Mean Percentage Change Research Articles

Effect of liraglutide on thigh muscle fat and muscle composition in adults with overweight or obesity: Results from a randomized clinical trial.

Excess muscle fat is observed in obesity and associated with greater burden of cardiovascular risk factors and higher risk of mortality. Liraglutide reduces total body weight and visceral fat but its effect on muscle fat and adverse muscle composition is unknown. This is a pre-specified secondary analysis of a randomized, double-blind, placebo-controlled trial that examined the effects of liraglutide plus a lifestyle intervention on visceral adipose tissue and ectopic fat among adults without diabetes with body mass index ≥30kg/m2 or ≥27kg/m2 and metabolic syndrome. Participants were randomly assigned to a once-daily subcutaneous injection of liraglutide (target dose 3.0mg) or matching placebo for 40weeks. Body fat distribution and muscle composition was assessed by magnetic resonance imaging at baseline and 40-week follow-up. Muscle composition was described by the combination of thigh muscle fat and muscle volume. Treatment difference (95% confidence intervals [CI]) was calculated by least-square means adjusted for baseline thigh muscle fat. The association between changes in thigh muscle fat and changes in body weight were assessed using Spearman correlation coefficients. The effect of liraglutide versus placebo on adverse muscle composition, denoted by high thigh muscle fat and low thigh muscle volume, was explored. Among the 128 participants with follow-up imaging (92.2% women, 36.7% Black), median muscle fat at baseline was 7.8%. The mean percent change in thigh muscle fat over median follow-up of 36weeks was -2.87% among participants randomized to liraglutide (n=73) and 0.05% in the placebo group (absolute change: -0.23% vs. 0.01%). The estimated treatment difference adjusted for baseline thigh muscle fat was -0.24% (95% CI, -0.41 to -0.06, P-value 0.009). Longitudinal change in thigh muscle fat was significantly associated with change in body weight in the placebo group but not the liraglutide group. The proportion of participants with adverse muscle composition decreased from 11.0% to 8.2% over follow-up with liraglutide, but there was no change with placebo. In a cohort of predominantly women with overweight or obesity in the absence of diabetes, once-daily subcutaneous liraglutide was associated with a reduction in thigh muscle fat and adverse muscle composition compared with placebo. The contribution of muscle fat improvement to the cardiometabolic benefits of liraglutide requires further study.

Geopolymer Production From Waste Polyethylene Terephthalate and Glass For Clay Subgrade Stabilization

In this study, the efficacy of Polyethylene Terephthalate (PET) and Waste Glass Powder (WGP) as soil stabilizers was investigated to address the research questions and objectives. It examines the enhancement of mechanical strength of clayey subgrade soils sourced from Ogun state, Nigeria across varying proportions (5% −20%) including the potential cost analysis. Providing experimental insights into soil stabilization using PET individually and in combination with WGP-based geopolymers. Optimal stabilization was achieved at 5% PET, accompanied by 5%-20% WGP, and activated with a 2M NaOH solution. Results demonstrated enhanced mechanical strength with both stabilizers, with the combination of PET and WGP proving the most effective. Specifically, stabilization with 5% PET (1.18mm) WGP geopolymer, activated with 2% NaOH, yielded optimal results, exhibiting UCS values ranging from 180kN/m2 to 320kN/m2, surpassing cement-based stabilization (UCS value: 380kN/m2). Moreover, durability testing revealed significant improvements, with PET+WGP samples displaying a UCS mean of 259.4kN/m2, a weight of 89.67g, and a percent change in mean and weight of −25.79% and −25.86%, respectively, compared to cement-stabilized soil (UCS mean: 408.66 kN/m2, percent change: 2.15%, weight mean: 109.25g, percent change: -25.86%). Furthermore, PET+WGP exhibited a 125% increase in CBR compared to PET alone and a better cost reduction of $6,153,850,000.00 for 100km, highlighting its superior performance and cost reduction. The findings of this study hold significance for informed decision-making in material selection for road pavement works, offering an alternative method and contributing to Sustainable Development Goals and Circular Economy initiatives by advocating sustainable waste management and road infrastructure.

Analysis of 10-year income trends for pharmacists and other select health professionals.

In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. To evaluate income trends among pharmacists and other select health professions (dentists, nurse practitioners, registered nurses, and physicians) in the US for the 10-year period of 2012 to 2021, with special attention given to the first 2 years of the COVID-19 pandemic (2020 and 2021). A retrospective analysis was conducted of 2012 to 2021 income data for select health professions, collected from the American Community Survey. Univariate time series analysis was conducted using exponential smoothing to examine income patterns over the 10-year study period and forecast income for the next 5-year period (2022 to 2026) for each health profession. Additionally, time series regression models were constructed for each health profession. Descriptive statistics (mean percent change in income and SD) were calculated for each health profession for the prepandemic era (2012 to 2019) and the first 2 years of the pandemic (2020 and 2021). Goodness-of-fit statistics for each forecast model indicate highly accurate forecasts. The model for each health profession indicates a significant positive trajectory in income (P < 0.001), although pharmacists are projected to have a lower rate of income growth among the 5 health professions for the next 5-year period, 2022 to 2026. During the first 2 years of the pandemic, pharmacists had the lowest mean percent change in income (mean, 2.0%; SD, 2.0%) among the 5 health professions. Growth in pharmacist income is projected to lag behind that in other health professions in the near future. Individual-, organization-, and profession-level strategies may facilitate opportunities for income growth among pharmacists.

