit from umeclidinium (UMEC), a long-acting muscarinic antagonist. METHODS: This Phase IIb, double-blind study included patients with reversible, uncontrolled/partially-controlled asthma for ≥6 months, receiving ≥100 mcg/day fluticasone propionate (or equivalent) for ≥12 weeks. Following a 2-week run-in on open-label fluticasone furoate (FF) 100 mcg, patients were randomised (1:1:1) to receive UMEC 31.25 mcg, UMEC 62.5 mcg or placebo on top of FF 100 mcg once-daily for 24 weeks. As-needed salbutamol was provided. Primary and secondary endpoints were change from baseline in clinic trough forced expiratory volume in 1 s (FEV1) and clinic FEV1 3 h post-dose, respectively, at Week 24. Other endpoints included change from baseline in home daily spirometry (trough FEV1, evening FEV1, morning [pre-dose] and evening peak expiratory flow) over 24 weeks. Safety was assessed throughout the study. RESULTS: The intent-to-treat population comprised 421 patients (UMEC 31.25 mcg: n =139, UMEC 62.5 mcg: n =139, placebo: n =143). UMEC 31.25 mcg and 62.5 mcg demonstrated significantly greater improvements from baseline in clinic trough FEV1 at Week 24 (difference [95% CI]: 0.176 L [0.092, 0.260; p<0.001] and 0.184 L [0.101, 0.268; p<0.001], respectively), clinic FEV1 3 h post-dose at Week 24 (0.190 L [0.100, 0.279; p<0.001] and 0.198 L [0.109, 0.287; p<0.001], respectively) and mean change from baseline in daily home spirometry over 24 weeks versus placebo. No new safety signals were identified. CONCLUSIONS: UMEC is a highly effective bronchodilator that leads to improved lung function when administered as a single bronchodilator on top of FF in subjects with fully reversible, uncontrolled/partially-controlled moderate asthma. These data support a favourable benefit/risk profile for UMEC (31.25 mcg and 62.5 mcg). TRIAL REGISTRATION: GSK study ID: 205832; Clinicaltrials.gov ID: NCT03012061.

A nebulised antitumour necrosis factor receptor-1 domain antibody in patients at risk of postoperative lung injury: A randomised, placebo-controlled pilot study.

BACKGROUND: Tumour necrosis factor receptor 1 (TNFR1) signalling mediates the cell death and inflammatory effects of TNF-α. OBJECTIVE: The current clinical trial investigated the effects of a nebulised TNFR1 antagonist (GSK2862277) on signs of lung injury in patients undergoing oesophagectomy. DESIGN: Randomised double-blind (sponsor unblind), placebo-controlled, parallel group study. SETTING: Eight secondary care centres, the United Kingdom between April 2015 and June 2017. PATIENTS: Thirty-three patients undergoing elective transthoracic oesophagectomy. INTERVENTIONS: Patients randomly received a single nebulised dose (26 mg) of GSK2862277 (n = 17) or placebo (n = 16), given 1 to 5 h before surgery; 14 and 16, respectively competed the study. MAIN OUTCOME MEASUREMENTS: Physiological and biochemical markers of lung injury, pharmacokinetic and safety endpoints were measured. The primary endpoint was the change from baseline in pulmonary vascular permeability index (PVPI) at completion of surgery, measured using single-indicator transpulmonary thermodilution. Adjusted point estimates and 95% credible intervals (analogous to conventional confidence intervals) were constructed for each treatment using Bayesian statistical models. RESULTS: The mean change (with 95% credible intervals) from baseline in PVPI on completion of surgery was 0.00 (-0.23, 0.39) in the placebo and 0.00 (-0.24, 0.37) in the GSK2862277 treatment groups. There were no significant treatment-related differences in PaO2/FiO2 or Sequential Organ Failure Assessment score. Levels of free soluble TNFR1, Macrophage Inflammatory Protein-1 alpha and total protein were significantly reduced in the bronchoalveolar lavage fluid of patients treated with GSK2862277 (posterior probability of decrease with GSK2862277 vs. placebo:≥0.977; equivalent to P < 0.05). The frequency of adverse events and serious adverse events were distributed evenly across the two treatment arms. CONCLUSION: Pre-operative treatment with a single 26 mg inhaled dose of GSK2862277 did not result in significantly lower postoperative alveolar capillary leak or extra vascular lung water. Unexpectedly small increases in transpulmonary thermodilution-measured PVPI and extra vascular lung water index at completion of surgery suggest less postoperative lung injury than historically reported, which may have also compromised a clear assessment of efficacy in this trial. GSK2862277 was well tolerated, resulted in expected lung exposure and reduced biomarkers of lung permeability and inflammation. TRIAL REGISTRATION: clinicaltrials.gov: NCT02221037.

Open Versus Arthroscopic Repair of 1B Ulnar-Sided Triangular Fibrocartilage Complex Tears: A Systematic Review.

