Meaningful Improvement Research Articles

Differences in uni-dimensional breathlessness measures and thresholds for clinical response in a randomised controlled trial in people with chronic breathlessness: an exploratory study

IntroductionOptimally measuring improvements in chronic breathlessness in clinical practice and research continues to evolve. The aim of this study was to consider the performance of uni-dimensional measures in chronic breathlessness...

Laryngeal Vibrotactile Stimulation Is Feasible, Acceptable To People With Unexplained Chronic Cough.

Unexplained chronic cough (UCC) is common and has significant impacts on quality of life. Ongoing cough can sensitize the larynx, increasing the urge to cough and perpetuating the cycle of chronic cough. Vibrotactile stimulation (VTS) of the larynx is a noninvasive stimulation technique that can modulate laryngeal somatosensory and motor activity. Study objectives were to assess feasibility and acceptability of VTS use by people with UCC. Secondarily, changes in cough-related quality of life measures were assessed. Adults with UCC recorded cough measures at baseline and after completing 2 weeks of daily VTS. Feasibility and acceptability were assessed through participant-reported device use and structured feedback. Cough-related quality of life measures were the Leicester Cough Questionnaire (LCQ) and the Newcastle Laryngeal Hypersensitivity Questionnaire (NLHQ). Nineteen adults participated, with mean age 67 years and cough duration 130 months. Notably, 93% of planned VTS sessions were logged, 94% of participants found the device comfortable to wear, 89% found it easy to operate and 79% would recommend it to others. Pre-post LCQ change achieved a minimal important difference (MID) (mean 1.3 [SD 2.4, p = 0.015]). NLHQ scores improved, but did not reach an MID. Laryngeal VTS use was feasible and acceptable for use by patients with UCC and was associated with a meaningful improvement in cough-related quality of life. Future studies will include VTS dose refinement and the inclusion of a comparison arm to further assess the potential for laryngeal VTS as a novel treatment modality for UCC. 4 Laryngoscope, 134:5010-5014, 2024.

Incorporating changes in land surface temperature improves BESS evapotranspiration estimates under water-deficit conditions: A case study for US Midwest and Great Plains grasslands

Evapotranspiration (ET) is a critical climate and ecosystem variable that interconnects water, energy, and carbon cycles. Breathing Earth System Simulator (BESS) is one of the state-of-the-art biophysical models capable of producing spatio-temporal continuous ET results. However, we found that since the BESS model does not use an explicit constraint on soil moisture (SM), it has a relatively lower performance under drier conditions. Given that changes in land surface temperature (LST) are closely associated with surface water status and sensible heat energy, we hypothesize that integrating LST changes could explicitly add the soil moisture constraints and thus enhance BESS’s ability to estimate ET. Here we used the morning rise rate of LST (Trate) as a proxy of LST change because of the low noise level in Trate as well as Trate’s close relationship with daily mean sensible heat. To test the hypothesis, this study first assessed whether the performance of BESS ET can be explained by the LST change, targeting grassland sites of the AmeriFlux network in the US Midwest and Great Plains. Specifically, the ET deviation (i.e., the difference between BESS-modeled ET and field-measured ET) and Trate deviation, as well as their relationships, were investigated under different conditions of precipitation, SM, and vapor pressure deficit (VPD) at the AmeriFlux sites. Results indicated that BESS ET exhibited consistently higher performance under well-watered conditions than water-deficit conditions. Also, the deviations of ET and Trate became more negatively correlated under water-deficit conditions. Leveraging the empirical relationship between ET and Trate deviations, this study developed a new way to calibrate BESS ET based on Trate calculated from LST diurnal observations, particularly under soil or atmospheric water-deficit conditions. After calibrating BESS ET, the statistical indicators between the calibrated ET and the ground measurements showed meaningful improvements relative to those before calibration. Specifically, in the Midwest (Great Plains), R2 increased from 0.42 to 0.51 (from 0.45 to 0.46), and RMSE and absolute bias decreased by 12% and 42% (11% and 45%), respectively. This study highlights that the morning rise rate of LST can effectively constrain the ET models that have no SM constraints under water-deficit conditions.

Interventions for the management of long covid (post-covid condition): living systematic review

ObjectiveTo compare the effectiveness of interventions for the management of long covid (post-covid condition).DesignLiving systematic review.Data sourcesMedline, Embase, CINAHL, PsycInfo, Allied and Complementary Medicine Database, and Cochrane Central Register of...

Randomized Controlled Trial of a Virtually Delivered Exercise and Stress Management Program to Improve Physical Performance of Hematopoietic Cell Transplant Survivors.