Abstract P176: Consumption of Sugar-Sweetened Beverages Lowers Lipoprotein(a) Levels in Obese and Overweight Adults: Findings in a Double-Blind Parallel-Arm Study

Elevated levels of lipoprotein(a) [Lp(a)] are a genetically regulated, causal, and prevalent risk factor for atherosclerotic cardiovascular disease. A size polymorphism in the apolipoprotein(a) [apo(a)] gene, determined by the number of Kringle (K) repeats, inversely regulates Lp(a) plasma levels. Despite strong genetic regulation, non-genetic factors such as diet influence Lp(a) levels. However, the relationship between Lp(a) level and sugar consumption remains understudied. In this double-blinded parallel arm study, we investigated the effect of consuming glucose- or fructose-sweetened beverages providing 25% of energy requirements for 10 weeks on plasma Lp(a) levels in 32 overweight/obese adults. Lp(a) levels were measured using an apo(a) size insensitive ELISA and apo(a) isoform sizes were determined by Western blotting. The mean (SD) age of participants was 54 ± 8 years, 50% were women, and 75% were of European descent. The mean body mass index was 29 ± 3 kg/m 2 and 28% of participants had metabolic syndrome. In all participants, baseline median Lp(a) level was 10.3 mg/dL (IQR: 4, 28 mg/dL). At the end of the 10-week intervention, Lp(a) levels were reduced by an average of -4 mg/dL (-13%) in all participants, by -4 mg/dL (-15%) in the glucose group (n=15) and by -5 mg/dL (-11%) in the fructose group (n=17), respectively. The mean percent changes in Lp(a) levels in the low (≤25 mg/dL) (n=23) vs high (&gt;25 mg/dL) (n=9) baseline Lp(a) groups were similar: -14% (-2 mg/dL) vs -11% (-11 mg/dL), respectively. Notably, the carrier status of an atherogenic small (≤22K repeats) apo(a) size did not substantially impact Lp(a) responses as the mean Lp(a) changes were similar in carriers (-15%) (n=8) vs non-carriers (-13%) (n=24). In conclusion, in overweight/obese adults, consuming sugar-sweetened beverages providing 25% of energy requirements for 10 weeks reduced Lp(a) levels by ~13% independent of apo(a) size variability. The findings suggest that pathways involving carbohydrates and fatty acid metabolism might potentially impact Lp(a) levels. The specific mechanisms underlying the effect of sugar-sweetened beverage consumption to reduce circulating Lp(a) levels warrant further investigation.

Aspirin for Metabolic Dysfunction–Associated Steatotic Liver Disease Without Cirrhosis

ImportanceAspirin may reduce severity of metabolic dysfunction–associated steatotic liver disease (MASLD) and lower the incidence of end-stage liver disease and hepatocellular carcinoma, in patients with MASLD. However, the effect of aspirin on MASLD is unknown.ObjectiveTo test whether low-dose aspirin reduces liver fat content, compared with placebo, in adults with MASLD.Design, Setting, and ParticipantsThis 6-month, phase 2, randomized, double-blind, placebo-controlled clinical trial was conducted at a single hospital in Boston, Massachusetts. Participants were aged 18 to 70 years with established MASLD without cirrhosis. Enrollment occurred between August 20, 2019, and July 19, 2022, with final follow-up on February 23, 2023.InterventionsParticipants were randomized (1:1) to receive either once-daily aspirin, 81 mg (n = 40) or identical placebo pills (n = 40) for 6 months.Main Outcomes and MeasuresThe primary end point was mean absolute change in hepatic fat content, measured by proton magnetic resonance spectroscopy (MRS) at 6-month follow-up. The 4 key secondary outcomes included mean percentage change in hepatic fat content by MRS, the proportion achieving at least 30% reduction in hepatic fat, and the mean absolute and relative reductions in hepatic fat content, measured by magnetic resonance imaging proton density fat fraction (MRI-PDFF). Analyses adjusted for the baseline value of the corresponding outcome. Minimal clinically important differences for study outcomes were not prespecified.ResultsAmong 80 randomized participants (mean age, 48 years; 44 [55%] women; mean hepatic fat content, 35% [indicating moderate steatosis]), 71 (89%) completed 6-month follow-up. The mean absolute change in hepatic fat content by MRS was −6.6% with aspirin vs 3.6% with placebo (difference, −10.2% [95% CI, −27.7% to −2.6%]; P = .009). Compared with placebo, aspirin treatment significantly reduced relative hepatic fat content (−8.8 vs 30.0 percentage points; mean difference, −38.8 percentage points [95% CI, −66.7 to −10.8]; P = .007), increased the proportion of patients with 30% or greater relative reduction in hepatic fat (42.5% vs 12.5%; mean difference, 30.0% [95% CI, 11.6% to 48.4%]; P = .006), reduced absolute hepatic fat content by MRI-PDFF (−2.7% vs 0.9%; mean difference, −3.7% [95% CI, −6.1% to −1.2%]; P = .004]), and reduced relative hepatic fat content by MRI-PDFF (−11.7 vs 15.7 percentage points; mean difference, −27.3 percentage points [95% CI, −45.2 to −9.4]; P = .003). Thirteen participants (32.5%) in each group experienced an adverse event, most commonly upper respiratory tract infections (10.0% in each group) or arthralgias (5.0% for aspirin vs 7.5% for placebo). One participant randomized to aspirin (2.5%) experienced drug-related heartburn.Conclusions and RelevanceIn this preliminary randomized clinical trial of patients with MASLD, 6 months of daily low-dose aspirin significantly reduced hepatic fat quantity compared with placebo. Further study in a larger sample size is necessary to confirm these findings.Trial RegistrationClinicalTrials.gov Identifier: NCT04031729

