Run-in Period Research Articles

A phase 2 study of EIK1001, a Toll-like receptor 7/8 (TLR7/8) agonist, in combination with pembrolizumab and chemotherapy in patients with stage 4 non-small cell lung cancer.

TPS8667 Background: Immune checkpoint inhibitors (ICIs) relieve immunosuppression of tumor-reactive T cells and enhance antitumor immune response. Significant advances for the treatment of non-small cell lung cancer (NSCLC) have been made using the ICI pembrolizumab in combination with chemotherapy, which confers significant clinical benefit relative to chemotherapy and placebo. Not all patients benefit, however, and some become refractory. As a result, there remains a critical unmet need to develop therapies for the treatment of NSCLC. EIK1001 is a TLR7/8 agonist that stimulates myeloid and plasmacytoid dendritic cells, activating immune and inflammatory responses. This dual activity provides another pathway, distinct from effects on checkpoint proteins, to enhance antitumor T-cell activity alone or in combination with ICIs. Methods: Study EIK1001-005 is a multicenter, Phase 2, open-label study of EIK1001 in combination with pembrolizumab and chemotherapy – carboplatin plus either pemetrexed or paclitaxel – in participants (pts) with histologically confirmed Stage 4 nonsquamous or squamous NSCLC, respectively. This study includes a safety run-in period for pts enrolled in each NSCLC cohort. If < 2 dose-limiting toxicities occur, an expansion phase for each NSCLC cohort will be conducted at the target dose to evaluate the tolerability and efficacy of EIK1001 (QW) in combination with pembrolizumab and chemotherapy (administered Q3W per label). Key eligibility criteria include pts ≥ 18 years of age with a life expectancy of at least 3 months, histologically or cytologically confirmed Stage 4 NSCLC (nonsquamous or squamous) without prior therapy for advanced NSCLC, confirmation that mutation-directed therapy is not indicated as first-line, and at least 1 measurable lesion at Baseline according to RECIST 1.1. The primary objective of this study is to determine the safety and tolerability of EIK1001 in combination with pembrolizumab and chemotherapy. The secondary objectives are evaluation of antitumor activity by objective response rate (ORR; defined as the proportion of pts who have a confirmed complete response [CR] or partial response [PR] per RECIST 1.1) and duration of response (DOR) by RECIST 1.1. Other exploratory objectives include evaluation of anti-tumor activity (ORR/DOR) by immune-related RECIST 1.1, overall survival, progression-free survival, investigation of the relationship between treatment with EIK1001 in combination with pembrolizumab/chemotherapy and biomarkers predictive of response, and the pharmacokinetic parameters of EIK1001. This study opened on 29 Jan 2024. Clinical trial information: NCT06246110 .

Cadonilimab plus lenvatinib in patients with advanced endometrial cancer: A multicenter, single-arm, phase II trial.

5600 Background: Lenvatinib plus pembrolizumab is the standard treatment for patients with advanced endometrial cancer with mismatch repair-proficient (pMMR) disease who had disease progression after the receipt of prior systemic platinum-based therapy. Cadonilimab is a PD-1/CTLA-4 bi-specific antibody. We aimed to assess the combination of cadonilimab and lenvatinib in patients with advanced endometrial cancer who had previously received at least one platinum-based chemotherapy. Methods: In this phase II study with a safety-run in, eligible patients were aged 18 years or older with advanced endometrial cancer of any histologic subtype, except sarcoma, progressed after at least one prior platinum-based chemotherapy, had an Eastern Cooperative Oncology Group performance status of 0 or 1. In the safety run-in period, a 3+3 dose de-escalation design was used to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of lenvatinib (16 mg or 12 mg once daily) combined with cadonilimab 10 mg/kg every 3 weeks. After the completion of safety run-in period, the phase II cohort at the RP2D will open. Approximately 29 patients are planned to receive treatment at the RP2D. The primary endpoint was objective response rate (ORR) at the RP2D. Key secondary endpoints included disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Results: Between 8 May 2023 and 18 December 2023, 24 patients were enrolled. As of 31 December 2023, enrollment was ongoing. No DLTs were observed during the safety run-in period. The RP2D of lenvatinib is 16 mg once daily. Among 21 efficacy-evaluable patients, the ORR was 52.4% (95% CI: 29.1–75.7), and the DCR was 90.5% (95% CI: 69.6–98.8). The Medians for DOR, PFS, and OS were not reached. Grade 3–4 treatment-related adverse events included increased ALT (2 [8.3%]), increased AST (1 [4.2%]), increased creatine phosphokinase (1 [4.2%]), hypertension (1 [4.2%]), and intestinal perforation (1 [4.2%]). Conclusions: Cadonilimab plus lenvatinib showed promising antitumor activity in patients with advanced endometrial cancer who have experienced disease progression after prior systemic platinum-based therapy. The combination therapy had a favorable and manageable safety profile. Clinical trial information: NCT05824481 . [Table: see text]

Short-course radiotherapy (SCRT) followed by fruquintinib plus adebrelimab and CAPOX in the total neoadjuvant therapy of locally advanced rectal cancer (LARC): A multicenter, single-arm, open-label, phase II study.