Because of advances in hematopoietic cell transplant (HCT), meeting the long-term health needs of increasing numbers of HCT survivors remains challenging. This multicenter trial aimed to assess the short- and long-term effects of an exercise and mindfulness intervention delivered by telehealth. One hundred thirty-nine participants >6 months post-HCT were randomly assigned 1:1 to a 6-week personalized exercise and mindfulness training with three motivation sessions at 3-6 months via an online meeting platform or usual care. Physical and quality-of-life (QOL) assessments were conducted online for 12 months. The primary end point was the 6-minute walk test (6-MWT) at 3 months. The median time post-HCT was 21 months (range, 7-67 months). Improvement in mean difference of 6-MWT was found in the intervention group compared with control (intention-to-treat) at 3 months (51.4 m [95% CI, 27.3 to 75.5]; P < .001; effect size [ES], 0.52) and was maintained at 12 months (59.3 m, P = .003; ES, 0.60). Sustained improvements in mean difference for sit-to-stand (STS) at 3 and 12 months were seen. There were no significant changes in hand grip strength or QOL outcomes between groups. A significant difference in serum soluble intercellular adhesion molecule-1 (sICAM-1) concentration was observed between the intervention and control groups in the exploratory study. No intervention adverse events were found. The supervised multimodal telehealth intervention provided clinically meaningful and durable improvement of physical capacity in HCT survivors. This home-based program has the potential to provide an unmet need for HCT survivors. Similar programs may benefit survivors of other cancers, organ transplants, and chronic disorders.

The reliability of basketball shooting tests with binary outcomes.

This paper addresses distinct questions related to the reliability of basketball shooting tests: (i) how to appropriately model data from tests with binary outcomes, (ii) how many shots are needed for the tests to be reliable, and (iii) can additional information from shot trajectories (shot hit location and entry angle) improve the reliability of the shooting tests? We designed a Bayesian statistical model that takes into account the binary nature of the outcomes and can be used to model test data for multiple individuals simultaneously. We demonstrated the utility of our approach with a simulation study and on a real-world example with 27 basketball players and 7309 shots across 4 different shooting tests. Results showed the practical importance of modelling data as binary and the relatively large sample sizes required for the tests to be reliable. We also showed that additional information from shot trajectories provides valuable insights into an individual's shooting, but we were unable to achieve a meaningful improvement in the estimation of shooting ability.

Long-term visual outcomes and histopathologic findings after cataract surgery in Ebola virus disease survivors in the Ebola virus RNA persistence in ocular tissues and fluids (EVICT) study.

Ebola virus disease (EVD) survivors develop post-acute ophthalmic sequelae, including a high prevalence of uveitis that may be complicated by vision-threatening cataract. After the non-detection of Ebola virus (EBOV) RNA in sampled ocular fluid, vision impairment due to cataract can be treated safely and effectively via manual small incision cataract surgery (MSICS). However, the long-term ocular visual outcomes and assessment of ocular tissues, including for genomic RNA, have been infrequently or not reported in Western African survivors. A cohort of EVD survivors with visually significant cataract, in whom EBOV RNA was not detected by RT-PCR testing of ocular fluid sampled prior to MSICS, were followed for a year after intraocular lens replacement. Ophthalmic outcomes, including visual acuity (VA), adverse events, and follow-up examinations, were recorded. Ocular tissue specimens obtained at MSICS underwent histopathologic examination and in-situ hybridization (ISH) targeting EBOV genomic RNA. Thirty-four EVD survivors underwent MSICS and were included for analysis. The median age of EVD survivors who underwent surgery at enrollment was 22.5 years (Interquartile range, IQR: 16.5-33) and the cohort was comprised of 20 females (58.8%). Median logMAR VA at preoperative baseline was 3 (IQR: 1-3) which improved to 0.4 (IQR: 0-0.6; n = 10; p = 0.002) and 0.6 (IQR: 0.18-0.78; n = 18; p < 0.0001) at 6- and 12-months following surgery, respectively. EBOV RNA was not detected in 7 cataract and capsular tissue specimens obtained at the time of MSICS. After MSICS, meaningful improvement in vision was maintained in EVD survivors at long-term follow-up. EBOV RNA was not detected in cataract and lens capsule specimens, providing additional reassurance of the low risk of EBOV RNA exposure during cataract surgery. Further study is needed to understand long-term ocular outcomes, including adverse events, in this population. Ebola virus disease (EVD) survivors may develop several ophthalmic sequelae including uveitis and cataract that may lead to severe vision loss if left untreated. Manual small incision cataract surgery (MSICS) has been utilized to treat cataract in EVD survivors with encouraging short-term outcomes, but the long-term visual acuity outcomes and the potential for Ebola virus RNA to reside in cataract material is unknown. In this study, we reported long-term visual acuity outcomes following MSICS in a cohort of EVD survivors along with histopathology findings from materials collected during surgery. Visual acuity improved over 12-month follow-up with encouraging safety measures. Ebola virus RNA was not detected in cataract and lens capsular tissue analyzed from EVD survivors. This study provides additional assurance regarding the safety and efficacy of cataract surgery, with potential for improved vision for EVD survivors.

