bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase 1b trial of IRAK 1/4 inhibition for low-risk myelodysplastic syndrome refractory/resistant to prior therapies.
Authors: Garcia-Manero Guillermo , Silverman Lewis R. , Sekeres Mikkael A. , Yan Lucy
Published: June 2024

TPS6591

Background: Chronic stimulation of both the interleukin-1 receptor (IL-1R) and toll-like receptors (TLRs) in myeloid progenitors is thought to promote a proinflammatory environment in the bone marrow that causes persistent cytopenia in patients with low-risk myelodysplastic syndrome (LR-MDS). The serine/threonine kinases IRAK1 and IRAK4 are critical for the signaling downstream of IL-1R and most TLRs promote production of proinflammatory cytokines and NLRP3 inflammasome-driven pyroptosis, leading to bone marrow inflammation and cell death. IRAK1/4 is a potential target for inhibition for the treatment of LR-MDS by decreasing inflammation and cell death within the bone marrow, allowing for restoration of hematopoiesis. R289 is a prodrug for R835, a potent and selective inhibitor of IRAK1 and IRAK4 kinases. The safety and pharmacokinetic properties of R289/R835 were evaluated in a phase 1 study in healthy volunteers (Study C-906289-001). R289 was well tolerated with no serious or severe adverse events (AEs) reported. Most AEs were mild and transient; the most common AEs (mild/moderate) were headache and GI disturbance. Overall, the study supported the further evaluation of R289. An open-label, phase 1b study to determine the tolerability and preliminary efficacy of R289 for patients with LR-MDS refractory to prior therapies is currently enrolling patients. Methods: The R289 phase 1b open label, single arm, multi-center study (NCT05308264) includes a dose escalation phase (up to 24 patients) and a dose expansion phase (up to 10 patients). Inclusion criteria for both phases: patients ≥18 years with a definitive diagnosis of LR-MDS. Exclusion criteria include prior MDS treatment(s) within 4 weeks of study treatment. Dose Escalation Phase: A 3+3 dose escalation design will be used to determine the maximum tolerated dose (MTD). An initial R289 dose of 250 mg qd, will be given orally, with or without food, progressing to 1 g qd with dose limiting toxicity (DLT) assessed at each dose level. The DLT evaluation period will be 28 days. After completion, patients without DLTs may remain at their respective dose levels if clinical benefit continues without toxicity. Dose Expansion Phase: R289 will be administered to up to 10 additional patients with LR-MDS at a dose not exceeding the MTD in the dose escalation phase. The primary endpoint is safety and tolerability of R289. Secondary endpoints include preliminary efficacy and pharmacokinetics of R289. Statistical analyses will be primarily descriptive. The trial is currently ongoing at 9 US sites. Clinical trial information: NCT05308264 .
Phase 2 study evaluating selinexor monotherapy in patients with JAKi-naïve myelofibrosis and moderate thrombocytopenia.
Authors: Scandura Joseph , Gerds Aaron Thomas , Ritchie Ellen K. , Wang Xulong , Kye Steve , Rampal Raajit
Published: June 2024

TPS6593

Background: While multiple JAKi therapies are approved in myelofibrosis, thrombocytopenia, which commonly occurs in myelofibrosis and is associated with poor outcomes, is an on-target side effect; use of suboptimal ruxolitinib doses used to manage adverse effects leads to reduced efficacy. In a Phase 1 study (NCT04562389) of selinexor, an investigational XPO1 inhibitor, plus the JAKi ruxolitinib in JAKi-naïve myelofibrosis the most common AEs in the 60 mg cohort were nausea (79%), anemia (64%), thrombocytopenia (64%), and fatigue (57%). Nausea events were predominantly Grade 1 and transient in nature. Among patients who received at least one prophylactic antiemetic (64% of 60 mg cohort), nausea (Grade 1 only) was experienced by 67% of patients compared with 100% of those who did not receive prophylactic antiemetics (Grades 1-3). In the selinexor 60 mg cohort, 79% of the intent-to-treat population achieved SVR35 and 58% achieved TSS50 at Week 24. Response rates were consistent across subgroups, including sex and regardless of ruxolitinib dose. In a Phase 2 study, selinexor monotherapy in patients with myelofibrosis refractory or intolerant to JAKi therapy (NCT03627403; ESSENTIAL) was generally tolerable and preliminary signs of efficacy were observed with single-agent selinexor. These results provide rationale to explore selinexor monotherapy in myelofibrosis subpopulations with high unmet need such as those with thrombocytopenia. Methods: XPORT-MF-044 (NCT05980806) is a two arm, sequential, multicenter, open-label, Phase 2 study evaluating the efficacy of selinexor (40 mg or 60 mg QW; N=29 per arm) in patients with JAKi-naïve MF and moderate thrombocytopenia (platelet count: 50-100x109/L) with optional expansion arms (n=30 per arm). Optional ruxolitinib or pacritinib, or momelotinib treatment (based on platelet count) may be added for patients whose SVR from baseline is <10% at week 12 or <35% at week 24. Inclusion criteria include ≥18 years of age, spleen volume ≥450 cm3 by MRI or CT scan, DIPSS intermediate-1 with symptoms, intermediate-2, or high-risk, ECOG ≤2, platelet counts of 50-100x109 /L, and not eligible for stem cell transplantation. Select exclusion criteria include >10% blast in peripheral blood or bone marrow and previous treatment with JAKi for myelofibrosis. Primary endpoint is SVR35 at week 24. Key secondary endpoints are safety, TSS50 at week 24, anemia response at week 24, overall survival, and overall response rate. Clinical trial information: NCT05980806 .
BELLWAVE-011: Phase 3 randomized trial of nemtabrutinib versus ibrutinib or acalabrutinib in untreated chronic lymphocytic leukemia/small lymphocytic lymphoma.
Authors: Tadmor Tamar , Eyre Toby A. , Benjamini Ohad , Chaudhry Arvind , Shen Juan , Leng Siyang , Farooqui Mohammed Z.H. , Lavie David
Published: June 2024