A New Peptide Skin-Brightening Facial Cream Demonstrated Clinical Improvement in Jawline Sagging, Discoloration and Overall Photodamage

Besides fine lines and wrinkles, chronological aging leads to discoloration, age spots, and more importantly, sagging and loss of elasticity on facial skin. There are ample consumer needs to reduce age spots and skin sagging with an increasing desire for effective topical solutions that can provide meaningful benefits in these areas. A new microdipeptide (acetyl dipeptide) technology was developed that demonstrated the potential to reduce skin inflammation and stimulate the skin’s supporting matrix. This clinical study was designed to test the effectiveness of a facial cream with a unique blend of microdipeptide technology along with brightening and firming ingredients to reduce the key signs of facial aging with twice daily use. The 16-week study included 43 healthy female subjects, ages 40-70 with diverse skin tones, and having mild to moderate jawline sagging with fine lines and/or hyperpigmentation by expert visual grading (3 to 6 on a 0 to 9 scale). Visual grading exhibited statistically significant reduction in all targeted skin aging signs starting at week 8, and continuing improvement to week 16, including jawline sagging (19%), laxity (19%), lift/ firmness (15%), as well as improved evenness of skin tone (16%), hyperpigmentation (14%) and overall photodamage (23%) (mean percent change, p&lt; 0.05). Consumer perception questionnaires also revealed improvement after 16 weeks of use with tighter/tauter jawlines (88%), increased firmness (93%), skin elasticity (93%), refined facial contour (88%), less sagging (95%), and more lifted (91%) and volumized appearance (98%). Furthermore, subjects also indicated brighter skin (95%), increased radiance (93%), less discoloration (86%), fading dark spots (77%), reduced fine lines (93%) and wrinkles (95%), skin looks younger (95%), and overall less noticeable aging signs (95%). Clinical photography supported both the clinical grading and consumer perception of benefits. In addition, these clinical outcomes are further supported by in vitro and ex vivo investigations showing the microdipeptide activity on inhibiting the expression of inflammatory cytokines and inducing multiple matrix building biomarkers, beyond elastin, pro-collagen and hyaluronic acid to include decorin and fibronectin. Gene expression profiling showed changes associated with skin barrier and extracellular matrix organizations, therefore mimicking a younger-looking skin. These results demonstrated that this peptide facial cream was well-tolerated and effective in improving jawline sagging, facial skin firmness, skin brightening, and reducing the overall signs of aging.

Efficacy and Safety of Fixed-Dose Triple-Combination Clindamycin Phosphate 1.2%/Adapalene 0.15%/Benzoyl Peroxide 3.1% Gel for Moderate-to-Severe Acne Vulgaris in Children and Adolescents

Background: Topical clindamycin phosphate 1.2%/adapalene 0.15%/benzoyl peroxide 3.1% (CAB) gel is the first fixed-dose triple-combination formulation approved for acne vulgaris and is indicated for use in patients aged 12 years and older. As topical acne treatment in pediatric patients may be complicated by tolerability issues and/or a perceived lack of efficacy, the objective of this post hoc analysis was to investigate the efficacy and safety of CAB in children and adolescents.&#x0D; Methods: Data were pooled from two phase 3 double-blind, randomized, 12-week studies (NCT04214639; NCT04214652). Eligible participants ≥9 years of age with moderate-to-severe acne were randomized (2:1) to once-daily CAB or vehicle gel. This analysis evaluated adolescents aged 12-17 years (CAB: n=123; vehicle: n=50). Endpoints included ≥2-grade reduction from baseline in Evaluator’s Global Severity Score and clear/almost clear skin (treatment success), least-squares mean percent change from baseline in inflammatory/noninflammatory lesions, and treatment-emergent adverse events (TEAEs). Descriptive efficacy and safety data for five children aged 10-11 years enrolled in the study are also summarized (CAB: n=3; vehicle: n=2).&#x0D; Results: At week 12, 51.5% of CAB–treated participants aged ≥12 years achieved treatment success vs 24.9% with vehicle gel (P&lt;0.01). CAB treatment resulted in significant reductions of &gt;70% in inflammatory and noninflammatory lesion counts in adolescents (78.3% and 73.7%, respectively) vs vehicle (50.5% and 42.9%; P&lt;0.001, both). Most TEAEs were of mild-to-moderate severity, and the most common (&gt;3% in any treatment) treatment-related TEAE was application site pain. Less than 2.5% of participants withdrew due to AEs. For the 5 children aged &lt;12 years, all 3 treated with CAB achieved treatment success, with reductions in inflammatory/noninflammatory lesions ranging from 76%-100%; neither vehicle-treated participant achieved treatment success. Only one CAB–treated younger participant experienced TEAEs (application site pain/dryness, and erythema [all mild/moderate]) and none discontinued the study.&#x0D; Conclusions: In two pooled phase 3 studies, once-daily CAB gel—the first approved fixed-dose, triple-combination topical formulation for acne vulgaris—was well tolerated and efficacious in pediatric participants with moderate-to-severe acne, with over half achieving treatment success at week 12.&#x0D; Funding: Ortho Dermatologics

Early Acne Improvements With Fixed-Dose Clindamycin Phosphate 1.2%/ Adapalene 0.15%/Benzoyl Peroxide 3.1% Gel: What to Expect in the First 4 Weeks of Treatment