Improved Prediction of Ligand-Protein Binding Affinities by Meta-modeling.

The accurate screening of candidate drug ligands against target proteins through computational approaches is of prime interest to drug development efforts. Such virtual screening depends in part on methods to predict the binding affinity between ligands and proteins. Many computational models for binding affinity prediction have been developed, but with varying results across targets. Given that ensembling or meta-modeling approaches have shown great promise in reducing model-specific biases, we develop a framework to integrate published force-field-based empirical docking and sequence-based deep learning models. In building this framework, we evaluate many combinations of individual base models, training databases, and several meta-modeling approaches. We show that many of our meta-models significantly improve affinity predictions over base models. Our best meta-models achieve comparable performance to state-of-the-art deep learning tools exclusively based on 3D structures while allowing for improved database scalability and flexibility through the explicit inclusion of features such as physicochemical properties or molecular descriptors. We further demonstrate improved generalization capability by our models using a large-scale benchmark of affinity prediction as well as a virtual screening application benchmark. Overall, we demonstrate that diverse modeling approaches can be ensembled together to gain meaningful improvement in binding affinity prediction.

Efficacy and Safety of Sodium Oxybate in Isolated Focal Laryngeal Dystonia: A Phase IIb Double-Blind Placebo-Controlled Cross-Over Randomized Clinical Trial.

To examine the efficacy and safety of sodium oxybate versus placebo in a phase IIb randomized double-blind placebo-controlled 2-period cross-over clinical trial in patients with isolated laryngeal dystonia (LD). The study was conducted from January 2018 to December 2021, pausing during the COVID-19pandemic, at Massachusetts Eye and Ear in 106 patients with alcohol-responsive (EtOH+) and alcohol-non-responsive (EtOH-) LD (53 to receive 1.5g of sodium oxybate first, 53 to receive matching placebo first). The primary outcome was a change from baseline in LD symptom severity 40 minutes after drug intake. Safety was based on vital signs, cognitive function, suicidality, daytime sleepiness, and adverse events. Patients, investigators, and outcome assessors were masked to study procedures. Compared to baseline, EtOH+ but not EtOH- patients had a statistically significant improvement in LD symptoms following sodium oxybate versus placebo (EtOH+: 98.75% confidence interval [CI] = 0.6-26.9; p = 0.008; EtOH-: 98.75% CI = -6.2 to 18.7; p = 0.42). Statistically significant minimum drug efficacy in EtOH+ patients was found at ≥16% symptom improvement (OR = 2.09; 98.75% CI = 0.75-5.80; p = 0.036), with an average of 40.81% benefits (98.75% CI = 34.7-48.6). Drug efficacy waned by 300 minutes after intake without a rebound. No changes were found in cognitive function, suicidality, or vital signs. Common adverse events included mild dizziness, nausea, and daytime sleepiness. Sodium oxybate showed clinically meaningful improvement of symptoms in EtOH+ LD patients, with acceptable tolerability. Sodium oxybate offers the first pathophysiologically relevant oral treatment for laryngeal dystonia. ANN NEUROL 2024.

Effects of Tirzepatide on the Clinical Trajectory of Patients with Heart Failure, a Preserved Ejection Fraction, and Obesity.