TPS7088

Background: Bruton tyrosine kinase (BTK) inhibitors have significantly improved survival in patients (pts) with chronic lymphocytic leukemia (CLL). Nemtabrutinib is a reversible noncovalent inhibitor of wild-type and C481-mutated BTK that has shown promising antitumor activity in pts with CLL (Woyach JA et al. Cancer Discovery 2023). In this ongoing trial, we evaluate the efficacy and safety of nemtabrutinib versus investigator’s choice of ibrutinib or acalabrutinib in pts with untreated CLL/small lymphocytic lymphoma (SLL) requiring therapy (NCT06136559). Methods: This randomized, open-label, parallel group, active-controlled phase 3 trial will enroll approximately 1200 pts aged ≥18 years. Eligible pts will have confirmed CLL/SLL with active disease based on the IWCLL criteria, which include one of the following: 1) progressive marrow failure or lymphocytosis, 2) massive, progressive, or symptomatic splenomegaly or lymphadenopathy, 3) autoimmune complications, 4) extranodal involvement, or 5) disease-related symptoms. The study will enroll patients who are treatment naïve, with an ECOG performance status 0-2, adequate organ function, and provide blood, bone marrow, and/or a lymph node sample. Pts are excluded if they have Richter Transformation, central nervous system (CNS) involvement by CLL/SLL, an active second malignancy, or a severe bleeding disorder. Pts will be randomized 1:1 to receive oral nemtabrutinib 65 mg QD, or investigator’s choice of oral ibrutinib 420 mg QD or acalabrutinib 100 mg BID. Randomization will be stratified by TP53aberration, clinical stage, investigator’s choice of comparator, and region. Treatment will continue on both arms until unacceptable toxicity, disease progression, or withdrawal. Disease response assessments by physical examination, constitutional symptoms, imaging, and evaluation of blood and bone marrow will be performed Q12W up to week 97, and Q24W thereafter. Primary efficacy endpoints are objective response (OR) and progression free survival (PFS) by BICR per iwCLL 2018 criteria. Secondary endpoints are overall survival (OS), duration of response (DOR) by BICR per iwCLL 2018, and safety. OR will be tested via a non-inferiority comparison, while PFS and OS will be tested for superiority. Adverse events will be monitored throughout the trial and graded per NCI CTCAE v5.0 and iwCLL scales. Enrollment in this trial is ongoing. Clinical trial information: NCT06136559 .
BGB-11417-203: An ongoing, phase 2 study of sonrotoclax (BGB-11417), a next-generation BCL2 inhibitor, in patients with Waldenström macroglobulinemia.
Authors: Lee Hui-Peng , Opat Stephen , Hrom John , Kliman David S. , Marlton Paula , Liu Peng , Du Chenmu , Lussier Amber , Zhang Jun , Guo Haiyi , Treon Steven P.
Published: June 2024