Background: Treatments with fast and substantial acne clearance are highly desirable. While a three-pronged approach may increase treatment efficacy versus monotherapy or dual-combination therapy, it is unknown if triple-combination provides more rapid improvement. CAB gel—clindamycin phosphate (clin) 1.2%/adapalene 0.15%/benzoyl peroxide (BPO) 3.1%—is the first fixed-dose, triple-combination acne topical. Since rapid/substantial acne improvements and fewer side effects can increase adherence, the efficacy and safety of CAB in the first 4 weeks of treatment was evaluated.&#x0D; Methods: In a phase 2 (N=741; NCT03170388) and two phase 3 (N=183; N=180; NCT04214639; NCT04214652), double-blind, 12-week studies, participants aged ≥9 years with moderate-to-severe acne were randomized to once-daily CAB or vehicle gel; the phase 2 study included 3 additional dyad arms: BPO/adapalene; clin/BPO; and clin/adapalene. Efficacy assessments included least-squares mean percent change from baseline in inflammatory and noninflammatory lesions. Cutaneous safety/ tolerability assessments were graded from 0=none to 3=severe. Post hoc analyses included percentages of participants with one-third and one-half acne lesion reductions.&#x0D; Results: At week 4, CAB led to ~55% reductions from baseline in inflammatory acne lesions in the ph2 and pooled ph3 studies, significantly greater than vehicle (~40%) and its 3 dyads (ph2 range: 44.2-47.6%; P&lt;0.05, all). The percentages of participants with one-third and one-half reductions of inflammatory lesions were significantly greater with CAB than vehicle and dyads (P&lt;0.05, all). Similar trends were observed for noninflammatory lesions, though reductions were less pronounced. As expected for retinoids, transient increases from baseline to week 2 in scaling, erythema, itching, burning, and stinging were observed for CAB, BPO/adapalene, and clin/adapalene, with mean scores ≤0.6 (1=mild); no trends in dyspigmentation were observed. Mean scores for all cutaneous assessments were highest for BPO/adapalene, indicating that adding a third product in the fixed-dose CAB gel formulation did not worsen tolerability.&#x0D; Conclusions: Acne lesion reductions were significantly greater with clin 1.2%/ adapalene 0.15%/BPO 3.1% gel versus its dyads and vehicle gel as early as week 4. More rapid efficacy with this first fixed-dose triple-combination acne product—coupled with its optimized formulation, once-daily dosing, and tolerability—may positively impact treatment adherence.&#x0D; Funding: Ortho Dermatologics.

Evaluation of resin infiltration for inhibiting initial caries progression: An in vitro study using Micro-Computed Tomographic analysis

ObjectiveTo evaluate the changes in lesion depth and mineral density of resin infiltration-treated white spot lesions against asimulated oral environment using thermal and acidic challenges in vitro. Materials and methodsTwo enamel slabs were prepared from each buccal surface of permanent human premolars, for a total of 56 slabs. Artificial white spot lesions were induced. One specimen was treated with resin infiltration, while the other was used as an untreated control. A micro-CT was used to assess the lesion depth and mineral density of each specimen. Subsequently, all specimens were subjected to 10,000 cycles of thermocycling and pH cycling for 10 days before being re-evaluated using the micro-CT. Lesion depth and mineral density were examined and compared between before and after aging procedures within each group by the paired sample t-test. The independent samples t-test was utilized to compare lesion depth progression and percentage change of mineral density between groups. ResultsAfter aging, there was both a significant lesion depth progression and a mineral loss in the control and resin infiltration groups. Mean lesion depth progression was 132.88 ± 4.18 µm for the control group and 52.31 ± 4.16 µm for resin infiltration group. Percentage mineral density loss as a percentage for the control and resin infiltration groups were 16.1 ± 0.64 % and 8.83 ± 0.30 %, respectively. The resin infiltration group demonstrated a significantly lower mean lesion depth progression and percentage changes in mineral loss compared to the control group. ConclusionsThe lesion depth and mineral density changes in the resin infiltrated-treated group were lower than untreated white spot lesions after aging procedures using thermal and acidic challenges. Clinical significanceResin infiltration is a promising approach to inhibit the progression of white spot lesions related to the initial stage of dental caries.

A Mixed-Methods Comparison of Interventions to Increase Advance Care Planning.

Although interventions can increase advance care planning (ACP) engagement, it remains unclear which interventions to choose in primary care settings. This study compares a passive intervention (mailed materials) to an interactive intervention (group visits) on participant ACP engagement and experiences. We used mixed methods to examine ACP engagement at baseline and six months following two ACP interventions. Eligible patients were randomized to receive mailed materials or participate in two ACP group visits. We administered the 4-item ACP Engagement survey (n = 110) and conducted interviews (n = 23). We compared mean scores and percent change in ACP engagement, analyzed interviews with directed content analysis to understand participants' ACP experiences, and integrated the findings based on mailed materials or group visits intervention. All participants demonstrated increased ACP engagement scores. At six months, group visit participants reported higher percent change in mean overall score compared with mailed materials participants (+8% vs +3%, P < .0001). Group visits participants reported that being prompted to think about end-of-life preferences, gaining knowledge about ACP, and understanding the value of completing ACP documentation influenced their ACP readiness. While both interventions encouraged patients to start considering and refining their end-of-life preferences, group visits made patients feel more knowledgeable about ACP, highlighted the importance of completing ACP documentation early, and sparked further ACP discussions with others. While primary care patients may benefit from mailed ACP materials, patients reported increased readiness after ACP group visits. Group visits emphasized the value of upstream preparation, ongoing conversations, and increased knowledge about ACP.

An evaluation of root resorption associated with the use of photobiomodulation during orthodontic treatment with clear aligners: a retrospective cohort pilot study.