TPS3643 Background: For LARC patients (pts), long-course concurrent chemoradiotherapy or SCRT followed by chemotherapy is recommended by the NCCN guidelines (Version 1.2024) as neoadjuvant therapy. Compared with chemoradiotherapy, the addition of immune checkpoint inhibitors (ICIs) or anti-angiogenic drugs could further improve complete response (CR) rate in the neoadjuvant treatment of LARC. Fruquintinib, a highly selective small-molecule inhibitor of VEGFR-1, -2, and -3, has gained FDA approval for pts with metastatic colorectal cancer previously treated. For pts with LARC at high risk of recurrence, the CR rate of SCRT followed by chemotherapy was 29%. There is an urgent need for new therapeutical options to improve the CR rate in these pts. This study introduces an innovative approach, combining SCRT, chemotherapy, Fruquintinib, and ICIs as a total neoadjuvant therapy for high-risk LARC pts. Methods: This is a multicenter, single-arm, open-label, phase II study (NCT06234007) investigating the efficacy and safety of SCRT sequential fruquintinib, combined with adebrelimab (an anti-PD-L1 monoclonal antibody) and CAPOX in pts with LARC. Eligible participants were 18 years or older, with an ECOG PS of 0–1, and a biopsy-proven, newly diagnosed, primary, LARC, classified as high risk on pelvic MRI (with at least one of the following criteria: clinical tumour [cT] stage cT4a or cT4b, extramural vascular invasion, clinical nodal [cN] stage cN2, involved mesorectal fascia, or enlarged lateral lymph nodes), were mentally and physically fit for surgery. Total neoadjuvant therapy included SCRT (5 × 5 Gy over 5 days, 1-week rest) followed by six cycles of fruquintinib (4mg, qd, po, q3w. For the initial 6 pts in the safety run-in period, dosage was adjusted based on dose-limited toxicities in the 1st cycle) combined with adebrelimab (1200mg, iv, d1, q3w) and CAPOX (q3w). Subsequently, pts who did not reach clinical CR underwent total mesorectal excision, others received the “Watch and Wait” policy or surgery. Primary endpoint was CR rate (including clinical CR & pathologic CR). Secondary endpoints included 3-year event free survival rate, overall survival, R0 resection rate and adverse events (AEs). Exploratory endpoints aimed to evaluate the correlation between potential biomarkers and efficacy. Using PASS 15 software (version 15.0.5.0), in the Tests for One Proportion analysis, with a two-sided α of 5% and to guarantee the power over 80%. The null hypothesis of CR rate was 29%, and the alternative hypothesis was 51%, accounting for a 10% drop-out rate, resulting in a sample size of 39 pts. With the 6 pts in the safety run-in period, a total of 45 pts would be enrolled in the study. Until Feb 1, 2024, 7 of planned 45 pts have been enrolled. Clinical trial information: NCT06234007 .

Spawning run estimates and phenology for an extremely small population of Atlantic Sturgeon in the Marshyhope Creek–Nanticoke River system, Chesapeake Bay

AbstractObjectiveOnce thought to be extirpated from the Chesapeake Bay, fall spawning runs of Atlantic Sturgeon Acipenser oxyrinchus have been rediscovered in the Marshyhope Creek (MC)–Nanticoke River (NR) system of Maryland, United States. High recapture rates in past telemetry surveys suggested a small population in the two connected tributaries. This study aims to generate estimates of abundance and understand within system connectivity for spawning runs in 2020 and 2021.MethodsData from mobile side‐scan sonar surveys and detections of acoustically tagged adults on stationary telemetry receivers were analyzed in an integrated model to estimate spawning season abundance and examine run timing and system connectivity for this population. An array of acoustic receivers was deployed throughout the MC–NR system to monitor the movement of tagged fish during the spawning run period from mid‐August to late October. Side‐scan sonar surveys were conducted weekly in September in an area of high spawner aggregation to generate count data on spawning run abundance.ResultIn 2020 and 2021, 32 (95% credible interval [CRI] = 23–47) and 70 (95% CRI = 49–105) Atlantic Sturgeon, respectively, used the MC–NR system. The lower estimate for 2020 coincided with an earlier end to the spawning run related to cooler September temperatures in that year.ConclusionIn both years, high spawning run connectivity between MC and the upper NR was observed. Overall, run estimates supported previous hypotheses that the MC–NR system supports a very small population and that both MC and the upper NR serve as important areas for spawning activity.