TPS7090

Background: Bruton tyrosine kinase (BTK) inhibitors and anti-CD20 antibody-based systemic therapy are included within the preferred treatment algorithms for Waldenström macroglobulinemia (WM). However, to date, no treatments have been approved for patients with WM that is refractory to both BTK inhibitors and anti-CD20 therapy. Venetoclax, the first-generation BCL2 inhibitor, has demonstrated clinical activity in patients with relapsed/refractory (R/R) WM (Castillo et al. J Clin Oncol. 2022), but it has no regulatory approvals in WM. Sonrotoclax, a next generation BCL2 inhibitor, is more selective and a more pharmacologically potent inhibitor of BCL2 than venetoclax. In a phase 1 trial, sonrotoclax monotherapy was well tolerated at all dose levels tested up to 640 mg and showed promising evidence of antitumor activity in patients with R/R WM (Soumerai et al. Blood. 2022). Based on the data from these earlier studies, a phase 2 study of sonrotoclax monotherapy in patients with WM has been initiated and is currently recruiting. Methods: BGB-11417-203 (NCT05952037) is an open-label, international, phase 2 study. Eligible patients have histologically confirmed WM that is R/R to both BTK inhibitor therapy and anti-CD20–based systemic therapy combined with chemotherapy or a proteasome inhibitor (PI; Cohort 1); R/R to anti-CD20–based systemic therapy combined with chemotherapy or a PI and who are intolerant to BTK inhibitor therapy (Cohort 2); or R/R to a BTK inhibitor and who are unsuitable for chemoimmunotherapy (Cohort 3). Patients who have received previous treatment with a BCL2 inhibitor are ineligible. Approximately 85 patients will be enrolled across cohorts and will receive sonrotoclax until disease progression, death, unacceptable toxicity, patient withdrawal, loss to follow-up, or study termination. The primary endpoint is major response rate (MRR; defined as partial response or better) in Cohort 1 per IWWM-11 criteria, as assessed by independent review committee (IRC). Key secondary endpoints include MRR assessed by investigator (INV) in Cohort 1 and by IRC and INV in both Cohorts 2 and 3; overall response rate, duration of response, and progression-free survival by IRC and INV; overall survival; and safety and tolerability. Patient recruitment is ongoing in Australia, the US, China, and Europe. Clinical trial information: NCT05952037 .
An open label, single arm, multicenter phase II study of the efficacy and safety of LP-168 monotherapy for relapsed or refractory mantle cell lymphoma.
Authors: Song Yuqin , Tang Xiaoqiong , Cai Qingqing , Liu Lihong , Jing Hongmei , Jiang Ming , Sun Xiuhua , Wu Jianqiu , Yang Yu , Wu Huijing , Peng Zhigang , Ding Kaiyang , Yi Shuhua , Yan Xiaojing , Wu Guowu , Wu Yudan , Cui Jie , Ou Pengju , Tan Fenlai , Zhu Jun
Published: June 2024

TPS7098

Background: Targeting Bruton’s tyrosine kinase (BTK) has demonstrated impressive efficacy in relapsed or refractory mantle cell lymphoma (R/R MCL). Covalent BTK inhibitors (cBTKi) have produced extended disease remission and durable responses in R/R MCL. However, patients with continuous cBTKi treatment tend to develop selection or outgrowth of resistant clones, which triggers disease relapse. Non-covalent binding BTKi has become a treatment option for patients who progressed on cBTKi. LP-168 is a highly selective next-generation inhibitor of BTK that can bind wild-type BTK covalently and C481-mutated BTK non-covalently (reversibly) Here, we propose to evaluate the safety and efficacy of LP-168 monotherapy in patients with R/R MCL. Methods: NCT05716087 is an open-label, multicenter, single-arm, phase II study to assess the efficacy, safety, tolerability, and pharmacokinetics of LP-168 in Chinese patients with R/R MCL who have failed prior cBTKi treatment. Responses were evaluated using Lugano 2014 criteria. Eligible patients with R/R MCL must show evidence of disease progression or intolerance to at least a prior cBTKi. Patients are also required to have adequate bone marrow, liver function, kidney function, and heart function, and an ECOG performance status of 0-2. Moreover, patients must have at least one measurable lesion. Key exclusion criteria include previous non-covalent BTKi or BTK proteolysis-targeting chimeras (PROTAC) treatment, uncontrolled systemic disease, active infection, central nervous system (CNS) involvement, prior history of other malignancies within two years, and current pregnancy or breastfeeding. Concomitant use of strong or moderate CYP3A4 inducers and inhibitors or OATP1B1/OATP1B3 sensitive substrates is prohibited. LP-168 is orally administered at 150mg once daily in 28-day/cycle until progressive disease (PD), unacceptable toxicity, withdrawal of consent, death, or other reasons for treatment discontinuation. In this study, the primary endpoint was ORR according to an independent review committee (IRC) assessment based on the best overall response (BOR) of PR or better per Lugano 2014 criteria. Secondary endpoints include safety evaluation, quality of life assessment, PK parameters, ORR by investigator’s assessment, and other efficacy parameters, such as complete response ratio (CRR), progression-free survival (PFS), overall survival (OS), duration of response (DOR), and time to response (TTR). First patient was enrolled on May 12, 2023. Currently 41 study sites across China are actively enrolling patients. ClinicalTrials.gov Identifier: NCT05716087. Clinical trial information: NCT05716087 .
Evaluation of elranatamab vs EPd, PVd, or Kd in patients with relapsed or refractory multiple myeloma and prior anti-CD38–directed therapy: MagnetisMM-32.
Authors: Schuster Steven Robert , Ito Satoshi , Hoyle Margaret , Yver Anne , Hong Fangxin , Finn Gregory
Published: June 2024

