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Abstract Anti-HIV-1 broadly neutralizing antibodies (bNAbs) have the dual potential of mediating virus neutralization and antiviral effector functions through their Fab and Fc domains, respectively. So far, bNAbs with enhanced Fc effector functions in vitro have only been tested in NHPs during chronic simian-HIV (SHIV) infection. Here, we investigate the effects of administering in acute SHIVAD8-EO infection either wild-type (WT) bNAbs or bNAbs carrying the S239D/I332E/A330L (DEL) mutation, which increases binding to FcγRs. Emergence of virus in plasma and lymph nodes (LNs) was delayed by bNAb treatment and occurred earlier in monkeys given DEL bNAbs than in those given WT bNAbs, consistent with faster clearance of DEL bNAbs from plasma. DEL bNAb-treated monkeys had higher levels of circulating virus-specific IFNγ single-producing CD8+ CD69+ T cells than the other groups. In LNs, WT bNAbs were evenly distributed between follicular and extrafollicular areas, but DEL bNAbs predominated in the latter. At week 8 post-challenge, LN monocytes and NK cells from DEL bNAb-treated monkeys upregulated proinflammatory signaling pathways and LN T cells downregulated TNF signaling via NF-κB. Overall, bNAbs with increased affinity to FcγRs shape innate and adaptive cellular immunity, which may be important to consider in future strategies of passive bNAb therapy.

BACKGROUND: CEP290-associated inherited retinal degeneration causes severe early-onset vision loss due to pathogenic variants in CEP290. EDIT-101 is a clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein 9 (Cas9) gene-editing complex designed to treat inherited retinal degeneration caused by a specific damaging variant in intron 26 of CEP290 (IVS26 variant). METHODS: We performed a phase 1-2, open-label, single-ascending-dose study in which persons 3 years of age or older with CEP290-associated inherited retinal degeneration caused by a homozygous or compound heterozygous IVS26 variant received a subretinal injection of EDIT-101 in the worse (study) eye. The primary outcome was safety, which included adverse events and dose-limiting toxic effects. Key secondary efficacy outcomes were the change from baseline in the best corrected visual acuity, the retinal sensitivity detected with the use of full-field stimulus testing (FST), the score on the Ora-Visual Navigation Challenge mobility test, and the vision-related quality-of-life score on the National Eye Institute Visual Function Questionnaire-25 (in adults) or the Children's Visual Function Questionnaire (in children). RESULTS: EDIT-101 was injected in 12 adults 17 to 63 years of age (median, 37 years) at a low dose (in 2 participants), an intermediate dose (in 5), or a high dose (in 5) and in 2 children 9 and 14 years of age at the intermediate dose. At baseline, the median best corrected visual acuity in the study eye was 2.4 log10 of the minimum angle of resolution (range, 3.9 to 0.6). No serious adverse events related to the treatment or procedure and no dose-limiting toxic effects were recorded. Six participants had a meaningful improvement from baseline in cone-mediated vision as assessed with the use of FST, of whom 5 had improvement in at least one other key secondary outcome. Nine participants (64%) had a meaningful improvement from baseline in the best corrected visual acuity, the sensitivity to red light as measured with FST, or the score on the mobility test. Six participants had a meaningful improvement from baseline in the vision-related quality-of-life score. CONCLUSIONS: The safety profile and improvements in photoreceptor function after EDIT-101 treatment in this small phase 1-2 study support further research of in vivo CRISPR-Cas9 gene editing to treat inherited retinal degenerations due to the IVS26 variant of CEP290 and other genetic causes. (Funded by Editas Medicine and others; BRILLIANCE ClinicalTrials.gov number, NCT03872479.). [ABSTRACT FROM AUTHOR]

Background and Purpose: Aerobic exercise can elicit positive effects on neuroplasticity and cognitive executive function but is poorly understood after stroke. We tested the effect of 4 weeks of aerobic exercise training on inhibitory and facilitatory elements of cognitive executive function and electroencephalography markers of cortical inhibition and facilitation. We investigated relationships between stimulus-evoked cortical responses, blood lactate levels during training, and aerobic fitness postintervention. Methods: Twelve individuals with chronic (>6 months) stroke completed an aerobic exercise intervention (40 minutes, 3×/wk). Electroencephalography and motor response times were assessed during congruent (response facilitation) and incongruent (response inhibition) stimuli of a Flanker task. Aerobic fitness capacity was assessed as V ˙ o 2peak during a treadmill test pre- and postintervention. Blood lactate was assessed acutely (<1 minute) after exercise each week. Cortical inhibition (N2) and facilitation (frontal P3) were quantified as peak amplitudes and latencies of stimulus-evoked electroencephalographic activity over the frontal cortical region. Results: Following exercise training, the response inhibition speed increased while response facilitation remained unchanged. A relationship between earlier cortical N2 response and faster response inhibition emerged postintervention. Individuals who produced higher lactate during exercise training achieved faster response inhibition and tended to show earlier cortical N2 responses postintervention. There were no associations between V ˙ o 2peak and metrics of behavioral or neurophysiologic function. Discussion and Conclusions: These preliminary findings provide novel evidence for selective benefits of aerobic exercise on inhibitory control during the initial 4-week period after initiation of exercise training and implicate a potential therapeutic effect of lactate on poststroke inhibitory control. Video Abstract available for more insights from the authors (see the video, Supplemental Digital Content 1 available at: http://links.lww.com/JNPT/A450). [ABSTRACT FROM AUTHOR]