Patients with heart failure, a preserved ejection fraction (HFpEF), and obesity have significant disability and suffer frequent exacerbations of heart failure. We hypothesized that tirzepatide, a long-acting agonist of glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors, would improve a comprehensive suite of clinical endpoints, including measures of health status, functional capacity, quality of life, exercise tolerance, patient well-being, and medication burden in these patients. 731 patients in class II-IV heart failure, ejection fraction ≥50%, and body mass index ≥30 kg/m2 were randomized(double-blind) to tirzepatide(titrated up to 15mg subcutaneously weekly)(n=364) or placebo(n=367), added to background therapy for a median of 104 weeks (Q1=66, Q3=126 weeks). tirzepatide reduced the combined risk of cardiovascular death or worsening heart failure and improved Kansas City Cardiomyopathy Questionnaire Clinical Summary Score(KCCQ-CSS). The current expanded analysis included sensitivity analyses of the primary endpoints, 6-minute walk distance(6MWD), EQ-5D-5L health state index, Patient Global Impression of Severity Overall Health(PGIS), NYHA class, use of heart failure medications, and a hierarchical composite based on all-cause death, worsening heart failure, and 52-week changes in KCCQ-CSS and 6MWD. Patients were aged 65.2±10.7, 53.8%(n=393) were female; BMI 38.2±6.7kg/m2, KCCQ-CSS 53.5±18.5, 6MWD 302.8±81.7meters, and 53%(n=388) had a worsening heart failure event in the prior 12 months. Compared with placebo, tirzepatide produced a consistent beneficial effect across all composites of death and worsening heart failure events, analyzed as time-to-first-event (hazard ratios 0.41-0.67). At 52 weeks, tirzepatide increased KCCQ-CSS 6.9 points (95%CI, 3.3, 10.6, P<0.001), 6MWD 18.3 meters (95%CI, 9.9, 26.7, P<0.001) and EQ-5D-5L 0.06 (95%CI, 0.03, 0.09, P<0.001). The tirzepatide group shifted to a more favorable PGIS (proportional odds ratio 1.99 (95%CI, 1.44, 2.76) and NYHA class (proportional odds ratio 2.26 (95%CI, 1.54, 3.31), both P<0.001 and required less heart failure medications (P=0.015). The broad spectrum of effects was reflected in benefits on the hierarchical composite (win ratio 1.63, 95%CI, 1.17, 2.28;P=0.004). Tirzepatide produced a comprehensive, meaningful improvement in heart failure across multiple complementary domains; enhanced health status, quality of life, functional capacity, exercise tolerance and well-being; and reduced symptoms and medication burden in patients with HFpEF and obesity.

Bimekizumab impact on patient-reported outcomes in patients with moderate to severe hidradenitis suppurativa: Pooled Week 48 results from BE HEARD I&amp;II

Introduction: Hidradenitis suppurativa (HS) has substantial negative effects on patients’ lives,1 with debilitating symptoms, such as intense pain/fatigue/draining and odor, which lead to overall low quality of life (QoL).1,2 Bimekizumab (BKZ) is a humanized IgG1 monoclonal antibody that selectively inhibits interleukin (IL)-17F in addition to IL-17A; clinical efficacy was previously shown in the phase 3 BE HEARD I&amp;II trials.3 Here, the impact of BKZ on patient-reported outcomes (PROs) in patients with moderate to severe HS in BE HEARD I&amp;II is reported. Procedure/Study: Pooled data included an initial (Weeks [Wks]0–16) and maintenance (Wks16–48) treatment period. Patients were randomized 2:2:2:1 (initial/maintenance) to BKZ 320 mg every 2 wks (Q2W)/Q2W, BKZ Q2W/ Q4W, BKZ Q4W/Q4W or placebo (PBO)/BKZ Q2W. HS Symptom Questionnaire (HSSQ; each symptom item scored 0–10) mean values are reported to Wk48 for skin pain, itch, smell/odor, and drainage/oozing. Proportions of patients achieving minimal clinically important difference (MCID) for Dermatology Life Quality Index (DLQI; scored 0–30; improvement from baseline score ≥4) were reported at Wk16 and Wk48. Data are reported as observed case. Results: Overall, 1,014 patients were randomized to BKZ Q2W/Q2W (N=288), BKZ Q2W/Q4W (N=292), BKZ Q4W/Q4W (N=288), PBO/BKZ Q2W (N=146). Within each HSSQ item, similar baseline scores were observed across treatment groups. At Wk16, for skin pain, itch, smell/odor and draining/oozing, greater improvements (i.e. score reduction) from baseline were seen in BKZ- vs PBO-treated patients. HSSQ item scores were substantially reduced from Wk16 to Wk48 in Wk16 PBO/BKZ switchers, further decreases were observed in those continually treated with BKZ. At Wk16, a greater proportion of BKZ- vs PBO-treated patients achieved MCID in DLQI: BKZ Q2W/Q2W, 64.6%; BKZ Q2W/Q4W, 54.9%; BKZ Q4W/Q4W, 63.5% vs PBO, 49.1%. At Wk48, a greater proportion of patients continually treated with BKZ achieved MCID in DLQI vs at Wk16; Wk16 PBO/BKZ switchers attained similar proportions (BKZ Q2W/Q2W: 73.4%; BKZ Q2W/Q4W: 63.5%; BKZ Q4W/Q4W: 74.5%; PBO/BKZ Q2W: 76.5%). Conclusion: At Wk16, BKZ-treated patients achieved a reduction from baseline of HS symptoms: skin pain, itch, smell/odor, and drainage/oozing. Clinically meaningful health-related QoL improvements from baseline were observed and maintained/slightly improved through Wk48. PBO/BKZ switchers experienced improvements in PRO responses from Wk16 to Wk48 and achieved comparable outcomes at Wk48 to patients continually treated with BKZ.