TPS7576

Background: Elranatamab (ELRA), a humanized B-cell maturation antigen (BCMA)-CD3 bispecific antibody, has shown efficacy and manageable safety as a monotherapy in patients with relapsed or refractory multiple myeloma (RRMM). This study will evaluate ELRA monotherapy vs elotuzumab-pomalidomide-dexamethasone (EPd), pomalidomide-bortezomib-dexamethasone (PVd), or carfilzomib-dexamethasone (Kd) in patients with RRMM to determine whether ELRA can provide superior clinical benefit. Methods: MagnetisMM-32, a phase 3, open-label, multicenter, randomized study, will enroll ≈492 patients. Patients will receive ELRA (Arm A) or investigator’s choice of EPd, PVd or Kd (Arm B), until disease progression, unacceptable toxicity, withdrawal of consent, loss to follow-up, or study termination. Patients treated with ELRA will receive 2 step-up priming doses followed by weekly doses in a 28-day cycle. Patients who achieve a PR or better for ≥2 months will be eligible for reduced dosing frequency. Patients will be randomized 1:1 (stratified by prior line of therapy [1 vs 2 vs 3/4] and International Staging System disease stage [1/2 vs 3]). Key inclusion criteria include age of ≥18 years, prior multiple myeloma diagnosis with measurable disease (per IMWG criteria), evidence of progressive disease or failure to achieve a response to last line of multiple myeloma therapy, 1 to 4 prior lines of therapy including an anti–CD38 antibody–containing regimen (for ≥2 consecutive cycles) and a lenalidomide-containing regimen (for ≥2 consecutive cycles), adequate bone marrow function, and an ECOG performance status of ≤2. Key exclusion criteria include stem cell transplant ≤12 weeks prior to enrollment; active, uncontrolled infection; prior BCMA-directed or CD3-redirecting therapy; and unable to receive EPd, PVd, or Kd. The primary and key secondary endpoints are progression-free survival (PFS) by blinded independent central review (BICR) per IMWG criteria and overall survival (OS), respectively. Other secondary endpoints include PFS by investigator, objective response rate, duration of response, time to response by BICR, PFS on next line of therapy per IMWG criteria, MRD negativity rate, safety, pharmacokinetics of ELRA, immunogenicity, and health-related quality of life outcomes. The primary endpoint and OS will be compared statistically between treatment arms by stratified log-rank tests. Clinical trial information: NCT06152575 .
Reduced vacuolar ATPase protects mice from Friend virus infection – an unintended but instructive effect in Hif-2afl mice
Authors: Schreiber Timm , Koll Nora , Padberg Claudia , de los Reyes Buena , Quinting Theresa , Malyshkina Anna , Metzen Eric , Sutter Kathrin , Fandrey Joachim , Winning Sandra
Published: June 2024

During acute viral infections, innate immune cells invade inflamed tissues and face hypoxic areas. Hypoxia-inducible factors (HIFs) adapt cellular responses towards these conditions. We wanted to investigate the effects of a loss of HIF-2α in macrophages during acute Friend murine leukemia retrovirus (FV) infection in C57BL/6 mice using a Cre/loxP system. Remarkably, mice with floxed Hif-2a (Hif-2afl; Hif-2a is also known as Epas1) did not show any signs of FV infection independent of Cre activity. This prevented a detailed analysis of the role of macrophage HIF-2α for FV infection but allowed us to study a model of unexpected FV resistance. Hif-2afl mice showed a significant decrease in the expression of the Atp6v1e2 gene encoding for the E2 subunit of the vacuolar H+-ATPase, which resulted in a decreased acidification of lysosomes and limited virus entry into the cell. These findings highlight that the insertion of loxP sites is not always without functional consequences and has established a phenotype in the floxed Hif-2a mouse, which is not only unexpected, but unwanted and is of relevance for the use of this mouse strain in (at least virus) experiments.
Tropical and montane Apis cerana show distinct dance–distance calibration curves
Authors: A. K. Bharath Kumar , George Ebi Antony , Brockmann Axel
Published: June 2024