To evaluate the change in tooth root volume using cone-beam computed tomography (CBCT) in a group of patients treated concurrently with clear aligners and an adjunctive photobiomodulation (PBM) device. This retrospective cohort pilot study included the records of 32 consecutively treated clear aligner patients (23 female, 9 male) from the private practice of one orthodontist. The PBM group (n = 16) used the device once per day for 5 minutes per arch and was compared with a matched control group (n = 16). A semiautomated segmentation technique was used to obtain tooth volume of anterior teeth from CBCT imaging prior to (T0) and during or immediately following (T1) orthodontic treatment with clear aligners. The change in root volume between time points was assessed. There was no statistically significant difference between the pre- and posttreatment root volumes of maxillary and mandibular anterior teeth, regardless of which intervention group the patient belonged to (P > .05). There was also no difference in the mean percentage change in root volume between clear aligner patients in this study who were treated with the PBM device compared with a matched control group (P > .05). Clear aligner patients in this study who changed their aligners every 3 to 5 days and used adjunctive photobiomodulation therapy did not experience clinically relevant orthodontically induced external root resorption. Due to the small sample size and measurement error in the root segmentation process, the results should be interpreted with caution.

Combination Treatment with Verinurad and Allopurinol in CKD: A Randomized Placebo and Active Controlled Trial.

Key Points The SAPPHIRE trial was designed to assess albuminuria-lowering effects of the urate transporter 1 inhibitor verinurad combined with allopurinol in patients with CKD.Verinurad 3, 7.5, and 12 mg in combination with allopurinol 300 mg did not reduce albuminuria during 34 weeks treatment compared with allopurinol alone or placebo.Verinurad/allopurinol combination dose-dependently reduced serum urate concentrations compared with placebo. Background Hyperuricemia is associated with elevated risks of cardiovascular and chronic kidney disease (CKD). Since inhibition of urate transporter 1 has been suggested to be potentially nephroprotective, we performed a phase 2b study to assess albuminuria-lowering effects of the urate transporter 1 inhibitor verinurad combined with the xanthine oxidase inhibitor allopurinol in patients with CKD and hyperuricemia. Methods In this randomized placebo and active controlled trial, we enrolled participants with serum urate concentrations ≥6.0 mg/dl, eGFR ≥25 ml/min per 1.73 m2, and a urinary albumin-creatinine ratio (UACR) 30–5000 mg/g to one of five treatment arms: placebo, placebo+allopurinol 300 mg/day, verinurad 3 mg+allopurinol 300 mg/day, verinurad 7.5 mg+allopurinol 300 mg/day, or verinurad 12 mg+allopurinol 300 mg/day in a 1:1:1:1:1 ratio. The primary end point was the change in UACR from baseline to 34 weeks. Secondary end points were changes from baseline in UACR at week 60 and changes in serum urate and eGFR at weeks 34 and 60. Results Between August 2019 and November 2021, 861 adults with CKD (mean age 65 years, 33.0% female, mean eGFR 48 ml/min per 1.73 m2, median UACR 217 mg/g) were enrolled. At 34 weeks, the geometric mean percentage change in UACR from baseline did not differ among treatment groups (16.7%, 95% confidence interval [CI], −0.6 to 37.1 in the 3 mg group, 15.0% [95% CI, −1.85 to 34.6] in the 7.5 mg group, 14.0% [95% CI, −3.4 to 34.4] in the 12 mg group versus 9.9% [95% CI, −6.6 to 29.4] in the allopurinol group, and 37.3% [95% CI, 16.6 to 61.8] in the placebo group). UACR and eGFR change from baseline did not differ among treatment groups after 60 weeks. Verinurad/allopurinol combination dose-dependently reduced serum urate concentrations compared with placebo. The proportion of patients with adverse events and serious adverse events was balanced among treatment groups. Conclusions Verinurad in combination with allopurinol did not decrease UACR or eGFR decline, but further reduced serum urate compared with allopurinol alone or placebo. Clinical Trial registry name and registration number: SAPPHIRE Trial registration number, NCT03990363.

The Prostate Cancer Active Lifestyle Study (PALS): A randomized controlled trial of diet and exercise in overweight and obese men on active surveillance.

Active surveillance (AS) is increasingly used to monitor patients with lower risk prostate cancer (PCa). The Prostate Cancer Active Lifestyle Study (PALS) was a randomized controlled trial to determine whether weight loss improves obesity biomarkers on the causal pathway to progression in patients with PCa on AS. Overweight/obese men (body mass index >25kg/m2) diagnosed with PCa who elected AS were recruited. The intervention was a 6-month, individually delivered, structured diet and exercise program adapted from the Diabetes Prevention Program with a 7% weight loss goal from baseline. Control participants attended one session reviewing the US Dietary and Physical Activity Guidelines. The primary outcome was change in glucose regulation from baseline to the end of the 6-month intervention, which was measured by fasting plasma glucose, C-peptide, insulin, insulin-like growth factor 1, insulin-like growth factor binding protein-3, adiponectin, and homeostatic model assessment for insulin resistance. Among 117 men who were randomized, 100 completed the trial. The mean percentage weight loss was 7.1% and 1.8% in the intervention and control arms, respectively (adjusted between-group mean difference, -6.0kg; 95% confidence interval, -8.0, -4.0). Mean percentage changes from baseline for insulin, C-peptide, and homeostatic model assessment for insulin resistance in the intervention arm were -23%, -16%, and -25%, respectively, compared with +6.9%, +7.5%, and +6.4%, respectively, in the control arm (all p for intervention effects ≤ .003). No significant between-arm differences were detected for the other biomarkers. Overweight/obese men with PCa undergoing AS who participated in a lifestyle-based weight loss intervention successfully met weight loss goals with this reproducible lifestyle intervention and experienced improvements in glucose-regulation biomarkers associated with PCa progression.