Bimekizumab Efficacy and Safety Through 2 years in Patients with Hidradenitis Suppurativa: Results from the Phase 3 BE HEARD I&amp;II trials and Open-Label Extension BE HEARD EXT

Introduction: Interleukin (IL)-17F and IL-17A play a role in the immunopathogenesis of hidradenitis suppurativa (HS).1–3 Bimekizumab (BKZ) is a humanized IgG1 monoclonal antibody that selectively inhibits IL-17F in addition to IL-17A leading to clinically meaningful improvements in patients (pts) with HS.4,5 Here, BKZ efficacy and safety data (OC) are presented over 2 years (96 weeks [wks]) for the pooled BE HEARD I&amp;II (BHI&amp;II) trials and BE HEARD EXT (BHEXT).5,6 Procedure/Study: In BHI&amp;II, pts with moderate to severe HS were randomized 2:2:2:1 (16wk-initial/32wk-maintenance) to BKZ 320mg every 2 wks (Q2W)/Q2W, BKZQ2W/Q4W, BKZQ4W/Q4W or placebo/BKZQ2W.5 Wk48 completers could enroll in BHEXT and receive open-label BKZQ2W or BKZQ4W based on ≥90% HS Clinical Response (HiSCR90; averaged from Wks36/40/44). We report HiSCR50/75/90/100 rates, percentage change from baseline (%CfB, mean±SD) in International HS Severity Score System (IHS4) and draining tunnel (DT) count, and Dermatology Life Quality Index (DLQI) 0/1 achievement at Wks48/96 for patients randomized to BKZ in BHI&amp;II and entered BHEXT (BKZ Total, observed case). Safety outcomes reported for pts who received ≥1 BKZ dose across BHI&amp;II/BHEXT. Results: 556 pts randomized at baseline to BKZ in BHI&amp;II completed Wk48 and entered BHEXT; 446 pts completed Wk96. At Wk48, HiSCR50/75/90/100 was achieved by 79.9/64.0/42.3/30.2% of pts; responses improved to Wk96: 85.4/77.1/57.6/44.2%. Baseline IHS4 was 35.6±31.5; %CfB at Wk48/96 was –70.3±39.6/−79.8±28.1%. Baseline DTs were 3.8±4.3; the %CfB at Wk48/96 was −57.5±72.9%/−73.7±45.7%. Baseline DLQI was 11.0±6.8; 27.4% (151/551) of pts achieved DLQI 0/1 at Wk48 and 33.9% (149/439) at Wk96. Over 2 years, 917/995 (248.9/100 pt years [PY]) pts experienced a treatment-emergent adverse event (TEAE). Serious TEAEs were reported in 122 (7.2/100 PY) pts; 109 (6.3/100 PY) pts discontinued due to a TEAE. Serious infections occurred in 33 (1.9/100 PY) pts. Safety data were comparable with BHI&amp;II.5 Conclusion: In pts treated with BKZ, clinically meaningful improvements in efficacy outcomes observed at 1 year, including the HiSCR 75/90/100, IHS4, and DT count endpoints, were maintained to 2 years; improvements in quality of life were maintained. No new safety signals were observed; the safety profile over 2 years was consistent with BHI&amp;II and BKZ studies in other indications.5,7–9

Switching from Dupilumab to Upadacitinib in Adults and Adolescents with Moderate-to-Severe Atopic Dermatitis and Inadequate Response to Dupilumab: Efficacy and Safety Results from the Phase 3b/4 LEVEL UP Study