Social bees have evolved sophisticated communication systems to recruit nestmates to newly found food sources. As foraging ranges can vary from a few hundred meters to several kilometers depending on the environment or season, populations of social bee species living in different climate zones likely show specific adaptations in their recruitment communication. Accordingly, studies in the western honey bee, Apis mellifera, demonstrated that temperate populations exhibit shallower dance-calibration curves compared with tropical populations. Here, we report the first comparison of calibration curves for three Indian Apis cerana lineages: the tropical Apis indica, and the two montane Himalayan populations Apis cerana cerana (Himachal Pradesh) and Apis cerana kashmirensis (Jammu and Kashmir). We found that the colonies of the two montane A. cerana populations show dance–distance calibration curves with significantly shallower slopes than those of the tropical A. indica. Next, we transferred A. c. cerana colonies to Bangalore (∼ 2600 km away) to obtain calibration curves in the same location as A. indica. The common garden experiment confirmed this difference in slopes, implying that the lineages exhibit genetically fixed differences in dance–distance coding. However, the slopes of the calibration curves of the transferred A. c. cerana colonies were also significantly higher than those of the colonies tested in their original habitat, indicating an important effect of the environment. The differences in dance–distance coding between temperate and tropical A. cerana lineages resemble those described for Apis mellifera, suggesting that populations of both species independently evolved similar adaptations.
Towards an enhanced understanding of the oxidative ageing mechanisms in bitumen
Authors: Πιπιντάκος Γεώργιος
Published: June 2024

Το φαινόμενο γήρανσης στo ασφαλτόμιγμα και το συνδετικό της μέσο, ​​την άσφαλτο, είναι καλά τεκμηριωμένο στην επιστημονική βιβλιογραφία όσον αφορά τις ρεομηχανικές επιδράσεις της. Για να κατανοήσουμε τα «γιατί» πίσω από αυτές τις αλλαγές θα πρέπει να αναζητήσουμε επιπλέον τη χημεία της ασφάλτου. Αυτή η διατριβή υποστηρίζει πειραματικά την υπόθεση ενός σχήματος οξείδωσης που αποτελείται από μια γρήγορη και μια αργή φάση προσδιορισμού του ρυθμού γήρανσης. Αυτό επιτυγχάνεται με τη χρήση διαφόρων μη τροποποιημένων ασφάλτων διαφορετικής προέλευσης ακατέργαστης πηγής, διεργασίας διυλιστηρίου και απόδοσης τόσο στην κινητική οξείδωσης όσο και με τυπικές εργαστηριακές προσομοιώσεις γήρανσης. Τα ευρήματα της φασματοσκοπίας παραμαγνητικού συντονισμού ηλεκτρονίων (EPR) και φασματοσκοπίας υπέρυθρου μετασχηματισμού Fourier (FTIR) καταφέρνουν να διακρίνουν τις δύο φάσεις, ενώ η φασματοσκοπία πυρηνικού μαγνητικού συντονισμού πρωτονίων (1H-NMR) και η φασματοσκοπία μάζας δευτερογενούς ιόντος χρόνου πτήσης (TOF-SIMS) ξετυλίγουν τα κύρια οξυγονωμένα προϊόντα στην άσφαλτο. Οι χημικές έρευνες των κλασμάτων SARA δείχνουν επιπλέον την επίδραση της γήρανσης στα διάφορα κλάσματα. Επιπλέον, κάθε συνεισφορά της συζευγμένης αντίδρασης-διάχυσης μελετάται με FTIR και Dynamic Vapor Sorption (DVS). Στη συνέχεια, διερευνήθηκαν και επικυρώθηκαν οι θεμελιώδεις μηχανισμοί για την ανάπτυξη μιας ιδιόμορφης μικροδομής, των δομών της μέλισσας στην άσφαλτο, μέσω της Διαφορικής Θερμιδομετρίας Σάρωσης (DSC) και της Περίθλασης ακτίνων Χ ευρείας γωνίας (WAXD). Σε αυτή τη διατριβή, υιοθετείται η υπόθεση ότι οι κρυσταλλώσιμες ενώσεις στην άσφαλτο είναι ο κύριος λόγος για τέτοιες δομές, και έτσι μελετήθηκαν διάφορα κηρώδη συνδετικά για την επίδραση της εργαστηριακής γήρανσης με Μικροσκόπιο Ατομικής Δύναμης (AFM) και Συνεστιακή Μικροσκοπία Σάρωσης με Λέιζερ (CLSM). Οι μέθοδοι επεξεργασίας εικόνας επιτρέπουν στο συμπέρασμα ότι η κάλυψη των μελισσών μειώνεται κατά τη γήρανση. Επιπλέον, τα οξυγονωμένα προϊόντα, όπως αποκαλύπτονται από τους μηχανισμούς γήρανσης στην άσφαλτο, συνδέθηκαν μέσω πολυμεταβλητών στατιστικών με προηγμένες ρεολογικές παραμέτρους που εξάγονται μέσω του Δυναμικού Ρεομέτρου διάτμησης (DSR). Η σύγκλιση της φάσης προσδιορισμού του γρήγορου ρυθμού και της βραχυπρόθεσμης εργαστηριακής γήρανσης βρέθηκε τόσο για τη χημεία όσο και για τη ρεολογία. Η διατριβή τελειώνει με την περιγραφή ενός μοντέλου θερμοδυναμικής μη αναστρέψιμων διεργασιών για τη φάση οξείδωσης που προσδιορίζει τον γρήγορο ρυθμό, με το μοντέλο να λαμβάνει υπόψη τις λογικές αλλαγές των κλασμάτων SARA με την οξείδωση. Συνολικά, αυτή η διατριβή παρέχει μια βαθύτερη επιστημονική εικόνα των μηχανισμών οξειδωτικής γήρανσης στην άσφαλτο και διευκρινίζει τη σχέση μεταξύ χημικών και ρεολογικών χαρακτηριστικών, τα οποία μπορεί να συμβάλουν ως κατευθυντήρια γραμμή σε μια πιο βιώσιμη οδική υποδομή στο μέλλον.
Empowering Maneuvers: Boldly Mobilizing Military Medical Research and Training within the Kingdom of Saudi Arabia to Safeguard a Nation and its People.
Authors: Mandourah Yasser , Mottershead Richard , Alonaizi Nafi , Alriaini Hasan , Burhan Essam , Al-Yateem Nabeel
Published: June 2024