Running-in Period During Sliding Wear of Austenitic Steels

The running-in period during dry sliding wear might determine the evolution to steady-state wear behaviour. To this end, the running-in period during sliding wear of austenitic stainless steel, AISI 316L stainless steel, and Hadfield steel were studied through the testing pin (flat-ended)-on-disk configuration. The effects of the normal load, sliding speed, and alloy type were assessed, and the specific wear rate and strain hardening characteristics were determined. The wear rate was correlated with wear mechanism, friction coefficient, hardening, and roughness to characterize the changes occurring during the running-in period. These changes could influence the responses of these materials to wear during the steady-state period. The stabilization of the specific wear rate and hardness was noted to align with the end of the running-in period.Graphical

D.1 Efficacy, safety, and tolerability of subcutaneous efgartigimod in chronic inflammatory demyelinating polyneuropathy: results from the ADHERE trial

Background: Efgartigimod, a human immunoglobulin G (IgG)1 antibody Fc fragment, blocks the neonatal Fc receptor, decreasing IgG recycling and reducing pathogenic IgG autoantibody levels. ADHERE assessed the efficacy and safety of efgartigimod PH20 subcutaneous (SC; co-formulated with recombinant human hyaluronidase PH20) in chronic inflammatory demyelinating polyneuropathy (CIDP). Methods: ADHERE enrolled participants with CIDP (treatment naive or on standard treatments withdrawn during run-in period) and consisted of open-label Stage A (efgartigimod PH20 SC once weekly [QW]), and randomized (1:1) Stage B (efgartigimod or placebo QW). Primary outcomes were clinical improvement (assessed with aINCAT, I-RODS, or mean grip strength; Stage A) and time to first aINCAT score deterioration (relapse; Stage B). Secondary outcomes included treatment-emergent adverse events (TEAEs) incidence. Results: 322 participants entered Stage A. 214 (66.5%) were considered responders, randomized, and treated in Stage B. Efgartigimod significantly reduced the risk of relapse (HR: 0.394; 95% CI: 0.25–0.61) versus placebo (p=0.000039). Reduced risk of relapse occurred in participants receiving corticosteroids, intravenous or SC immunoglobulin, or no treatment before study entry. Most TEAEs were mild to moderate; 3 deaths occurred, none related to efgartigimod. Conclusions: Participants treated with efgartigimod PH20 SC maintained a clinical response and remained relapse-free longer than those treated with placebo.

Atrioventricular Interval Modulation (AVIM) therapy for ambulatory systolic blood pressure (aSBP) reduction with a dual chamber pacemaker: comparison of conduction system vs. right ventricular pacing

Abstract Background AVIM is a pacing algorithm incorporated into dual-chamber pacemakers to treat hypertension. AVIM delivers repeating sequences of short and longer atrioventricular delays leading to reduced preload and afterload. The therapy lowers blood pressure while simultaneously modulating the autonomic nervous system. The marked blood pressure reducing capability of AVIM has been already confirmed by a previous randomized clinical trial using conventional right ventricular (RV) pacing. Nevertheless, whether a similar blood pressure reduction could be also achieved by AVIM when conduction system pacing (CSP) is applied instead of RV pacing has not been investigated yet. Considering the facts that CSP using Left Bundle Branch Area Pacing (LBBAP) has been found to elicit more synchronous ventricular contraction and improved hemodynamics compared to RV pacing and AVIM is associated with a signficant burden of ventricular pacing, it is tempting to hypothesize that AVIM with CSP could be particularly beneficial. Purpose To compare the effects of AVIM therapy when delivered via an LBBAP location with the effects when delivered using a traditional RV lead location. Methods This single-center study evaluated subjects indicated for a dual chamber pacemaker who also had uncontrolled hypertension despite a stable dose of ³ 1 antihypertensive drug. Leads were placed in the RV or the LBBAP position. Subjects entered a run-in period of 4 weeks in which baseline office (oSBP)and 24-hour aSBP were measured. Subjects with baseline aSBP >130 mmHg and oSBP>140 mmHg at week 4 were included in the study. AVIM therapy was activated and a 24-hour aSBP was performed immediately after activation. Results Using a dedicated CSP pacemaker lab setup, CSP was performed in 5 patients with the Select Secure electrode (model 3830-69 cm) delivered via a fixed curve sheath (C315HIS). During the run in phase, in 3 out of the 5 CSP-AVIM patients, high blood pressure did not reach the level of inclusion and therefore these patients were not used for further analysis. In the remaining two patients, AVIM was activated. These two patients had a V6 stimulus-peak time of 69 ms and 61 ms, while V1 stimulus peak time was: 121ms and 109ms respectively. The effect of AVIM on 24-hour aSBP in the activated CSP-AVIM patients was compared to the average effect seen in patients from the same center enrolled in the prior randomized study with leads in the RV. Table 1 shows individual aSBP values for the two patient groups. Results suggest that delivery of AVIM therapy through leads in either position generates a significant reduction in blood pressure: -24.1 mmHg vs. -15.4 mmHg when the lead is placed in LBBAP or RV positions respectively. Conclusion These results demonstrate a significant reduction in aSBP in both lead locations. Additional studies evaluating larger sample sizes are required to assess if specific lead positions are preferable.Table 1

Effect of Ag content on the friction and wear properties of electrodeposited self-lubricating Ni–Ag coating

Thin film coatings are required to improve the performance of components to resist harsh environments as the modern industry grows. In this study, Ni–Ag coatings with various Ag content were deposited on the Cu surface using an electrodeposition technique. The Ni–Ag coatings were deposited to enhance the tribological properties of the coatings and increase the service life of the friction-sliding components. Ni–6wt%Ag, Ni–8wt%Ag, and Ni–10wt%Ag coatings were deposited. A solid solution of Ni–Ag was formed in the coatings. As the concentration of NiSO4 decreased in the electrolyte, the content of Ag in the coatings increased with the granular morphological characteristics. The increase in Ag content reduces the coefficient of friction (CoF) on comparing the initial running-in period and is stable after some time. The initial decrease was due to the surface roughness. The CoF and wear rate were low for all Ag contents compared to the copper substrate due to the effect of Ag solid lubricant material in prepared coatings.