Atopic dermatitis (AD) is a chronic skin disease characterized by intense itch and eczematous skin lesions. Upadacitinib (UPA), a selective oral Janus kinase (JAK) inhibitor, and dupilumab (DUPI), a monoclonal antibody targeting interleukin-4 and interleukin-13 signaling, are both approved treatments for moderate-to-severe AD. LEVEL UP is a phase 3b/4 efficacy assessor blinded monotherapy study comparing UPA to DUPI for treatment of moderate-to-severe AD in adults and adolescents over a 16-week period (Period 1). Patients not achieving ≥75% improvement in the Eczema Area and Severity Index (EASI 75) from baseline at Week 16 entered an additional 16-week extension phase (Period 2). In Period 2, patients either continued/escalated to UPA 30 mg (UPA/UPA 30) or switched from DUPI to UPA 15 mg (DUPI/UPA), with the potential to escalate to 30 mg based on clinical response. Efficacy for skin and itch outcomes in Period 2 were assessed using observed case analysis while on treatment, without statistical comparisons. Here we report efficacy and safety results for the DUPI/UPA switch group. A total of 355 patients who did not achieve EASI 75 at Week 16 entered Period 2 of the study (DUPI/UPA, N=208). At Week 32, response rates in the DUPI/UPA group were: 79.6%, 58.7%, and 19.9% achieving EASI 75, EASI 90, and EASI 100, respectively; 60.2% achieving WP-NRS improvement ≥4 among those with baseline WP-NRS ≥4; 37.0% achieving WP-NRS 0/1 among those with baseline WP-NRS &gt;1; and 26.8% simultaneously achieving EASI 90 and WP-NRS 0/1 by Week 32. Clinically meaningful outcomes were also observed at an earlier visit (Week 20). No new safety signals through Week 32 were identified compared to the established safety profile of UPA. Most patients with an inadequate response to DUPI at Week 16 experienced clinically meaningful improvements in skin clearance and itch at 4 weeks post-switch to UPA, with additional patients achieving these outcomes by 16 weeks post-switch. These findings suggest that switching from DUPI to UPA is an effective treatment strategy for patients who do not meet moderate or optimal treatment targets with DUPI.

Real-World Effectiveness of Upadacitinib in Moderate‑to‑Severe Atopic Dermatitis (AD): Results From Longitudinal Analyses of the CorEvitas AD Registry

Introduction: Clinical trials demonstrated that upadacitinib is efficacious in treating atopic dermatitis (AD). Its real-world effectiveness is less understood. In this study, we investigated the longitudinal real-world outcomes of upadacitinib-treated adults in the CorEvitas AD Registry. Methods: The CorEvitas AD Registry is a prospective, non-interventional registry of adults diagnosed with AD in the United States and Canada. We evaluated participants enrolled through April 30, 2024 with data available prior to upadacitinib exposure (baseline) and at the six-month follow-up visit, and were receiving upadacitinib at the follow-up visit. Outcomes evaluated include the achievement of: Validated Investigators Global Assessment Scale for Atopic Dermatitis (vIGA-ADTM) of “clear” or “almost clear” among participants rated “mild” or worse at baseline (vIGA-AD 0/1); Eczema Area and Severity Index improvement of ≥75%/≥90%/100% from baseline (EASI 75/90/100); Peak Pruritus Numeric Rating Scale (PP-NRS) improvement ≥4 among participants with a score ≥4 at baseline (∆PP-NRS≥4); PP-NRS score of 0 or 1 among participants with a score &gt;1 at baseline (PP-NRS 0/1); Dermatology Life Quality Index (DLQI) score improvement ≥4 among participants with a score ≥4 at baseline (∆DLQI≥4); and DLQI score of 0 or 1 among participants with a score &gt;1 at baseline (DLQI 0/1). Simultaneous achievement of both EASI 90 &amp; PP-NRS 0/1 was also assessed. Data were analyzed as observed with no imputation. Safety events were not assessed in this analysis. Results: The longitudinal analysis included 192 participants (mean age 46.2 years; 57.8% female; 69.8% White; 43.8% prior exposure to dupilumab or tralokinumab; 64.4% receiving 15 mg dose at follow-up visit; mean upadacitinib treatment duration of 6.0 months). More than half achieved clear/almost clear skin (66.1% vIGA-AD 0/1), EASI 75 (69.3%), and EASI 90 (59.2%); 45.3% achieved complete skin clearance (EASI 100). More than 40% reported little-to-no itch (44.4% PP-NRS 0/1) and no impact of AD on quality of life (43.3% DLQI 0/1), and more than half reported meaningful improvements in itch (58.6% ∆PP-NRS≥4) and quality of life (76.0% ∆DLQI≥4). Simultaneous attainment of both EASI 90 &amp; PP-NRS 0/1 was achieved in 46.6% of participants at 6 months. Conclusions: In the real-world setting, the majority of adults treated and remained on upadacitinib achieved clinically meaningful outcomes in skin lesions, itch, and quality of life, with many achieving complete skin clearance, little-to-no itch, and experiencing no impact of AD on their quality of life. These findings underscore upadacitinib's potential to offer multidimensional relief to patients with AD in everyday clinical practice.