Background: Peripheral 1B tears of the triangular fibrocartilage complex (TFCC) can result in distal radioulnar joint (DRUJ) instability. In the context of associated DRUJ instability, combined evidence supports successful outcomes for peripheral tear repair. Methods: The aim of this systematic review (SR) was to compare the surgical treatment of 1B TFCC tears via arthroscopic versus open methods of repair. The primary outcome measure was restored DRUJ stability. The secondary outcome measures included patient-reported outcomes and clinical outcome measures. An electronic database search of Ovid Embase, PubMed, and the Cochrane Central Register of Controlled Trials was performed to cover a 20-year period. Two authors independently screened records for eligibility and extracted data. Results: Only 3 studies met the strict inclusion criteria, highlighting the poor evidence base for TFCC 1B repairs. Hence, a "secondary analysis" group was developed with modified inclusion criteria which included a further 7 studies for analysis. Pooled data from the primary and secondary analysis groups demonstrated that postoperative DRUJ stability was achieved following open repair in 84% (76/90) of cases and following arthroscopic repair in 86% (129/150) of cases. Conclusions: This SR demonstrates a current lack of high-quality evidence required to draw firm conclusions on the merits of arthroscopic versus open repair of 1B TFCC tears. There is no scientific evidence to suggest superiority of one technique over the other, albeit some surgeons and authors may express a strong personal view.

FEV1 recovery following methacholine challenge in asthma: Variability and comparison of methods.

BACKGROUND: Methacholine challenges have been used in clinical trials to assess therapeutic effects and potential adverse reactions of interventions on pulmonary function in a sensitive population, such as in subjects with asthma. Here, we evaluate the variability of the methacholine challenge recovery model, and compare the results obtained for both incremental and bolus challenge methods. METHODS: The extent, time course and variability of change in forced expiratory volume in 1 s (FEV1) following repeated methacholine challenges in subjects with mild asthma were investigated in an open-label, four-period, fixed-sequence, two-method, replicate crossover study. At Visits 1 and 2, subjects underwent an incremental challenge using doubling doses of methacholine until a ≥20% decrease in FEV1 was observed; at Visits 3 and 4, subjects underwent a bolus challenge, inhaling a single dose of methacholine calculated from the cumulative dose established during Visit 1. RESULTS: A total of 19 subjects were included in the study. Both the mean FEV1 area under the curve (FEV1 AUC0-tz) and mean maximum reductions in FEV1 (absolute and relative) 120 min post-challenge values were higher for the incremental challenges than the bolus challenges, with no reported difference between repetitions of the same methodology. FEV1 AUC0-tz decrease 120 min post challenge demonstrated an intra-subject coefficient of variation (CV) of 47.2% (incremental) and 78.3% (bolus), suggesting considerable between-visit variability. The mean absolute, and similarly relative, maximum reductions in FEV1 compared with post-diluent baseline values demonstrated lower intra-subject variability (incremental 21.16%, bolus 40.67%) than the FEV1 AUC0-tz-based endpoint. There was a trend towards faster recovery following the bolus challenge than with the incremental challenge. The provocative dose of methacholine inducing a ≥20% decrease in FEV1 resulted in a between-group mean difference of 27.20% in the incremental challenge periods, with a high intra-subject CV of 80.64%, demonstrating considerable variability. CONCLUSION: Maximum reduction in FEV1 had the lowest variability. There was little difference between repetitions of the same methodology, as indicated by overlapping confidence intervals. There was a trend towards faster recovery following bolus challenge than with the incremental challenge. The results of this trial could be of value when designing future clinical trials using the methacholine challenge methodology.

Sulfate fertilization supports growth of ryegrass in soil columns but changes microbial community structures and reduces abundances of nematodes and arbuscular mycorrhiza.

The increased use of sulfate fertilizers to compensate for soil sulphur (S) limitation in agricultural soils may affect soil microbes and micro-fauna involved in S mobilization. Here, columns with podzolic soil material and ryegrass (Lolium perenne) were fertilized with 0, 5, 10 and 20 kg ha-1 (S0/S5/S10/S20) inorganic sulfate-S alongside a full complement of other nutrients. In the S10 and S20 columns, significantly higher amounts of sulfate were present in soil solution. After two grass cuts (14 weeks in total), there was a significant decrease in arylsulfatase activity, bacterial-feeding nematode abundances and mycorrhizal colonization in the S10 and S20 columns compared to the S0. Bacterial, fungal and AM community structures shifted significantly across the treatments. After final harvest, the S10 and S20 columns had significantly higher grass dry matter yield and uptake of S, N, K, Ca and Mg compared to the S0. While the overall bacterial diversity was reduced in the S20 treatment, abundance (asfA) and diversity (ssuD and atsA) of bacterial genes involved in S cycling were not significantly affected by one-time sulfate fertilization. These results indicate that short-term sulfate fertilization benefits to plant growth outweighed the negative feedback from parts of the soil biota. To improve nutrient use efficiencies in a sustainable manner, future studies should consider alternative S fertilizers which may be beneficial to both, the soil biota and plants in the long-term.