Effect of Europium and Gadolinium Alloying Elements on the Tribological Response of Low Hydrogen Content Amorphous Carbon.

Dopants and alloying elements are commonly introduced in amorphous carbon (a-C) materials to tailor their mechanical and tribological properties. While most published studies have focused on doping and alloying a-C coatings with metals or metalloids, doping a-C films with rare-earth elements has only recently been explored. Notably, our understanding of the shear-induced structural changes occurring in rare-earth-element-containing a-C films is still elusive, even in the absence of any liquid lubricants. Here, the friction response of Eu- and Gd-containing a-C films with low hydrogen content deposited by HiPIMS on silicon was evaluated in open air and at room temperature. The load-dependent friction measurements indicated that the introduction of Gd ((2.3 ± 0.1) at.%) and Eu ((2.4 ± 0.1) at.%) into the a-C matrix results in a significant reduction of the shear strength of the sliding interfaces ((41 ± 2) MPa for a-C, (16 ± 1) MPa for a-C:Gd2.3at.%, and (11 ± 2) MPa for a-C:Eu2.4at.%). NEXAFS spectromicroscopy experiments provided evidence that no stress-assisted sp3-to-sp2 rehybridization of carbon atoms was induced by the sliding process in the near-surface region of undoped a-C, while the amount of sp2-bonded carbon progressively increased in a-C:Gd2.3at.% and a-C:Eu2.4at.% upon increasing the applied normal load in tribological tests. The formation of an sp2-bonded carbon-rich surface layer in a-C:Gd2.3at.% and a-C:Eu2.4at.% films was not only proposed to be the origin for the reduced duration of the running-in period in tribological test, but was also postulated to induce shear localization within the sp2-carbon-rich layer and transfer film formation on the countersurface, thus decreasing the interfacial shear strength. These findings open the path for the use of Gd- and Eu-containing a-C even under critical conditions for nearly hydrogen-free a-C films (i.e., humid air).

Efficacy and Safety of Bojungikgi-Tang for Persistent Allergic Rhinitis: A Randomized, Double-Blinded, Placebo-Controlled, Phase II Trial.

Conventional treatments for allergic rhinitis (AR) exhibit insufficiency and long-term use-related side effects. Considering the reported anti-inflammatory and immunoregulatory effects of Bojungikgi-tang (BJIGT), we aimed to assess its efficacy on persistent AR (PAR). Patients with PAR were randomly assigned in a 1:1:1 ratio into high-dose BJIGT, standard-dose BJIGT, and placebo groups, followed by 1-week run-in and 4-week treatment periods. The primary outcome included the mean change in Total Nasal Symptom Score (TNSS), with secondary outcomes encompassing the Korean Allergic Rhinitis-Specific Quality of Life Questionnaire, biomarkers, overall assessment, TNSS by AR pattern identification, and the Sasang constitution. The mean TNSS change was more improved in the BJIGT group than in the placebo group; however, no statistically significant differences were observed. Additional interaction effect analysis revealed a statistically significant improvement in the high-dose BJIGT group compared with the placebo group from weeks 1-2 to weeks 3-4. Regarding secondary outcomes, the BJIGT group exhibited similar or improved results compared with the placebo group, showing no statistically significant differences. No serious adverse effects or clinically significant changes in safety assessments were observed. Given that this study validated clinical improvement and safety, it serves as potential groundwork for pertinent future studies.

A sequential, multiple-assignment, randomized trial of analgesic strategies for acute musculoskeletal Pain

BackgroundMost methodologically rigorous, ED-based, comparative effectiveness analgesic studies completed in the last two decades failed to find a clinically important difference between the comparators. We believe that many of these comparative effectiveness studies were biased towards the null hypothesis because some ED patients with intense pain will respond to relatively mild interventions. We hypothesized that including a run-in period would alter the results of an acute pain RCT. MethodsWe conducted a sequential, multiple-assignment, randomized study. Adults with acute moderate/severe musculoskeletal pain were randomized (3:1 ratio) to run-in period or no run-in. We administered 650 mg acetaminophen to run-in participants. Those run-in patients who reported insufficient relief one-hour later were randomized (1:1 ratio) to ibuprofen 800mg PO or ketorolac 20mg PO as were all participants randomized to no run-in. The primary outcome was achieving a clinically important improvement, defined as improvement ≥1.3 on a 0–10 scale. We built a logistic regression model including run-in/no run-in, ketorolac/ibuprofen, age and sex. ResultsOf 307 participants who received acetaminophen, 100 (32.6%) reported inadequate relief and were randomized to an NSAID. Of the 100 patients randomized to no run-in, 84/100 (84%) achieved the primary outcome versus 246/287 (86%) run-in participants (95% CI for difference = 2%:−7,10%). Among run-in participants who received an NSAID, 82/99(83%) achieved the primary outcome versus 84/100(84%) no run-in participants (p = 0.82). Among all ibuprofen participants, 44/49(90%) randomized to run-in and 42/50(84%) randomized to no run-in achieved the primary outcome. Among all ketorolac participants, 38/50(76%) randomized to run-in and 42/50 (84%) randomized to no run-in achieved the primary outcome. We observed the following results in a multivariable analysis: OR for ketorolac versus ibuprofen:0.60 (95% CI: 0.28, 1.28); OR for run-in versus no run-in:0.91(95% CI: 0.43, 1.93). ConclusionsAmong patients with acute musculoskeletal pain, using an acetaminophen first strategy did not alter pain outcomes.