Estimating Meaningful Differences in Measures of Neuropathic Impairment, Health‐Related Quality of Life, and Nutritional Status in Patients With Hereditary Transthyretin Amyloidosis

ABSTRACTIntroduction/AimsThe degree of change in neuropathic impairment and quality of life (QoL) that is clinically meaningful to patients with hereditary transthyretin amyloidosis with polyneuropathy (ATTRv‐PN) is not established. This study aimed to estimate the magnitude of treatment differences that are meaningful to patients in measures of neuropathy and QoL and to determine whether eplontersen achieved a meaningful improvement versus placebo.MethodsData from the NEURO‐TTRansform trial on patients with ATTRv‐PN treated with eplontersen (n = 141) or historical placebo (n = 59) were used. Anchor‐based approaches were used to estimate thresholds for meaningful differences in the modified Neuropathy Impairment Score +7 (mNIS+7) composite score, Norfolk QoL‐Diabetic Neuropathy (Norfolk QoL‐DN) total score, Neuropathy Symptoms and Change (NSC) total score, and modified body mass index (mBMI). Differences between the least squares means of the treatment groups were analyzed.ResultsMeaningful improvement in mNIS+7 was estimated as −4.0 points and deterioration as 1.8 points. The estimated ranges of meaningful improvement and deterioration in Norfolk QoL‐DN were −12.8 to −4.0 points, and 5.9 to 14.7 points, respectively. For NSC, ranges were −2.4 to −1.3 points for meaningful improvement, and 0.6 to 5.8 points for deterioration. The estimated meaningful improvement in mBMI was 9.8 kg/m2 × g/L and deterioration was −40.9 kg/m2 × g/L. Improvements in each measure with eplontersen versus placebo were greater than the estimates of meaningful differences.DiscussionEplontersen demonstrated a clinically meaningful effect on neuropathic impairment, QoL, and nutritional status. Such estimates have implications for clinical practice and trials.

Efficacy and safety of intranasal medications for allergic rhinitis: Network meta-analysis.

Intranasal antihistamines (INAH), corticosteroids (INCS), and their fixed combinations (INAH+INCS) are one of the cornerstones of the treatment of allergic rhinitis (AR). We performed a systematic review and network-meta-analysis comparing the efficacy and safety of INAH, INCS, and INAH+INCS in patients with AR. We searched four electronic bibliographic databases and three clinical trial databases for randomised controlled trials assessing the use of INAH, INCS, and INAH+INCS in adults with seasonal or perennial AR. We performed a network meta-analysis on the Total Nasal Symptom Score, Total Ocular Symptom Score, Rhinoconjunctivitis Quality-of-Life Questionnaire, development of adverse events, and withdrawals due to adverse events. Certainty of evidence was assessed using GRADE-NMA. We included 167 primary studies, most of which assessed patients with seasonal AR. Among individual medications, azelastine-fluticasone, and fluticasone furoate were the most frequently highest-ranked interventions for efficacy outcomes, being regularly associated with clinically meaningful larger improvements when compared to other active treatments. Considering drug classes, INAH+INCS were the highest-ranked interventions for all outcomes in which they were assessed, followed in most cases by INCS. In 105 out of 184 comparisons in seasonal AR, and 28 out of 97 comparisons in perennial AR, certainty of evidence was considered "high" or "moderate". Intranasal medications for AR display clinically relevant differences in their efficacy, but all show a good safety profile. To our knowledge, this is the first network meta-analysis comparing INAH, INCS, and INAH+INCS in AR, providing relevant evidence for guideline developers and practising physicians on the most efficacious treatments.

Initiating continuous glucose monitoring is associated with improvements in glycemic control and reduced health care resource utilization for people with diabetes in a large US-insured population: A real-world evidence study.

To examine the real-world impact of continuous glucose monitoring (CGM) use on glycemic management and health care resource utilization (HCRU) in people with diabetes in a large US-insured population. This retrospective observational study used Aetna administrative claims data from a cohort of fully insured commercial and Medicare Advantage beneficiaries with diabetes and with coverage for medical and pharmacy benefits. The index date was the first CGM pharmacy or medical claim observed between January 1, 2019, and December 31, 2021. Change in hemoglobin A1c was calculated using values from 3 months before and the latest values 10-12 months after the index date. HCRU was measured 12 months before and after the index date. Data were analyzed by the following patient groups: type 1 diabetes, type 2 diabetes (T2D) on intensive insulin therapy, T2D on basal-only insulin therapy, and T2D not on insulin therapy. Data from 7,336 patients (74% T2D, mean age 57 years, 42% Medicare-insured, 54% male, 56% White) were analyzed. Beneficiaries with available A1c data (n = 1,063) showed a significant improvement in A1c after CGM initiation (-0.7%, P < 0.0001), including -0.9% change in the T2D not on insulin group (n = 264). For the overall cohort, the number of patients with diabetes-related hospitalizations and emergency department visits decreased significantly by 67% and 40%, respectively (P < 0.0001 for both). This study showed that CGM use was associated with clinically meaningful improvements in A1c and reduced HCRU, suggesting potential for population-level clinical benefits, especially for patients not using insulin.