Category: Ankle; Ankle Arthritis Introduction/Purpose: Compared to more prevalent arthritic conditions, ankle arthritis is complicated by an earlier age of onset. With advancements in 4th generation primary and revision componentry, total ankle arthroplasty (TAA) is considered an option for end-stage ankle arthritis in younger patients aligning with paradigm shifts in knee arthroplasty. Recently published data demonstrates excellent survivorship and complication rates in short/mid-term follow-up of younger patients who received a primary TAA. Additionally, older TAA patients display comparable PROMIS relative to hip/knee arthroplasty. However, there remains a paucity of literature surrounding the PROMIS of younger patients undergoing TAA. Thus, our aim was to assess PROMIS of individuals less than 50 years of age receiving a primary total ankle arthroplasty Methods: A retrospective cohort analysis of adult patients < 50 years who received a primary total ankle replacement at a single academic institution between 2003 and 2019 was conducted. Patient demographics, diagnosis, treatment, and outcome characteristics were recorded from a chart review of 41 patients with at least one year of post-surgical follow-up (Table 1). Post- operative PROMIS scores were obtained via telephone interviews. Primary outcomes that were measured included emotional and physical health, activity limitation, ambulation, and global health. SF-36, PROMIS Global Health, and Sickness Impact Profile Ambulation were used. Functional outcomes in our study sample were compared with age and gender-matched norms from a general US population, and 95% confidence intervals were calculated for each functional outcome mean. Student t-test was used for continuous variables, and chi-square analysis was used for categorical variables. Results: Thirty-one of 41 eligible patients were interviewed. The average age at surgery was 40 years old. Clinical and radiographic follow-up was a mean of 59.7 months and 31.2 months following TAA, respectively. General health as measured with the SF-36 was not significantly different from age/gender-matched norms. Eighty-seven percent of patients would choose to have a TAR again. While 58% reported being limited in vigorous activities, 61% were able to ambulate frequently for long periods of time. On average the patients did not report ongoing pain, and only 16% reported fatigue that hindered activities. Eighty-one percent reported returning to full employment and performing their duties without difficulty, and 84% reported they resumed all normal social activities. Primary implant survivorship was 88%. Conclusion: Despite a younger age and potentially increased demands, patients younger than 50 years of age undergoing primary total ankle arthroplasty are generally very satisfied with their index procedure at a mean follow-up of nearly 5 years. Our findings of positive outcomes on their health and well-being may improve surgeon insight for TAA as a preferred treatment for younger individuals with end-stage ankle arthritis.

Category: Bunion; Midfoot/Forefoot Introduction/Purpose: There are many described techniques to approach surgical correction of bunion deformity and prevention of recurrence is still a topic of interest. Coronal plane instability evidenced by intermetarsal angle (IMA) widening with weight bearing is a cause for concern with respect to recurrence. The identification of patients who are at risk for recurrence intraoperatively is challenging and currently there are few described tests that guide physician treatment. The aim of this study was to demonstrate an intraoperative intermetarsal coronal plane 'squeeze stress test' utilized by the senior surgeon along with the clinical and radiographic outcomes of patients who underwent fixation for their identified instability following the modified Lapidus procedure for hallux valgus correction. Methods: All patients included in this study presented with clinical and radiographic documentation of hallux valgus that was treated by a first tarsometatarsal arthrodesis with additional middle column fixation following widening on intraoperative fluoroscopy 'squeeze stress test' (Figure 1) by a single senior surgeon from 2015-2020. Fixation of the middle column was achieved via endobutton (5), screw (23), or endobutton plus screw (5). Clinical descriptions were reviewed for the presence of symptomatic recurrence and for the need of revision surgery. A single observer measured the HVA and the IMA angle of the preoperative and final post-operative weight-bearing radiographs, respectively. A total of 33 patients were included with an average age of 58.5 (range, 40-80) years of age and a mean follow-up of 8.3(range, 1.5-30) months. Mean BMI was 29 (range, 19- 54). Statistical analysis of this data set utilized the chi-square test and two sample t-test. Results: Pre-operatively, the patients with identified coronal plane instability had a mean HVA and IMA of 33 (range, 16-74) and 14 (range, 7-23) degrees, respectively. At final follow-up, these patients maintained a mean HVA of 9.8 (range, 0-32) and IMA of 4.5 (range, 0-15). No patients sustained clinical recurrence. Two patients underwent elective removal of hardware. One patient sustained a deep infection that required removal of hardware and formal debridement, this subsequently resolved. Conclusion: Coronal plane instability remains one of the unsolved facets of effectively treating symptomatic hallux valgus. Vigilance is the first step in prevention of recurrence in these patients and the 'squeeze stress test' is a simple, quick option for their identification. Our case series demonstrates satisfactory outcomes in terms of clinical recurrence for these patients utilizing this new evaluation technique. We believe further investigation of the squeeze stress test as an instability identifier is warranted in all types of bunion correction procedures.