Effectiveness of an Artificial Intelligence-Assisted App for Improving Eating Behaviors: Mixed Methods Evaluation.

A plethora of weight management apps are available, but many individuals, especially those living with overweight and obesity, still struggle to achieve adequate weight loss. An emerging area in weight management is the support for one's self-regulation over momentary eating impulses. This study aims to examine the feasibility and effectiveness of a novel artificial intelligence-assisted weight management app in improving eating behaviors in a Southeast Asian cohort. A single-group pretest-posttest study was conducted. Participants completed the 1-week run-in period of a 12-week app-based weight management program called the Eating Trigger-Response Inhibition Program (eTRIP). This self-monitoring system was built upon 3 main components, namely, (1) chatbot-based check-ins on eating lapse triggers, (2) food-based computer vision image recognition (system built based on local food items), and (3) automated time-based nudges and meal stopwatch. At every mealtime, participants were prompted to take a picture of their food items, which were identified by a computer vision image recognition technology, thereby triggering a set of chatbot-initiated questions on eating triggers such as who the users were eating with. Paired 2-sided t tests were used to compare the differences in the psychobehavioral constructs before and after the 7-day program, including overeating habits, snacking habits, consideration of future consequences, self-regulation of eating behaviors, anxiety, depression, and physical activity. Qualitative feedback were analyzed by content analysis according to 4 steps, namely, decontextualization, recontextualization, categorization, and compilation. The mean age, self-reported BMI, and waist circumference of the participants were 31.25 (SD 9.98) years, 28.86 (SD 7.02) kg/m2, and 92.60 (SD 18.24) cm, respectively. There were significant improvements in all the 7 psychobehavioral constructs, except for anxiety. After adjusting for multiple comparisons, statistically significant improvements were found for overeating habits (mean -0.32, SD 1.16; P<.001), snacking habits (mean -0.22, SD 1.12; P<.002), self-regulation of eating behavior (mean 0.08, SD 0.49; P=.007), depression (mean -0.12, SD 0.74; P=.007), and physical activity (mean 1288.60, SD 3055.20 metabolic equivalent task-min/day; P<.001). Forty-one participants reported skipping at least 1 meal (ie, breakfast, lunch, or dinner), summing to 578 (67.1%) of the 862 meals skipped. Of the 230 participants, 80 (34.8%) provided textual feedback that indicated satisfactory user experience with eTRIP. Four themes emerged, namely, (1) becoming more mindful of self-monitoring, (2) personalized reminders with prompts and chatbot, (3) food logging with image recognition, and (4) engaging with a simple, easy, and appealing user interface. The attrition rate was 8.4% (21/251). eTRIP is a feasible and effective weight management program to be tested in a larger population for its effectiveness and sustainability as a personalized weight management program for people with overweight and obesity. ClinicalTrials.gov NCT04833803; https://classic.clinicaltrials.gov/ct2/show/NCT04833803.

The Efficacy and Tolerability of Irbesartan/Amlodipine Combination Therapy in Patients With Essential Hypertension Whose Blood Pressure Were not Controlled by Irbesartan Monotherapy