Smallest Clinically Meaningful Improvement in Amputation-Related Pain and Brief Pain Inventory Scores as Defined by Patient Reports of Global Improvement After Cryoneurolysis: a Retrospective Analysis of a Randomized, Controlled Clinical Trial.

The smallest meaningful improvement in pain scores (minimal clinically important difference [MCID]) after an analgesic intervention is essential information when both interpreting published data and designing a clinical trial. However, limited information is available for patients with chronic pain conditions, and what is published is derived from studies involving pharmacologic and psychological interventions. We here calculate these values based on data collected from 144 participants of a previously published multicenter clinical trial investigating the effects of a single treatment with percutaneous cryoneurolysis. In the original trial, we enrolled patients with a lower-limb amputation and established phantom pain. Each received a single-injection femoral and sciatic nerve block with lidocaine and was subsequently randomized to receive either ultrasound-guided percutaneous cryoneurolysis or sham treatment at these same locations. Investigators, participants, and clinical staff were masked to treatment group assignment with the exception of the treating physician performing the cryoneurolysis, who had no subsequent participant interaction. At both baseline and 4 months (primary end point), participants rated their phantom limb pain based on a numeric rating scale (NRS) and their interference of pain on physical and emotional functioning as measured with the Brief Pain Inventory's interference subscale. They subsequently qualitatively defined the change using the 7-point ordinal Patient Global Impression of Change (PGIC). The smallest clinically meaningful improvements in phantom limb pain and Brief Pain Inventory scores were calculated using an anchor-based method based on the PGIC. The median (interquartile range [IQR]) phantom pain NRS (0-10) improvements at 4 months considered small, medium, and large were 1 [1-1], 3 [3-4], and 4 [3-6], respectively. The median improvements in the Brief Pain Inventory interference subscale (0-70) associated with a small, medium, and large analgesic changes were 16 [6-18], 24 [22-31], and 34 [22-46]. The proportions of patients that experienced PGIC ≥5 were 33% and 36% in the active and placebo groups, respectively. The relative risk of a patient experiencing PGIC ≥5 in the active group compared to the sham group with 95% confidence interval was 0.9 (0.6-1.4), P = .667. Amputees with phantom limb pain treated with percutaneous cryoneurolysis rate analgesic improvements as clinically meaningful similar to pharmacologic treatments, although their MCID for the Brief Pain Inventory was somewhat larger than previously published values. This information on patient-defined clinically meaningful improvements will facilitate interpretation of available studies and guide future trial design.

Identifying thresholds for meaningful improvements in NTDT-PRO scores to support conclusions about treatment benefit in clinical studies of patients with non-transfusion-dependent beta-thalassaemia: analysis of pooled data from a phase 2, double-blind, placebo-controlled, randomised trial

ObjectivesTo estimate thresholds for defining meaningful within-patient improvement from baseline to weeks 13–24 and interpreting meaningfulness of between-group difference for the non-transfusion-dependent beta-thalassaemia patient-reported outcome (NTDT-PRO) tiredness/weakness (T/W) and shortness...

Psychometric evaluation of the Functional Assessment of chronic illness therapy-fatigue (FACIT-Fatigue) in adults with moderately to severely active Crohn's disease.

To provide further evidence on the psychometric properties of the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) in moderately to severely active Crohn's disease (CD), and to determine thresholds for meaningful improvement in fatigue. The FACIT-Fatigue is a 13-item patient-reported outcome measure (range, 0-52) assessing fatigue over the previous week. Using pooled data from the Phase 3 VIVID-1 study of moderately to severely active CD, psychometric properties of FACIT-Fatigue were evaluated up to Week 52. The Patient Global Rating of Severity (PGRS) and Patient Global Impression of Change (PGIC) were used as primary anchors to estimate the FACIT-Fatigue score change representing meaningful improvement. Psychometric analyses included 1065 adults. The FACIT-Fatigue demonstrated good internal consistency, and correlations between individual items and the total score were moderate to strong. The FACIT-Fatigue score showed moderate to strong correlations with other patient-reported assessments and weak correlations with endoscopic/laboratory assessments. The FACIT-Fatigue differentiated between distinct groups of participants varying in disease severity, quality of life, and fatigue based on PGRS and other assessments. FACIT-Fatigue improvements during the study differed significantly between most PGRS change and PGIC categories. Anchor-based estimates suggested a 6-9-point increase in the FACIT-Fatigue total score as meaningful improvement. The FACIT-Fatigue demonstrated strong psychometric properties in the VIVID-1 population of adults with moderately to severely active CD and determined a FACIT-Fatigue score change threshold representing meaningful improvement. NCT03926130. Registered 23 April 2019, https://clinicaltrials.gov/study/NCT03926130 .