Dupliumab therapy for alopecia areata: a case series and review of the literature

Background A growing body of research supports the important role of the TH2 axis in alopecia areata (AA). Dupilumab is a humanized monoclonal antibody against IL-4Rα that downregulates TH2 response. Although efficacy has been shown in clinical trials, real-world data on the use of dupilumab in AA patients is limited. Objectives To report on a case series of 10 patients with AA who were treated with dupilumab and provide real-world evidence regarding its efficacy in treating severe AA. Methods In this retrospective single-center study, all AA patients treated with dupilumab treatment were included between May 2022 and October 2023. Clinical outcome measures (Severity of Alopecia Tool, SALT) and adverse events (AEs) were analyzed. In addition, a literature review was conducted to summarize the efficacy of AA with dupilumab and the characteristics of patients previously reported in the literature. Results We identified 10 patients with AA who were or are being treated with dupilumab, with a median (range) treatment duration of 8 (3-15) months. Of these, four patients have high serum immunoglobulin E (IgE) levels (≥200IU/ml). The mean (IQR) pretreatment SALT score was 79% (52-100). Seven of 10 patients achieved at least 50% re-growth. Of those who improved, the mean (IQR) percentage change in SALT score at 3 months and the end of follow-up was 57% (29%-89%) and 95% (68-100), respectively. Notably, seven patients (70%) had white hair regrowth, with the white hair slowly decreasing over time and the proportion of pigmented black hair increasing. Dupilumab was well tolerated by all patients. No adverse events were reported. Conclusions Overall, our research supports dupilumab as another candidate that possesses potential benefits for AA. High levels of IgE may be not prerequisites for dupilumab’s successful treatment response.

Efficacy and safety of stapokibart (CM310) in uncontrolled seasonal allergic rhinitis (MERAK): an investigator-initiated, placebo-controlled, randomised, double-blind, phase 2 trial

There is no trial to assess the benefits of periodically using biologics during the pollen season in patients with uncontrolled seasonal allergic rhinitis (SAR), who have moderate-to-severe symptoms even after standard-of-care. This trial aimed to evaluate the efficacy and safety of the add-on administration of stapokibart, a humanised monoclonal antibody that targets interleukin-4 receptor alpha, in patients with uncontrolled SAR. In this investigator-initiated, randomised, double-blind, placebo-controlled trial, eligible patients received either stapokibart 600-300mg weekly (QW), every 2 weeks (Q2W), or placebo QW for 4 weeks. All patients were given mometasone furoate nasal spray and loratadine throughout the trial. The primary endpoint was the mean change from baseline in daily reflective total nasal symptom score (rTNSS) during 2-week treatment. Secondary efficacy outcomes included: the mean change from baseline in daily rTNSS during 4-week treatment; the mean changes and the mean percentage changes from baseline during 2-week and 4-week treatment in 1) daily rTNSS and reflective total ocular symptom score (rTOSS), 2) morning (AM)/evening (PM) rTNSS and rTOSS, 3) AM instantaneous total nasal symptom score (iTNSS) and instantaneous total ocular symptom score (iTOSS), 4) individual nasal and ocular symptoms; the change from baseline in Rhinoconjunctivitis Quality of-Life Questionnaire score during 4-week treatment. Exploratory endpoints included the change of prespecified markers related to type 2 inflammation pre- and post-treatment. Safety, immunogenicity, and pharmacokinetics were also evaluated. This study is registered with www.clinicaltrials.gov (NCT05470647). Between August 17, 2022, and December 28, 2022, 92 patients with uncontrolled SAR were enrolled from 4 centres in China and randomly assigned to receive stapokibart 600-300mg QW (n=31), stapokibart 600-300mg Q2W (n=30), or placebo QW (n=31), of whom 86 (93%) completed the study. Both stapokibart Q2W and QW did not significantly improve mean change from baseline in daily rTNSS compared with placebo in 2 weeks. The least-squares (LS) mean differences (97.5% confidence interval [CI]) compared with placebo were-1.0 (-2.3, 0.2) in stapokibart Q2W group (p=0.065) and-0.2 (-1.5, 1.0) in stapokibart QW group (p=0.67). For the secondary outcomes, compared with placebo, stapokibart Q2W presented significant improvements in the mean percentage change from baseline in daily rTNSS in 2 weeks (LS mean difference-12.9%, 95% CI-25.3%,-0.4%, p=0.043), as well as AM iTNSS over 2 weeks (LS mean difference-17.4%, 95% CI-31.0%,-3.8%, p=0.013) and 4 weeks (LS mean difference-15.4%, 95% CI-29.0%,-1.9%, p=0.026). Additionally, the nasal congestion score was significantly lower in stapokibart Q2W than placebo during 2-week (LS mean difference-0.4, 95% CI-0.7,-0.1, p=0.014) and 4-week (LS mean difference-0.4, 95% CI-0.7,-0.04, p=0.028) treatment. Treatment-emergent adverse events (TEAEs) occurred in 48% (15/31), 33% (10/30), and 61% (19/31) of patients receiving stapokibart QW, Q2W, and placebo, respectively. Most reported TEAEs were sinus bradycardia, hyperlipidaemia, and blood uric acid increased. In this phase 2 trial, both stapokibart regimens had an acceptable safety and tolerability profile but did not significantly improve daily rTNSS in patients with uncontrolled SAR. The efficacy of stapokibart in patients with uncontrolled SAR is being further investigated in ongoing phase 3 trials (clinicaltrials.gov, NCT05908032). Ministry of Science and Technology of the People's Republic of China; Ministry of Education of the People's Republic of China; National Natural Science Foundation of China; Chinese Academy of Medical Sciences.