In 2023 Alkhathami and colleagues from the Prince Sultan Military College of Health Sciences highlighted the Kingdom of Saudi Arabia’s transformative upgrades across various sectors, notably including enhancements to the healthcare system, and called for action to extend these upgrades to the military healthcare field. Prompted by this call to action, the leadership of the military healthcare system swiftly commenced initiatives, acting in less than three months from this pivotal appeal. In January 2023 the first author ordered a decree via the General Directorate of Armed Forces Medical Services of Saudi Arabia, in collaboration with US central Command and international partners, to host the 3rd International Conference of Military Medicine. The event graciously welcoming more than 1000 military representatives from 20 participating nations. The Military Medical Conference, fostering a global military community dialogue on the necessity to explore collective capacities to endure and overcome humanitarian challenges, thereby sustaining health, promoting well-being, and nurturing life through strategies that align with the insights of Alkhathami et al. (2023). The response and the need underlined by the original article are discussed by the Major General, staff of the Saudi Military Medical Services and academics from the University of Sharjah.
Auditor Choice and Peer Firms Similarity: the Case of Tunisian Firms
Authors: Ben Hassoun Amira
Published: June 2024

The aim of this study is to offer novel factor perceived by firms to select an external auditor in developing countries, like Tunisia, given their unique cultural, economic and institutional context. Specifically, we examine how peer firms’ product similarity affects their decision to engage the same auditor. The data sample of this study covers the period between 2014 and 2021, across 36 firms and 1297 firm-peer-year observations. Using a novel measure for industry product similarity, results of logistic regression show that the likelihood of sharing auditor by peer firms increases when their product offering are more similar. This study finding provide evidence that Tunisian firm’s auditor selection decision focus more on knowledge and expertise of external auditor than exercising caution to protect their proprietary information. In additional test, we evaluate whether our primary result remains when we isolate Big4 and Non-Big 4 clienteles and we find a supportive evidence that the likelihood of choosing the same auditor is greater for firm pairs that are audited by a Big N. Overall, this study extends the literature on auditor choice determinant in developing country by highlighting the importance of peer firms’ product similarity in choosing external auditor and provide important evidence for investors and practitioners whether it is important for the external auditor to invest in industry specialization and build a reputation as a specialist.
The Analysis of Financial Reporting Quality and Firm Value
Authors: Harjanto Karina
Published: June 2024

The objective of this research is to obtain empirical evidence about the effect of financial reporting quality on firm value. Financial reporting quality is measured using two proxies, accrual quality through Ball-Shivakumar Model (AQ) and earnings management through Modified Jones Model (EM). Firm value is measured using share price, Price to Book Value, Tobin’s Q, and Market Value-Added. Control variables used are leverage (Debt to Equity Ratio), profitability (Return on Asset), and firm size (ln total assets). This study focuses on manufacturing businesses that were listed on the Indonesia Stock Exchange during the years 2018 and 2021. The sample was chosen through a purposive sampling technique, specifically targeting companies listed on the Indonesia Stock Exchange that operate in the manufacturing sector and provide audited financial statements. Analyzed the secondary data utilizing descriptive statistics, normality test, classical assumption tests, and hypothesis testing. The findings of this investigation are (1) AQ has no effect on share price, PBV, Tobin’s Q and MVA (2) EM has positive and significant effect on all proxies of firm value, except MVA. The quality of financial reporting, the level of leverage, the size of the firm, and its profitability all have a simultaneous and considerable impact on the value of the firm.
Stochastic First-Order Algorithms for Constrained Distributionally Robust Optimization
Authors: Im Hyungki , Grigas Paul
Published: June 2024