The Chowan River flows from southern Virginia through northeastern North Carolina and into the Albemarle Sound, a part of the second largest U.S. estuary. The Chowan, which serves as an important recreational area and provides critical nursery habitat for multiple vulnerable species, has garnered much attention in recent years due to recurrent cyanobacterial harmful algal blooms (cHABs) associated with microcystins (MCs). Here we document unprecedented toxic blooms of Microcystis spp. during summer and fall of 2019 with MC concentrations two to three orders above the recreational guidelines of the Environmental Protection Agency (EPA, 2019). Based on 16S sequencing results in this study and previously published reports, the genus Microcystis emerged as a primary concern within the region. Shifts in assemblage composition, including relative abundance of Microcystis spp. and contributions from potential MC-degraders, linked to overall toxin concentrations and bloom stage. Congeners of varying toxicity, mainly MC-RR and MC-LR, were the most prevalent, corroborating that congeners other than MC-LR should be considered as health risk guidelines are developed. Downstream toxin transport was indicated based on changes in accumulated dissolved MC within the western Albemarle Sound which matched toxin dynamics in the Chowan River. This study provides important novel data on bacterial community composition, MC dynamics, and spatial connectivity for the Chowan River region that can aid monitoring approaches and management strategies for the protection of public health along the Chowan River and within the western Albemarle Sound., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Background: Lebrikizumab, a high-affinity monoclonal antibody targeting IL-13, previously demonstrated clinical efficacy in three randomized, double-blind, placebo-controlled Phase 3 trials that included adults and adolescents with moderate-to-severe atopic dermatitis (AD): ADvocate1, ADvocate2, and ADhere., Aim: This subset analysis evaluated 16-week physician- and patient-reported outcomes of lebrikizumab in the adolescent patients enrolled in these three trials., Methods: Eligible adolescents (≥12 to <18 years weighing ≥40kg) were randomized 2:1 to subcutaneous lebrikizumab (500 mg loading doses at baseline and Week 2 followed by 250 mg every 2 weeks) or placebo as monotherapy in ADvocate1&2, and in combination with topical corticosteroids (TCS) in the ADhere study. Week 16 analyses included clinical efficacy outcomes (IGA (0,1) with ≥2-point improvement, EASI 75, EASI 90), patient-reported Pruritus NRS ≥4-point improvement and Sleep-Loss Scale ≥2-point improvement., Results: Pooled ADvocate1&2 16-week results in lebrikizumab ( N  = 67) vs placebo ( N  = 35) were: IGA (0,1) 46.6% vs 14.3% ( p  < 0.01), EASI 75 62.0% vs 17.3% ( p  < 0.001), EASI 90 40.7% vs 11.5% ( p  < 0.01), Pruritus NRS 48.9% vs 13.1% ( p  < 0.01), and Sleep-Loss Scale 26.9% vs 6.9% ( p  = 0.137). Corresponding results for ADhere, (lebrikizumab + TCS, N  = 32; placebo + TCS, N  = 14), were consistent., Conclusions: Lebrikizumab treatment demonstrated efficacy in improving the signs and symptoms of AD in adolescent patients, consistent with the ADvocate and ADhere overall population results.

Background: Lebrikizumab improved itch, interference of itch on sleep, and quality of life (QoL) in patients with moderate-to-severe atopic dermatitis (AD), in two Phase 3 trials at 16 weeks compared to placebo., Objectives: We assess improvements in itch and sleep interference due to itch and their impact on QoL measurements after treatment., Methods: Data were analyzed from ADvocate1 (NCT04146363) and ADvocate2 (NCT04178967) in patients with moderate-to-severe AD. QoL was evaluated using Dermatology Life Quality Index (DLQI) at Week 16 in patients (>16 years of age) who were itch responders/non-responders (defined as ≥4-point improvement in Pruritus Numeric Rating Scale) or Sleep-Loss Scale responders/non-responders (defined as ≥2-point improvement in itch interference on sleep)., Results: In ADvocate1 and ADvocate2, significantly greater proportions of itch responders had a clinically meaningful improvement in measures related to QoL (DLQI scores (0/1), ≤5 DLQI total score and ≥4-point DLQI improvement) compared to itch non-responders. In both studies, a significantly greater proportion of Sleep-Loss Scale responders, reported a DLQI score of (0/1), DLQI total score of ≤5 and DLQI improvement of ≥4 points compared to Sleep-Loss Scale non-responders., Conclusions: Improvement in itch and sleep interference due to itch is associated with improvement in the QoL of patients after treatment with lebrikizumab for moderate-to-severe AD., ClinicalTrials.gov registration NCT04146363 (ADvocate1) and NCT04178967 (ADvocate2).