PurposeThis study aimed to evaluate the efficacy and tolerability of irbesartan (IRB) and amlodipine (AML) combination therapy in patients with essential hypertension whose blood pressure (BP) was not controlled by IRB monotherapy. MethodsTwo multicenter, randomized, double-blind, placebo-controlled, phase III studies were conducted in Korea (the I-DUO 301 study and the I-DUO 302 study). After a 4-week run-in period with either 150 mg IRB (I-DUO 301 study) or 300 mg IRB (I-DUO 302 study), patients with uncontrolled BP (ie, mean sitting systolic BP [MSSBP] ≥140 mmHg to <180 mmHg and mean sitting diastolic BP <110 mmHg) were randomized to the placebo, AML 5 mg, or AML 10 mg group. A total of 428 participants were enrolled in the 2 I-DUO studies. In the I-DUO 301 study, 271 participants were randomized in a 1:1:1 ratio to receive either IRB/AML 150/5 mg, IRB/AML 150/10 mg, or IRB 150 mg/placebo. In the I-DUO 302 study, 157 participants were randomized in a 1:1 ratio to receive IRB/AML 300/5 mg or IRB 300 mg/placebo. The primary endpoint was the change in MSSBP from baseline to week 8. Tolerability was assessed according to the development of treatment-emergent adverse events (TEAEs) and clinically significant changes in physical examination, laboratory tests, pulse, and 12-lead electrocardiography. FindingsIn I-DUO 301, the mean (SD) changes of MSSBP at week 8 from baseline were −14.78 (12.35) mmHg, −21.47 (12.78) mmHg, and −8.61 (12.19) mmHg in the IRB/AML 150/5 mg, IRB/AML 150/10 mg, and IRB 150 mg/placebo groups, respectively. In I-DUO 302, the mean (SD) changes of MSSBP at week 8 from baseline were −13.30 (12.47) mmHg and −7.19 (15.37) mmHg in the IRB/AML 300/5 mg and IRB 300 mg/placebo groups, respectively. In both studies, all combination groups showed a significantly higher reduction in MSSBP than the IRB monotherapy groups (P < 0.001 for both). TEAEs occurred in 10.00%, 10.99%, and 12.22% of participants in the IRB/AML 150/5 mg, IRB/AML 150/10 mg, and IRB 150 mg/placebo groups, respectively, in I-DUO 301 and in 6.33% and 10.67% of participants in the IRB/AML 300/5 mg and IRB 300 mg/placebo groups, respectively, in I-DUO 302, with no significant between-group differences. Overall, there was one serious adverse event throughout I-DUO study. ImplicationsThe combination of IRB and AML has superior antihypertensive effects compared with IRB alone over an 8-week treatment period, with placebo-like tolerability. Clinical Trial RegistrationClinicalTrials.gov identifier: NCT05476354 (I-DUO 301), NCT05475665 (I-DUO 302).

Abstract PS17-08: A Phase Ib Study to Evaluate the Efficacy and Safety of Afuresertib Plus Fulvestrant in Patients with Locally Advanced or Metastatic HR+/HER2- Breast Cancer Who Failed Standard of Care Therapies

Abstract Background The combination of an aromatase inhibitor with a CDK4/6 inhibitor is the mainstay of first-line endocrine therapy (ET) for locally advanced or metastatic HR+/HER2− breast cancer (LA/mBC). Management of recurrent disease in the post-CDK4/6 inhibitor setting includes additional lines of ET single agent or in combination with a targeted agent. For patients with HR+/HER2− LA/mBC tumors, fulvestrant monotherapy as the second- or third-line therapy has limited activity with a median PFS of 1.9-3.6 months. Effective targeted treatments for these patients are needed to maintain quality of life, improve survival, and delay the initiation of cytotoxic chemotherapy. Methods This ongoing single arm, open-label global study (NCT04851613) is to evaluate the efficacy and safety of the combination therapy of afuresertib (a pan-AKT inhibitor) plus fulvestrant in patients with HR+/HER2− LA/mBC. Eligible patients must have received 1-2 prior lines of ET. Patients may have prior treatment of CDK4/6 inhibitors (up to 1 therapy), and/or up to 1 line of chemotherapy. Patients received afuresertib (125 mg PO, QD) in combination with fulvestrant (500 mg IM; Day 1 and 15 in Cycle 1, and Day 1 in subsequent 28-day cycles). The safety of the initial treatment doses of the combination therapy was evaluated in the first 6 patients during the Cycle 1 safety run-in period. Radiographic assessment per RECIST 1.1 was performed every 8 weeks for the first 6 cycles and every 12 weeks thereafter. The primary endpoint was the investigator-assessed objective response rate (ORR). The secondary endpoints included safety and tolerability of the combination therapy and pharmacokinetic characterization. Results Twenty patients (1 male and 19 females, 3 in the US and 17 in China) were enrolled between May 2022 and April 2023. As of the data cut-off date of May 26th, 2023, 10 patients had discontinued the study treatment (9 due to disease progression, 1 due to patient’s withdrawal of consent) and 10 patients were still in treatment. Of the 19 patients who had at least one post-baseline tumor assessment, 4 patients observed confirmed Partial Response (cPR), 12 had best overall response of Stable Disease, and 3 had Progressive Disease (PD). The Disease Control Rate is 84%. Of the 15 patients who had at least 2 tumor assessments or who discontinued treatment early due to PD, the confirmed ORR is 26.7% (4 cPR). No dose modification was required during the safety run-in. The most common treatment-emergent adverse events (TEAEs, &amp;gt; 20% of patients) of all grades were hyperglycemia (50%), diarrhea (45%), ALT/AST increase (40%), nausea (35%), rash (35%), hypercholesterolemia (35%), and anemia (30%), the majority of which were Grade 1. Grade 3 AEs were reported in 4 patients, including diarrhea (1 patient), WBC increase (1 patient), creatine phosphokinase increase (1 patient), and ALT/AST increase and rash (1 patient). No SAE or TEAE &amp;gt;= Grade 4 were reported. No patient discontinued treatment due to TEAE. Conclusions The preliminary data from the combination therapy of afuresertib plus fulvestrant has shown promising efficacy with a well-tolerated safety profile in patients with HR+/HER2− LA/mBC who progressed on 1-2 prior lines of standard of care therapies. These results support further evaluation of this combination therapy in this patient population in an upcoming phase III study. Citation Format: Binghe Xu, Pin Zhang, Tao Sun, Ying Wang, Zhongsheng Tong, Sneha Phadke, Trevor Feinstein, Pengfei Guo, Jing Qu, Xiaoyu Wang. A Phase Ib Study to Evaluate the Efficacy and Safety of Afuresertib Plus Fulvestrant in Patients with Locally Advanced or Metastatic HR+/HER2- Breast Cancer Who Failed Standard of Care Therapies [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS17-08.