We consider distributionally robust optimization (DRO) problems, reformulated as distributionally robust feasibility (DRF) problems, with multiple expectation constraints. We propose a generic stochastic first-order meta-algorithm, where the decision variables and uncertain distribution parameters are each updated separately by applying stochastic first-order methods. We then specialize our results to the case of using two specific versions of stochastic mirror descent (SMD): (i) a novel approximate version of SMD to update the decision variables, and (ii) the bandit mirror descent method to update the distribution parameters in the case of [Formula: see text]-divergence sets. For this specialization, we demonstrate that the total number of iterations is independent of the dimensions of the decision variables and distribution parameters. Moreover, the cost per iteration to update both sets of variables is nearly independent of the dimension of the distribution parameters, allowing for high-dimensional ambiguity sets. Furthermore, we show that the total number of iterations of our algorithm has a logarithmic dependence on the number of constraints. Experiments on logistic regression with fairness constraints, personalized parameter selection in a social network, and the multi-item newsvendor problem verify the theoretical results and show the usefulness of the algorithm, in particular when the dimension of the distribution parameters is large.

History: Accepted by Antonio Frangioni, Area Editor for Design & Analysis of Algorithms—Continuous.

Funding: This work was supported by the National Science Foundation [Grant 2112533].

Supplemental Material: The online appendix is available at https://doi.org/10.1287/ijoc.2023.0167 .
The Terminator: An Integration of Inner and Outer Approximations for Solving Wasserstein Distributionally Robust Chance Constrained Programs via Variable Fixing
Authors: Jiang Nan , Xie Weijun
Published: June 2024

We present a novel approach aimed at enhancing the efficacy of solving both regular and distributionally robust chance constrained programs using an empirical reference distribution. In general, these programs can be reformulated as mixed-integer programs (MIPs) by introducing binary variables for each scenario, indicating whether a scenario should be satisfied. Whereas existing methods have focused predominantly on either inner or outer approximations, this paper bridges this gap by studying a scheme that effectively combines these approximations via variable fixing. By checking the restricted outer approximations and comparing them with the inner approximations, we derive optimality cuts that can notably reduce the number of binary variables by effectively setting them to either one or zero. We conduct a theoretical analysis of variable fixing techniques, deriving an asymptotic closed-form expression. This expression quantifies the proportion of binary variables that should be optimally fixed to zero. Our empirical results showcase the advantages of our approach in terms of both computational efficiency and solution quality. Notably, we solve all the tested instances from literature to optimality, signifying the robustness and effectiveness of our proposed approach.

History: Accepted by Andrea Lodi/Design & Analysis of Algorithms — Discrete.

Funding: This work was supported by Office of Naval Research [N00014-24-1-2066]; Division of Civil, Mechanical and Manufacturing Innovation [2246414].

Supplemental Material: The software that supports the findings of this study is available within the paper and its Supplemental Information ( https://pubsonline.informs.org/doi/suppl/10.1287/ijoc.2023.0299 ) as well as from the IJOC GitHub software repository ( https://github.com/INFORMSJoC/2023.0299 ). The complete IJOC Software and Data Repository is available at https://informsjoc.github.io/ .
Improving Students’ Argumentation Skills Using Dynamic Machine-Learning–Based Modeling
Authors: Wambsganss Thiemo , Janson Andreas , Söllner Matthias , Koedinger Ken , Leimeister Jan Marco
Published: June 2024

This study explores the potential of dynamic, machine learning (ML)-based modeling to enhance students’ argumentation skills—a crucial component in education and professional success. Traditional educational tools often rely on static modeling, which does not adapt to individual learner needs or provide real-time feedback. In contrast, our research introduces an innovative ML-based system designed to offer dynamic, personalized feedback on argumentation skills. We conducted three empirical studies comparing this system against traditional methods such as scripted and adaptive support modeling.

Our results show that dynamic behavioral modeling significantly improves learners’ objective argumentation skills across domains, outperforming all established methods. The results further indicate that, compared with adaptive support, the effect of the dynamic modeling approach holds across complex (large effect) and simple tasks (medium effect) and supports learners with lower and higher expertise alike.

This research has important implications for educational policy and practice; incorporating such dynamic systems could transform learning environments by providing scalable, individualized support. This would not only foster essential skills but also cater to diverse learner profiles, potentially reducing educational disparities. Our work suggests a shift toward integrating more adaptive technologies in educational settings to better prepare students for the demands of the modern workforce.
On the Robustness of Idiosyncratic Volatility Effect
Authors: Barinov Alexander
Published: June 2024

The idiosyncratic volatility (IVol) effect is robust to restricting the sample to New York Stock Exchange (NYSE) firms (once the proper listing indicator is used) and to excluding from the sample small, illiquid, and low-price stocks. The idiosyncratic volatility effect is also unlikely to stem from the short-run reversal, as the IVol effect stays significant for about six months and seems stronger for high turnover firms, which do not exhibit short-term reversal. The IVol effect also does not seem to weaken postpublication.