Background and Objective: Apalutamide (APA) is a treatment for metastatic castration-sensitive prostate cancer (mCSPC). In the ARON-3 study we investigated real-world experiences with APA treatment for mCSPC., Methods: We retrospectively assessed real-world clinical outcomes for patients with mCSPC treated with APA in the ARON-3 study. Overall survival (OS) was calculated from APA initiation to death from any cause. PSA 90 was defined as a prostate-specific antigen decline of ≥90% from baseline, and PSA 0.2 as achievement of a PSA level ≤0.2 ng/ml. Data for adverse events were retrospectively collected from electronic and paper charts and categorized according to Common Terminology Criteria for Adverse Events v5.0., Key Findings and Limitations: We included 531 patients with mCSPC treated with APA. High-volume disease was reported for 214 patients (40%), and 56 (11%) had visceral metastases. Median OS was not reached. PSA 90 was experienced by 461 patients (87%) and PSA 0.2 by 368 (69%). Median OS was significantly longer for patients with PSA 90 or PSA 0.2 than for subjects without these responses (p < 0.001). The incidence of grade 3-4 fatigue was higher among elderly patients (≥80 yr) than among younger patients (19% vs 5%), but the incidence of other adverse events was comparable between the age groups., Conclusions and Clinical Implications: APA is an effective and tolerable treatment for mCSPC in the real-world setting., Patient Summary: The ARON-3 project collects data for patients with prostate cancer treated in multiple centers worldwide to assess outcomes in the real-world setting. We analyzed data for patients with metastatic hormone-sensitive prostate cancer receiving apalutamide. Our results show that apalutamide is a safe and effective drug in the real-world setting as well as in clinical trials., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: Atopic dermatitis is a complex, chronic, inflammatory skin disease that requires long-term control of symptoms like itch and sleep loss and improvement in quality of life, in addition to reduction of clinical signs. Lebrikizumab is a selective interleukin-13 inhibitor approved in the European Union, United Kingdom, United Arab Emirates, Canada, and Japan for treatment of moderate-to-severe atopic dermatitis in adults and adolescents. Here, we assess the magnitude of changes across signs and symptoms of atopic dermatitis with lebrikizumab monotherapy over the 16-week induction period in two phase 3 studies, ADvocate1 and ADvocate2., Methods: Eligible adults (aged ≥ 18 years) and adolescents (aged 12 to < 18 years and weighing ≥ 40 kg) with moderate-to-severe atopic dermatitis were randomized to receive either 250 mg of lebrikizumab or placebo subcutaneously every two weeks. Least squares mean percentage change from baseline through week 16 was compared between lebrikizumab and placebo using mixed model repeated measure analysis for the following endpoints: Eczema Area and Severity Index (EASI), Pruritus Numeric Rating Scale (NRS), Sleep-Loss Scale, Patient-Oriented Eczema Measure (POEM), and Dermatology Life Quality Index (DLQI)., Results: In both trials, significant (P < 0.05) improvements were observed for lebrikizumab treatment compared with placebo at each 2-week timepoint for EASI, Pruritus NRS, Sleep-Loss Scale, and POEM, and at each 4-week timepoint for DLQI, through week 16. Statistically significant (P < 0.001) improvements were observed at 16 weeks for lebrikizumab treatment versus placebo in ADvocate1/ADvocate2 for EASI (71.9%/75.0% vs. 35.6%/43.3%), Pruritus NRS (53.3%/46.3% vs. 21.4%/18.0%), Sleep-Loss Scale (57.7%/55.6% vs. 23.9%/25.5%), POEM (54.4%/45.8% vs. 18.8%/16.9%), and DLQI (64.2%/60.5% vs. 28.5%/32.2%). Patient photos show improvements in skin appearance when disease measures improve., Conclusions: Lebrikizumab monotherapy resulted in significant and fast improvements in multiple dimensions of disease (clinical signs, symptoms, and quality of life) over 16 weeks in patients with moderate-to-severe atopic dermatitis., Trial Registration: ClinicalTrials.gov identifiers, NCT04146363; NCT04178967., (© 2024. The Author(s).)

Introduction: Lebrikizumab, a high-affinity IgG4 monoclonal antibody that selectively inhibits interleukin-13 with high binding affinity and slow dissociation rate, prevents the formation of the interleukin-4Rα/interleukin-13Rα1 heterodimer receptor signaling complex. Here we report the impact of lebrikizumab on responses to two non-live vaccines in adult patients with moderate-to-severe atopic dermatitis (AD)., Methods: ADopt-VA (NCT04626297) was a double-blind, placebo-controlled, parallel-group, 16-week, phase 3 randomized study to assess the impact of lebrikizumab treatment on non-live vaccine immune responses, and efficacy and safety of lebrikizumab compared with placebo. Eligible patients included adults from 18 to 55 years of age with moderate-to-severe chronic AD who were randomly assigned 1:1 to lebrikizumab 250 mg every 2 weeks or placebo and stratified according to disease severity. The primary endpoints were the development of a booster response to tetanus toxoid and a positive antibody response to meningococcal conjugate vaccine (MCV), 4 weeks after administration of the corresponding vaccine., Results: At week 16, 73.6% of patients in the lebrikizumab group (n = 78/106) achieved Tdap booster response compared with 73.4% of patients in the placebo group (n = 58/79). MCV vaccine response was observed in 86.9% of patients in the lebrikizumab group (n = 86/99) and 75.0% of patients in the placebo group (n = 60/80). At week 16, IGA 0,1 with ≥ 2-point improvement from baseline was achieved by 40.6% (n = 51/125) of patients treated with lebrikizumab and 18.9% (n = 23/122) of patients who received placebo (p < 0.001). There was a higher proportion of patients achieving EASI 75 at week 16 in the lebrikizumab-treated patients (58.0%, n = 72/125) compared with placebo (32.7%, n = 40/122, p < 0.001)., Conclusions: Treatment with lebrikizumab did not impact response to non-live vaccines Tdap and MCV in this study. Lebrikizumab treatment had a significant degree of efficacy compared to placebo across multiple endpoints., Trial Registration: ClinicalTrials.gov identifier NCT04626297., (© 2024. The Author(s).)