CRISPR-Cas9 In Vivo Gene Editing of KLKB1 for Hereditary Angioedema

BackgroundHereditary angioedema is a rare genetic disease that leads to severe and unpredictable swelling attacks. NTLA-2002 is an in vivo gene-editing therapy based on clustered regularly interspaced short palindromic repeats (CRISPR)–CRISPR-associated protein 9. NTLA-2002 targets the gene encoding kallikrein B1 (KLKB1), with the goal of lifelong control of angioedema attacks after a single dose.MethodsIn this phase 1 dose-escalation portion of a combined phase 1–2 trial of NTLA-2002 in adults with hereditary angioedema, we administered NTLA-2002 at a single dose of 25 mg, 50 mg, or 75 mg. The primary end points were the safety and side-effect profile of NTLA-2002 therapy. Secondary and exploratory end points included pharmacokinetics, pharmacodynamics, and clinical efficacy determined on the basis of investigator-confirmed angioedema attacks.ResultsThree patients received 25 mg of NTLA-2002, four received 50 mg, and three received 75 mg. At all dose levels, the most common adverse events were infusion-related reactions and fatigue. No dose-limiting toxic effects, serious adverse events, grade 3 or higher adverse events, or clinically important laboratory findings were observed after the administration of NTLA-2002. Dose-dependent reductions in the total plasma kallikrein protein level were observed between baseline and the latest assessment, with a mean percentage change of −67% in the 25-mg group, −84% in the 50-mg group, and −95% in the 75-mg group. The mean percentage change in the number of angioedema attacks per month between baseline and weeks 1 through 16 (primary observation period) was −91% in the 25-mg group, −97% in the 50-mg group, and −80% in the 75-mg group. Among all the patients, the mean percentage change in the number of angioedema attacks per month from baseline through the latest assessment was −95%.ConclusionsIn this small study, a single dose of NTLA-2002 led to robust, dose-dependent, and durable reductions in total plasma kallikrein levels, and no severe adverse events were observed. In exploratory analyses, reductions in the number of angioedema attacks per month were observed at all dose levels. (Funded by Intellia Therapeutics; ClinicalTrials.gov number, NCT05120830.)

Enhanced future vegetation growth with elevated carbon dioxide concentrations could increase fire activity

Many regions of the planet have experienced an increase in fire activity in recent decades. Although such increases are consistent with warming and drying under continued climate change, the driving mechanisms remain uncertain. Here, we investigate the effects of increasing atmospheric carbon dioxide concentrations on future fire activity using seven Earth system models. Centered on the time of carbon dioxide doubling, the multi-model mean percent change in fire carbon emissions is 66.4 ± 38.8% (versus 1850 carbon dioxide concentrations, under fixed 1850 land-use conditions). A substantial increase is associated with enhanced vegetation growth due to carbon dioxide biogeochemical impacts at 60.1 ± 46.9%. In contrast, carbon dioxide radiative impacts, including warming and drying, yield a negligible response of fire carbon emissions at 1.7 ± 9.4%. Although model representation of fire processes remains uncertain, our results show the importance of vegetation dynamics to future increases in fire activity under increasing carbon dioxide, with potentially important policy implications.

P683 Economic impact of achieving mucosal healing on UC-related hospitalisations and work productivity in patients with moderately to severely active UC: A post-hoc analysis of risankizumab Phase 2b/3 trials

Abstract Background The value of endoscopic-histologic healing is incompletely understood, and definitions are variable. We assessed the clinical and economic value of achieving mucosal healing in patients with ulcerative colitis (UC) by evaluating the relationship of histologic-endoscopic mucosal improvement (HEMI) and subsequent UC-related hospitalisation and work productivity, and associated costs in the United States (US); United Kingdom (UK); and France, Germany, Italy, and Spain (EU4). Methods Data from the risankizumab (RZB) INSPIRE induction (NCT03398148) and COMMAND maintenance (NCT03398135) studies were analysed. The number of UC-related hospitalisations was compared in patients who achieved HEMI or no HEMI using a chi-square test. The mean percent changes in Work Productivity and Activity Impairment (WPAI)-UC domains from baseline to induction week 12 and maintenance week 52 were compared in patients who achieved HEMI or no HEMI using analysis of variance test. Hospitalisation and work productivity differences during induction and maintenance were converted to annualised costs based on average earnings and hospitalisation cost inputs from US, UK, and EU4. Results UC-related hospitalisations were significantly lower in patients who achieved HEMI at induction week 12 than those who did not (0% vs 2.9%, p≤0.05). A similar result was found at maintenance week 52, but the difference was not significant. In patients who achieved HEMI vs no HEMI, a greater mean change in activity impairment, impairment while working, and overall work impairment from baseline to induction week 12 was observed (p≤0.001). Improvements were sustained at maintenance week 52 for patients who achieved HEMI vs those who did not. Estimated annualised cost benefits from maintenance data for UC-related hospitalisations in patients who achieved HEMI was $490 in the US, £29 in the UK, and €28–€58 in EU4. Greater monetised benefits accrued from work productivity gains, where estimated annualised cost savings were $5,085 in the US, £3,507 in the UK, and €3,240–€4,456 in EU4. Conclusion These findings demonstrate that patients treated with RZB who achieved HEMI had fewer UC-related hospitalisations and greater improvement in work productivity and ability to perform daily activities than those who did not, which results in moderate direct cost savings and substantial indirect cost savings to healthcare systems in the US, UK, and EU4.