Bifenthrin Caused Parkinson's-Like Symptoms Via Mitochondrial Autophagy and Ferroptosis Pathway Stereoselectively in Parkin-/- Mice and C57BL/6 Mice.

It has been proposed that pyrethroid exposure contributes to the increasing prevalence of neurodegenerative diseases. However, the potential mechanisms remain unclear. The current study aimed to investigate the effects of the widely used pyrethroid bifenthrin on Parkinson's disease (PD) risk. Bifenthrin (1S-cis-bifenthrin, 1R-cis-bifenthrin, raceme) was administered to male Parkin-/- mice and C57BL/6 mice by oral gavage at a dose of 10mg/kg bw/day for 28days. Bifenthrin exposure significantly increased the time of pole climbing and decreased the period of rotarod running, indicating that bifenthrin decreased motor coordination in Parkin-/- mice, which was more evident by 1S-cis-bifenthrin. Furthermore, administration of bifenthrin induced obvious decreases in tyrosine hydroxylase (TH)+ cell count and the protein expression of TH. Increased protein of mitochondrial autophagy LC3B and p62 was observed after exposure to bifenthrin. Increased iron deposition and protein expression of iron transport transferrin (Tf) and transferrin receptor 2 (TfR2) was detected. 1S-cis-bifenthrin bound with Tf, TfR2, and GPX4 with lower binding energies than 1R-cis-bifenthrin, resulting in stronger interactions with these proteins. These results show structure-dependent PD-like effects of bifenthrin on motor activity and coordination associated with the disturbed mitochondrial autophagy and ferroptosis-related pathway. These data demonstrate that pyrethroid exposure increases the potential of Parkinson's-like symptoms via the ferroptosis pathway in Parkin-/- mice that is more pronounced than in C57BL/6 mice, providing a prospective enantioselective toxic effect of environmental neurotoxins on PD risk.

SINGLE-PILL COMBINATION OF THIRD-DOSE TRIPLE ANTIHYPERTENSIVE THERAPY VERSUS STANDARD-DOSE MONOTHERAPY IN PATIENTS WITH MILD TO MODERATE HYPERTENSION

Objective: The study compared the single-pill combination of third-dose triple antihypertensive therapy (amlodipine 1.67 mg, losartan potassium 16.67 mg, chlorthalidone 4.17 mg) with standard-dose monotherapy (amlodipine 5mg) in reducing systolic blood pressure (SBP) among patients with mild to moderate hypertension. Design and method: This was a multicenter, randomized, double-blind, active-controlled, parallel-group phase III noninferiority trial. Eligible participants aged &gt;=19 years with SBP &gt;=140 to &lt;180 mmHg and diastolic blood pressure (DBP) &lt;110 mmHg after 4 weeks placebo run-in period were randomized to either 8 weeks of combination therapy (ALC) or monotherapy (A5). The primary efficacy endpoint, noninferiority in SBP reduction, was assessed using the upper limit of the one-sided 97.5% confidence interval (97.5%CI) for the difference in SBP reduction between treatments at week 8, with a noninferiority margin of 3 mmHg. Results: The efficacy endpoint analysis included 167 and 166 in the ALC and A5 groups. After 8 weeks, the ALC and A5 groups showed SBP reductions of -18.3±11.9 and -19.4±12.5, respectively, and DBP reductions of -8.5±7.3 and -9.8±7.0 mmHg, respectively (p&gt;0.025 for both). The unadjusted least-square mean (LSM) difference in SBP reduction was 1.15 mmHg, with a 97.5%CI upper limit of 3.51 mmHg. More female patients were allocated to the A5 than the ALC groups (47.6% vs. 34.1%, p=0.012). Both treatments exhibited greater SBP reduction in women than men (-21.4 vs. -16.8 mmHg, p=0.009 in the ALC group; -21.9 vs -17.1 mmHg, p&lt;0.001 in the A5 group). The sex-adjusted LSM difference in SBP reduction was 0.46 mmHg, with a 97.5%CI upper limit of 2.79 mmHg. The response rates (achieving SBP &lt;140 mmHg and DBP &lt;90 mmHg and/or reduction of SBP &gt;=20 mmHg and/or DBP &gt;=10 mmHg from baseline) were 73.1% for ALC and 75.3% for A5 groups (p=0.633). Adverse drug reactions (ADRs) occurred in 3 patients receiving ALC and 5 patients receiving A5, all being mild. Conclusions: The study demonstrated that the single-pill third-dose triple antihypertensive therapy is comparable to standard-dose monotherapy in reducing SBP over 8 weeks without increasing ADRs, providing further support for the low-dose combination antihypertensive drugs in the initial treatment of hypertension. (NCT05362110)