Background: Lebrikizumab demonstrated significant improvement versus placebo for measures of skin clearance and patient-reported outcomes at weeks 16 and 52 in patients with moderate-to-severe atopic dermatitis (AD). We report the sustained impact of lebrikizumab monotherapy, over 52 weeks and between visits, on the frequency of itch and sleep loss symptoms, as assessed by Patient-Oriented Eczema Measure (POEM), in patients with moderate-to-severe AD., Methods: In ADvocate1 and ADvocate2, Week-16 lebrikizumab responders (EASI75 or IGA 0/1 with ≥ 2-point improvement and without rescue medication) were randomized to lebrikizumab every 2 weeks (Q2W), every 4 weeks (Q4W), or placebo for 36 weeks. This pooled analysis reports improvement from Week 16 to 52 in patients achieving POEM response 0 (no days) or 1 (1-2 days) for Items 1 (itch) and 2 (sleep disturbance) for the lebrikizumab Q2W and Q4W treatment arms. Observed (excluding data collected after treatment discontinuation, rescue medication use, or patient transfer to escape arm) results were reported., Results: At Week 16, for lebrikizumab Q2W and Q4W, 35.9% (n = 37/103) and 39.3% (n = 42/107) of patients responded 0 or 1 to Item 1 of POEM (Itch) and 12.6% (n = 13/103) and 12.1% (n = 13/107) responded 0. A total of 66.0% (n = 68/103) and 72.6% (n = 77/106) of patients responded 0 or 1 to Item 2 of POEM (Sleep) and 37.9% (n = 39/103) and 44.3% (n = 47/106) responded 0, respectively. By Week 52, for lebrikizumab Q2W and Q4W, 44.6% (n = 29/65) and 48.0% (n = 36/75) responded 0 or 1 to Item 1 of POEM (Itch), and 21.5% (n = 14/65) and 18.7% (n = 14/75) of patients responded 0. A total of 83.1% (n = 54/65) and 78.4% (n = 58/74) responded 0 or 1 to Item 2 of POEM (Sleep), and 67.7% (n = 44/65) and 59.5% (n = 44/74) responded 0, respectively., Conclusion: Weekly POEM responses for itch and sleep disturbance remained stable between doses and visits, and continued to improve from Week 16 through 52, in lebrikizumab-treated patients, demonstrating consistent improvement over time for key AD symptoms., Trial Registration Numbers: ADvocate1 (NCT04146363) and ADvocate2 (NCT04178967)., (© 2024. The Author(s).)

Introduction: Lebrikizumab is a novel monoclonal antibody with established efficacy in patients with moderate-to-severe atopic dermatitis (AD) in multiple Phase 3 trials. One of the ultimate treatment goals for patients with moderate-to-severe AD is to achieve stable disease control without concern for planning future life events., Methods: In ADvocate1 and ADvocate2, lebrikizumab-treated patients meeting the protocol-defined response criteria at Week 16 were re-randomized 2:2:1 to receive lebrikizumab every 2 weeks (Q2W), lebrikizumab every 4 weeks (Q4W), or placebo Q2W (lebrikizumab withdrawal) for 36 additional weeks. In this post hoc analysis, we evaluated the proportions of patients with no or minimal fluctuations of efficacy during the 36-week maintenance period and plotted individual patient trajectories. We defined no or minimal fluctuations as achieving and maintaining the defined endpoint (≥ 75% improvement in the Eczema Area and Severity Index [EASI 75], ≥ 90% improvement in EASI, Pruritus Numeric Rating Scale [NRS] ≥ 4-point improvement, or Pruritus NRS ≥ 3-point improvement) for ≥ 80% of the study visits. If patients used rescue medication, discontinued treatment, or transferred to the escape arm, data collected at or after the event were imputed as non-response., Results: The proportions of lebrikizumab responders who maintained EASI 75 with no or minimal fluctuations were 70.8% (lebrikizumab Q2W), 71.2% (lebrikizumab Q4W), and 60.0% (lebrikizumab withdrawal). Of the patients with baseline Pruritus NRS ≥ 4 and who achieved ≥ 4-point improvement at Week 16, 66.1% (lebrikizumab Q2W), 62.7% (lebrikizumab Q4W), and 55.2% (lebrikizumab withdrawal) maintained ≥ 4-point Pruritus NRS improvement with no or minimal fluctuations., Conclusions: Patients who met the response criteria at Week 16 and continued treatment with lebrikizumab Q2W or Q4W demonstrated a stable response with no or minimal fluctuations of efficacy in measures of skin and itch up to Week 52., Clinical Trial Registration: NCT04146363 (ADvocate1) and NCT04178967 (ADvocate2)., (© 2024. The Author(s).)