Contribution of neoadjuvant chemotherapy and radiation therapy (intensity-modulated radiation therapy with concurrent chemotherapy versus stereotactic body radiation therapy alone) on tumor volume regression in patients with borderline resectable or locally advanced pancreatic ductal adenocarcinoma: A single institution experience.

707 Background: Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis with a minority of patients (pts) eligible for curative resection. Pts with borderline resectable or locally advanced (BR/LA) PDAC frequently receive neoadjuvant chemotherapy (NAC) +/- radiation therapy (RT) to improve resectability. Here, we report the individual contribution of NAC and RT (either intensity modulated RT + concurrent chemotherapy (IMRT+CC) or stereotactic body RT (SBRT) alone) on tumor regression by measuring tumor volumes. Methods: We performed a single institution retrospective review of PDAC pts who underwent resection between 2011-2021 and were part of a tumor biobank registry. Tumor measurements were performed at baseline, post-NAC, and post-RT by five independent, blinded abdominal radiologists. Analyses were performed using paired t-tests, two-proportion z-tests, log-rank tests, and Mann-Whitney U test. Results: We identified 49 BR/LA pts who received NAC followed by RT who had complete pre- and post-treatment imaging. Fifteen pts received IMRT+CC and 28 received SBRT. The effect of NAC on tumor volumes (-29.2% vs -26.3%, p=0.66; mean percent change) and maximum diameter (-9.2% vs -12.0%, p=0.58) was similar within the IMRT+CC and SBRT groups. Both IMRT+CC (-7.12 cm3, p=0.003) and SBRT (-2.70 cm3, p=0.001) resulted in significant tumor regressions. IMRT+CC achieved a significantly greater overall mean percent change in tumor volume (-53.4% vs -28.8%, p=0.024) and maximum diameter (-30.4% vs -16.2%, p=0.020) compared to SBRT. Pts receiving IMRT+CC or SBRT had similar tumor volumes (10.88 vs 11.74 cm3, p=0.87, respectively) and maximum diameter (3.45 vs 3.17 cm, p=0.48) prior to RT. IMRT+CC resulted in improved tumor volume response (&gt;30% regression; 80.0% vs 46.4%; p=0.033) but not an improved response rate by RECIST criteria (46.7% vs 21.4%; p=0.085). Mean resected tumor volumes (by pathological review) for those receiving IMRT+CC (n=9) and SBRT (n=23) were 4.34 vs 13.1 cm3 (p=0.049). The R0 (86.7% vs 85.7%, p=0.93) and N0 (73.3% vs 53.6%, p=0.21) resection rates between the two groups were similar. Compared to SBRT, IMRT+CC resulted in an improved recurrence free survival (RFS; 2.36 vs 1.31 years; p=0.026), but did not meet statistical significance for an overall survival benefit (mOS; 2.85 vs 2.03 years, p=0.19). Conclusions: We found that IMRT+CC yielded superior radiographic volumetric regression and improved RFS but did not significantly impact mOS. Correspondingly, resected tumors from patients treated with IMRT+CC were smaller than those obtained from patients treated with SBRT. The role of IMRT+CC and SBRT in PDAC remains to be clearly defined.

Analysis of projected climate change in sorghum growing semi-arid rift valley of Ethiopia

Global warming projected to have a significant impact on agricultural water availability for crops in Africa in particularly in Ethiopia. Therefore, the study was conducted to analyze the projected change of temperature and rainfall in sorghum growing semi-arid rift valley of Ethiopia. The weather data for 11 stations were generated using AgiMP5 technique for RCP 4.5 and 8.5 and for the period of 2050s and 2080s. MAKESENS employed for the detection of trend of extreme indices. InStat v3.37 were used for the analysis of start, end, and length of growth season. Under RCP 4.5, the projected mean annual minimum air temperatures in CRV, ERVE and NRVE could increase respectively by 1.9 °C (2050s) and 2.6 °C (2080s), 1.8 °C (2050s) and 2.5 °C (2080s) and 1.88 °C (2050s) and 2.69 °C (2080s). Under RCP 8.5, however, with same location it will projected to increase in both time frames (2050s and 2080s) in all studied sites. The mean annual maximum air temperature, projected under RCP 4.5 in the CRV, ERV and NRVE will increase by 1.59 °C (2050s) and 2.18°C (2080s),1.42 °C (2050s) and 2.08 °C (2080s) and 1.46 °C (2050s) and 2.09 °C (2080s) respectively. However, under the RCP 8.5, at same regions it projected to rise in both periods (2050s and 2080s). This will be convoy with increase of the hot and cold extremes’ indices in regions. The mean percentage change of annual rainfall is projected to decrease insignificantly in (0.6-5.5% and 2.6%) and increase (0.85-12.3% and 22.3%) in half of the stations located in CRV and ERVE, whereas, in NRVE it will projected to increase (6.1-14.6%) under RCP 4.5 in all stations in 2050s. Though the annual projected rainfall under RCP 4.5 in 2080s will decline in range of 2.1-10.1%, 3.12-4.5% and 0.9-4.6% at CRV, ERVE and NRVE respectively. In most of the location in CRV and ERVE stations growing season rainfall will projected to decline from 1.45% to 53.8% and 0.8 to 8.8%, whereas, in NRVE it will projected to increase in 9.2 to 19% under RCP 4.5 in period of 2050. The projected SOS will be changed in mixed pattern, whereas and LGP will prolonged in most locations. The findings indicated that there has been a change of projected climate change in semi-arid RV, which will be alter the agricultural practices in depletion of soil moisture. Therefore, in adjusting planting timing and using early/medium maturation sorghum varieties, may be necessary for farmers in the region. Soil and water management needs attention.