Synergistic effect of graphene and nanodiamonds to achieve ultra-low friction on rough DLC coatings

Diamond-like carbon (DLC) with its protective, antiwear and self-lubricant properties represents an outstanding coating material to improve the tribological performance of bare metal-to-metal contacts. The DLC friction response is strictly related to the generation of a carbon-rich transfer layer on the sliding countersurfaces. This key process may benefit from the DLC surface functionalization with carbon nanomaterials, as attested by the recent observation of wearless sliding and ultra-low friction for nanorough model interfaces. In this study, we show by ball-on-disc tribometer that the tribological response of microrough steel-DLC contacts is considerably improved in dry atmosphere through DLC functionalization with graphene sheets (GSs) and nanodiamonds (NDs). The functionalization effectiveness is demonstrated exclusively with both allotropic forms, that synergically lower friction after a unique run-in period. We attribute the enhanced lubricity, with steady coefficient of friction <0.05 at 1 N load, to the formation of a transfer layer which incorporates GSs, NDs and nanoscroll structures self-assembled during sliding. High-resolution electron microscopy and Raman spectroscopy indicate that NDs, besides enabling the erosion of the highest interfacial micro-asperities, do assist the transfer layer development via GSs milling. Our findings contribute to the current quest for superlubricity in realistic tribocontacts meeting industrial standards.

The LHCb Upgrade I

The LHCb upgrade represents a major change of the experiment. The detectors have been almost completely renewed to allow running at an instantaneous luminosity five times larger than that of the previous running periods. Readout of all detectors into an all-software trigger is central to the new design, facilitating the reconstruction of events at the maximum LHC interaction rate, and their selection in real time. The experiment's tracking system has been completely upgraded with a new pixel vertex detector, a silicon tracker upstream of the dipole magnet and three scintillating fibre tracking stations downstream of the magnet. The whole photon detection system of the RICH detectors has been renewed and the readout electronics of the calorimeter and muon systems have been fully overhauled. The first stage of the all-software trigger is implemented on a GPU farm. The output of the trigger provides a combination of totally reconstructed physics objects, such as tracks and vertices, ready for final analysis, and of entire events which need further offline reprocessing. This scheme required a complete revision of the computing model and rewriting of the experiment's software.

Self-lubricating, self-healing and anti-corrosion coating with ultra-short run-in period

Mechanical equipment serves in harsh environments and always fails due to wear and corrosion, especially at the beginning of friction operation (run-in period). A lubricating, wear-resistant, corrosion-resistant, and self-repairing coating have been developed by combining MXene and polytetrafluoro-wax (PFW) with a water-based epoxy resin (EP). In the coating, MXene and PFW work together to form a moderately soft and hard transfer film, reducing the coefficient of friction from 0.236 to 0.009 and the run-in period from 1400 s to 7 s. In addition, the barrier properties of the MXene lamellar structure work synergistically with the phase-change capability of the PFW to provide self-healing and anti-corrosion properties. These coatings offer a new approach to the long-term protection of mechanical equipment.

Dietary n-3 alpha-linolenic and n-6 linoleic acids modestly lower serum lipoprotein(a) concentration but differentially influence other atherogenic lipoprotein traits: A randomized trial

Background and aimsLipoprotein(a) [Lp(a)] is a causal, genetically determined cardiovascular risk factor. Limited evidence suggests that dietary unsaturated fat may increase serum Lp(a) concentration by 10–15 %. Linoleic acid may increase Lp(a) concentration through its endogenous conversion to arachidonic acid, a process regulated by the fatty acid desaturase (FADS) gene cluster. We aimed to compare the Lp(a) and other lipoprotein trait-modulating effects of dietary alpha-linolenic (ALA) and linoleic acids (LA). Additionally, we examined whether FADS1 rs174550 genotype modifies Lp(a) responses. MethodsA genotype-based randomized trial was performed in 118 men homozygous for FADS1 rs174550 SNP (TT or CC). After a 4-week run-in period, the participants were randomized to 8-week intervention diets enriched with either Camelina sativa oil (ALA diet) or sunflower oil (LA diet) 30–50 mL/day based on their BMI. Serum lipid profile was measured at baseline and at the end of the intervention. ResultsALA diet lowered serum Lp(a) concentration by 7.3 % (p = 0.003) and LA diet by 9.5 % (p < 0.001) (p = 0.089 for between-diet difference). Both diets led to greater absolute decreases in individuals with higher baseline Lp(a) concentration (p < 0.001). Concentrations of LDL cholesterol (LDL-C), non-HDL-C, remnant-C, and apolipoprotein B were lowered more by the ALA diet (p < 0.01). Lipid or lipoprotein responses were not modified by the FADS1 rs174550 genotype. ConclusionsA considerable increase in either dietary ALA or LA from vegetable oils has a similar Lp(a)-lowering effect, whereas ALA may lower other major atherogenic lipids and lipoproteins to a greater extent than LA. Genetic differences in endogenous PUFA conversion may not influence serum Lp(a) concentration.