Background: Sleep loss is a key factor contributing to disease burden in people with atopic dermatitis (AD). Mitigating itch to improve sleep is an important outcome of AD treatment. This study explored the content validity and measurement properties of the Sleep-Loss Scale, a single-item rating scale for assessing itch interference with sleep in clinical trials of AD treatments., Methods: Concept elicitation and cognitive debriefing interviews were conducted with 21 adults and adolescents (12-17 years of age) with moderate-to-severe AD to develop a conceptual model of patient experience in AD and explore the content validity of the scale. Data collected from adults with moderate-to-severe AD enrolled in a phase 2b study (NCT03443024) were used to assess Sleep-Loss Scale's psychometric performance, including reliability, construct validity, and ability to detect change. Meaningful within-patient change (MWPC) thresholds were also determined using anchor-based methods., Results: Qualitative findings from concept elicitation highlighted the importance of sleep-loss related to itch in AD. Debriefing analysis of the Sleep-Loss Scale indicated that the scale was relevant, appropriate, and interpreted as intended. Trial data supported good reliability, construct validity and ability to detect improvement. MWPC was defined as a 1-point improvement using trial data, a finding supported by qualitative data., Conclusions: The Sleep-Loss Scale provides a valid and reliable patient-reported measure of the impact of itch on sleep in patients with AD, and can detect change, indicating it is fit-for-purpose to evaluate the efficacy of AD treatments in moderate-to-severe patients., (© 2024. The Author(s).)

Halo gravity traction (HGT) is a preoperative modality for children with severe spinal deformity used to optimize spine flexibility and balance while decreasing the likelihood of neurologic injury. HGT is a dependable solution for these challenging spinal deformities. Aligning treatment guidelines and providing resources, education, and training for staff are key components for a successful HGT program. The HGT program at Children's Mercy Hospital was then developed with a systems approach with the holistic goal of multidisciplinary collaboration with physical/occupational therapy, hospital medicine, pulmonology, psychology, nutrition, child life, and complex care management. Education, research, and national collaboration to standardize this therapy should improve patient safety and support quality improvement., (Copyright © 2024 by National Association of Orthopaedic Nurses.)

Introduction: Alopecia areata (AA) is an autoimmune disease associated with high rates of emotional and psychosocial distress. The analysis reported here describes the evolution of measures assessing health-related quality of life (HRQoL) and symptoms of anxiety and depression up to week 104 in patients who achieved sustained scalp hair regrowth during treatment with baricitinib in the BRAVE-AA phase III trials., Methods: This post-hoc analysis included data from the double-blind, parallel-group, randomized, placebo-controlled phase III trials BRAVE-AA1 (ClinicalTrials.gov number: NCT03570749) and BRAVE-AA2 (ClinicalTrials.gov number: NCT03899259). Adults with severe AA (defined as a Severity of Alopecia Tool [SALT] score ≥ 50) randomized to baricitinib 4 mg or baricitinib 2 mg at baseline who achieved SALT score ≤ 20 by week 36 and maintained SALT score ≤ 20 through week 104 on the same dose of baricitinib were included in this analysis of integrated data. Scalp hair regrowth (SALT score) and improvements in Skindex-16 AA Scale and Hospital Anxiety and Depression Scale (HADS) domain scores were analyzed over the 104-week period using descriptive statistics., Results: In total, 131 patients (88 on baricitinib 4 mg and 43 on baricitinib 2 mg) were included in this analysis. Across the two groups, the mean age (standard deviation) was 37.2 years (12.7), and 84 (64.1%) patients were female. The interquartile range) for time to achieve a SALT score ≤ 20 for patients treated with baricitinib 4 mg and baricitinib 2 mg was 13.1 and 19.6 weeks, respectively. By week 104, 91% (baricitinib 2 mg) and 96% (baricitinib 4 mg) of patients had achieved a SALT score ≤ 10 on baricitinib treatment. In both groups, progressive improvements in the Skindex-16 AA and HADS domain scores were observed up to week 104., Conclusion: This analysis of adults with severe AA treated with baricitinib revealed that achievement of sustained clinically meaningful scalp hair regrowth (SALT score ≤ 20) was associated with improvements in both measures of HRQoL and symptoms of anxiety and depression up to week 104., (© 2024. The Author(s).)

Introduction: Atopic dermatitis (AD) is a chronic inflammatory skin disease for which signs and symptoms have a negative impact on a patient's quality of life (QoL) and mental health. Here, we assess the impact of lebrikizumab on QoL and mental health after 16 weeks of treatment in patients with moderate-to-severe AD., Methods: Data were analyzed over 16 weeks from two separate phase 3, randomized, placebo-controlled, monotherapy trials (ADvocate1 and ADvocate2). Patient-reported outcomes were assessed using the following measures: Dermatology Life Quality Index (DLQI), EQ-5D-5L visual analogue scale (VAS), EQ-5D-5L index scores (UK and US), Patient-Reported Outcomes Measurement Information System (PROMIS) Anxiety, and PROMIS Depression., Results: Treatment with lebrikizumab 250 mg every 2 weeks in two studies led to statistically significant improvements (based on nominal p values) versus placebo in DLQI since week 4 (the first timepoint assessed) for the following measures: change from baseline in DLQI total score (ADvocate1 - 7.8 vs - 2.8; ADvocate2 - 7.3 vs - 3.9), proportion of patients with DLQI ≥ 4-point improvement (ADvocate1 69.5% vs 36.2%; ADvocate2 60.5% vs 42.6%), DLQI total score ≤ 5 (ADvocate1 36.7% vs 8.8%; ADvocate2 29.6% vs 10.8%), and DLQI (0, 1) (ADvocate1 12.3% vs 1.7%; ADvocate2 9.2% vs 1.7%). Improvements in DLQI measures, EQ-5D-5L index scores (UK and US), and EQ-5D-5L VAS were sustained through week 16. Additionally, lebrikizumab improved PROMIS Anxiety and PROMIS Depression scores, and improvements were higher in patients with at least a mild score (≥ 55) versus placebo for PROMIS Anxiety (ADvocate1 - 7.43 vs - 1.51; ADvocate2 - 4.95 vs - 0.82) and PROMIS Depression (ADvocate1 - 7.42 vs - 2.46; ADvocate2 - 4.28 vs - 2.00)., Conclusions: Treatment with monotherapy 250 mg lebrikizumab for 16 weeks provided clinically meaningful improvements in outcomes related to QoL and mental health for patients with moderate-to-severe AD. Lebrikizumab-treated patients reported improvements in DLQI as early as week 4, the first measure since baseline., Trial Registration: ClinicalTrials.gov Registration NCT04146363 (ADvocate1) and NCT04178967 (ADvocate2)., (© 2024. The Author(s).)

We quantified the sensitivity of surveillance for lumpy skin disease (LSD) and foot and mouth disease (FMD) in cattle in the Kimberley region of Western Australia. We monitored producer and veterinary activity with cattle for 3 years commencing January 2020. Each year, ~274,000 cattle of 685,540 present on 92 pastoral leases (stations) were consigned to other stations, live export or slaughter. Veterinarians examined 103,000 cattle on the stations, 177,000 prior to live export, and 10,000 prior to slaughter. Detection probabilities for the disease prior to transport or during veterinary procedures and inspections were elicited by survey of 17 veterinarians working in Northern Australia. The veterinarians estimated the probabilities that they would notice, recognise, and submit samples from clinical cases of LSD and FMD, given a 5% prevalence of clinical signs in the herd. We used scenario tree methodology to estimate monthly surveillance sensitivity of observations made by producers and by veterinarians during herd management visits, pre-export inspections, and ante-mortem inspections. Average monthly combined sensitivities were 0.49 for FMD and 0.37 for LSD. Sensitivity was high for both diseases during the dry season and low in the wet season. We estimated the confidence in freedom from the estimated surveillance sensitivity given one hypothetically infected herd, estimated probability of introduction, and prior confidence in freedom. This study provided assurance that the Kimberley is free of these diseases and that routine producer and veterinary interactions with cattle are adequate for the timely detection of the disease should they be introduced., (© 2024 Australian Veterinary Association.)

Background: Pruritus, or itch, is a key symptom of atopic dermatitis (AD); as such, mitigating itch is an important outcome of AD treatment. This study explored the content validity and measurement properties of the Pruritus Numeric Rating Scale (Pruritus NRS), a novel single-item scale for assessing itch severity in clinical trials of AD treatments., Methods: In this mixed-methods study, qualitative interviews were conducted with 21 people with moderate-to-severe AD (n = 15 adult, n = 6 adolescent) to develop a conceptual model of the patient experience in AD and explore the content validity of the Pruritus NRS. Data collected daily from adults with moderate-to-severe AD enrolled in a phase 2b study (NCT03443024) were used to assess the Pruritus NRS' psychometric performance, including reliability, construct validity, and responsiveness. Meaningful within-patient change (MWPC) thresholds were also determined using anchor-based methods., Results: Qualitative findings highlighted the importance of itch in AD, including severity, persistence, frequency, and daily life interference. Patient debriefing of the Pruritus NRS indicated that the scale was relevant, appropriate, and interpreted as intended. Trial data supported overall good psychometric properties. MWPC was defined as a 3-point improvement in Pruritus NRS score, a finding supported by qualitative data., Conclusions: The Pruritus NRS provides a valid and reliable patient-reported measure of itching severity in patients with moderate-to-severe AD, and can detect change, indicating it is fit-for-purpose to evaluate the efficacy of AD treatments in this population., Trial Registration: ClinicalTrials.gov identifier, NCT03443024., (© 2024. The Author(s).)

Peat moss (Sphagnum spp.) develops mutualistic interactions with cyanobacteria by providing carbohydrates and S compounds in exchange for N-rich compounds, potentially facilitating N inputs into peatlands. Here, we evaluate how colonization of Sphagnum angustifolium hyaline cells by Nostoc muscorum modifies S abundance and speciation at the scales of individual cells and across whole leaves. For the first time, S K-edge X-ray Absorption Spectroscopy was used to identify bulk and micron-scale S speciation across isolated cyanobacteria colonies, and in colonized and uncolonized leaves. Uncolonized leaves contained primarily reduced organic S and oxidized sulfonate- and sulfate-containing compounds. Increasing Nostoc colonization resulted in an enrichment of S and changes in speciation, with increases in sulfate relative to reduced S and sulfonate. At the scale of individual hyaline cells, colonized cells exhibited localized enrichment of reduced S surrounded by diffuse sulfonate, similar to observations of cyanobacteria colonies cultured in the absence of leaves. We infer that colonization stimulates plant S uptake and the production of sulfate-containing metabolites that are concentrated in stem tissues. Sulfate compounds that are produced in response to colonization become depleted in colonized cells where they may be converted into reduced S metabolites by cyanobacteria., (© 2023 UT-Battelle, LLC New Phytologist © 2023 New Phytologist Foundation.)

Competing Interests: Conflicts of interest see Appendix S1 for the full Conflicts of Interest statement.

Introduction: This post hoc analysis assessed association between scalp hair regrowth and improvements in health-related quality of life (HRQoL) and psychological burden in patients with severe alopecia areata (AA)., Methods: Data were pooled from two phase-3 trials ( N  = 1200). Patients randomized to once-daily placebo, baricitinib 2-mg, or 4-mg were analyzed independently of treatment allocation, and categorized according to scalp hair regrowth (at Week 36): meaningful regrowth (Severity of Alopecia Tool (SALT) score ≤20); intermediate regrowth (≥30% SALT improvement [SALT 30 ] at any post-baseline visit to Week 36, but SALT score > 20 at Week 36); no/minimal regrowth (never achieved SALT 30 ). Skindex-16 for AA score change-from-baseline and proportion of patients with baseline Hospital Anxiety and Depression Scale (HADS) scores ≥8 that shifted to <8 (normal) were assessed., Results: Patients with meaningful regrowth achieved greater improvements in all Skindex-16 AA domains versus no/minimal regrowth. More patients with meaningful versus no/minimal regrowth shifted from HADS ≥8 to <8 (anxiety:46.8% versus 26.4%; depression:52.3% versus 24.0%). Improvements occurred with intermediate regrowth but to a lesser extent versus meaningful regrowth., Conclusions: Patients with severe AA and scalp hair regrowth at Week 36 experienced greater improvements in HRQoL and anxiety and depression versus patients with no/minimal regrowth. The highest benefit was observed in patients with meaningful regrowth (SALT score ≤20). ClinicalTrials.gov listing: NCT03570749 and NCT03899259.

Background: Real-world data on the effectiveness of systemic therapy in atopic dermatitis (AD) are limited., Methods: Adult patients with AD in the CorEvitas AD registry (2020-2021) who received systemic therapies for 4-12 months prior to enrollment were included based on disease severity: body surface area (BSA) 0%-9% and BSA ≥10%. Demographics, clinical characteristics, and outcomes were assessed using descriptive statistics. Pairwise effect sizes (ES) were used to compare BSA groups., Results: The study included 308 patients (BSA 0%-9%: 246 [80%]; BSA ≥10%: 62 [20%]). Despite systemic therapy, both BSA groups reported the use of additional topical therapy and the presence of lesions at difficult locations. Moderate-to-severe AD (vIGA-AD ® ) was reported by 11% (BSA 0%-9%) and 66% (BSA ≥10%; ES = 0.56) of patients. Mean disease severity scores: total BSA (2% and 22%; ES = 3.59), EASI (1.1 and 11.1; ES = 2.60), and SCORAD (12.1 and 38.0; ES = 1.99). Mean scores for PROs: DLQI (3.7 and 7.5; ES = 0.75), and peak pruritus (2.2 and 4.5; ES = 0.81). Inadequate control of AD was seen in 27% and 53% of patients (ES = 0.23)., Conclusions: Patients with AD experience a high disease burden despite systemic treatment for 4-12 months. This study provides potential evidence of suboptimal treatment and the need for additional effective treatment options for AD.

Background: Patients who completed the originating studies, BREEZE-AD1 (NCT03334396), BREEZE-AD2(NCT03334422), and BREEZE-AD7 (NCT03733301), were eligible for enrollment in the multicenter,phase-3, long-term extension study BREEZE-AD3 (NCT03334435)., Methods: At week 52, responders and partial responders to baricitinib 4 mg were re-randomized (1:1) into the sub-study to dose continuation (4 mg, N = 84), or dose down-titration (2 mg, N = 84). Maintenance of response was assessed from week 52 to 104 of BREEZE-AD3. Physician-rated outcomes included vIGA-AD (0,1), EASI75, and mean change from baseline in EASI. Patient-reported outcomes included DLQI, P OEM total score, HADS, and from baseline: WPAI (presenteeism, absenteeism, overall work impairment, daily activity impairment) and change from baseline in SCORAD itch and sleep loss., Results: With continuous treatment with baricitinib 4 mg, efficacy was maintained up to week 104 in vIGA-AD (0,1), EASI75, EASI mean change from baseline, SCORAD itch, SCORAD sleep loss, DLQI, P OEM, HADS, and WPAI (all scores). Patients down-titrated to 2 mg maintained most of their improvements in each of these measures., Conclusion: The sub-study of BREEZE AD3 supports flexibility in baricitinib dosing regimens. Patients who continued treatment with baricitinib 4 mg and down-titrated to 2 mg maintained improvements in skin, itch, sleep, and quality of life for up to 104 weeks.