This paper was accepted by Lukas Schmid, finance.

Supplemental Material: The online appendix and data files are available at https://doi.org/10.1287/mnsc.2022.04140 .
The Best Decisions Are Not the Best Advice: Making Adherence-Aware Recommendations
Authors: Grand-Clément Julien , Pauphilet Jean
Published: June 2024

Many high-stake decisions follow an expert-in-loop structure in that a human operator receives recommendations from an algorithm but is the ultimate decision maker. Hence, the algorithm’s recommendation may differ from the actual decision implemented in practice. However, most algorithmic recommendations are obtained by solving an optimization problem that assumes recommendations will be perfectly implemented. We propose an adherence-aware optimization framework to capture the dichotomy between the recommended and the implemented policy and analyze the impact of partial adherence on the optimal recommendation. Our framework provides useful tools to analyze the structure and to compute optimal recommendation policies that are naturally immune against such human deviations and are guaranteed to improve upon the baseline policy.

This paper was accepted by Nicolas Stier-Moses, special issue on the human-algorithm connection.

Funding: J. Grand-Clément was supported by the Agence Nationale de la Recherche [Grant 11-LABX-0047] and Hi! Paris.

Supplemental Material: The data files are available at https://doi.org/10.1287/mnsc.2023.01851 .
Boundary Effects in the Diffusion of New Products on Cartesian Networks
Authors: Fibich Gadi , Levin Tomer , Gillingham Kenneth T.
Published: June 2024

The Role of Boundaries in the Spreading of Solar

Peer effects by neighbors play a key role in the spreading of residential solar. Thus, people are more likely to install a solar system on their roof if some of their neighbors have already done so. Because people who live near the municipality boundary have fewer neighbors, does this imply that they are less likely to adopt solar? In “Boundary Effects in the Diffusion of New Products on Cartesian Networks,” Fibich, Levin, and Gillingham analyze this problem analytically using the Bass model on two-dimensional networks and empirically using data on installations of solar systems. They show that boundaries have a significant impact on the adoption of residential units near the municipality boundary. Their effect on the aggregate adoption in the municipality, however, is negligible.
Dynamic Exception Points for Fair Liver Allocation
Authors: Celdir Musa Eren , Akan Mustafa , Tayur Sridhar
Published: June 2024

There are disparities in access to livers based on transplant patients’ height, which disproportionately affects Hispanics, Asians, and women (across all ethnicities), because short patients can receive transplants from a smaller pool of available deceased donors for medical reasons. Reduced likelihood of transplantation leads to higher mortality rates and longer waiting times. We analyze fairness within the current U.S. liver allocation system where patients receive priority dynamically, based on their model for end-stage liver disease (MELD) scores, which reflect the severity of liver disease. We propose a simple adjustment, providing additional (exception) points based on height and MELD score, that can be easily implemented in practice, which materially reduces the disparity without sacrificing overall efficiency. We model the liver allocation system as a multiclass fluid model of overloaded queues with heterogeneous servers. We impose explicit equity constraints for all static patient classes, that is, height. We characterize the optimal solution under the objective of minimizing pretransplant mortality. The discretized version of the optimal policy is numerically solved using estimates from clinical data and a detailed simulation study demonstrates its effectiveness. The optimal policy, called the equity adjusted mortality risk policy, advocates ranking patients based on their short-term mortality risk adjusted for equity among height classes. Interpretation of the shadow prices of equity constraints in the optimal control problem as MELD exception points is novel in the transplant context since they can be seamlessly mapped into the existing system. Our simulations show that for women, the disparity can be almost completely eliminated. Hispanics and Asians greatly benefit from receiving these MELD exception points also. Our work provides a remedy to reduce the disparities in access to liver transplantation within the MELD-based allocation. Our approach can help the on-going analysis of the continuous distribution model for livers because it also considers aspects of candidate biology, notably height and body surface area.

Funding: M. Akan was supported by the National Science Foundation [Grant CMMI-1334194] and the Carnegie Mellon University (CMU) [Onetto Fellowship in Operations Management].

Supplemental Material: The online appendix is available at https://doi.org/10.1287/serv.2023.0092 .
Is there an impending crisis for patients with cardiovascular disease?
Authors: Morrell-Scott Nicola
Published: June 2024

Nicola Morrell-Scott highlights concerning trends in cardiovascular mortality since 2020 and discusses changes in the nursing profession and education that may lead to further problems in the near future.
A tale of two eras
Authors: Ridpath Nick
Published: June 2024

New research from the Institute for Fiscal Studies shows Sure Start had a big impact on the later academic attainment of children from low-income backgrounds. Nick Ridpath, research economist from the IFS, discusses what made Sure Start effective in its different phases and shares more about the research.
NEGLECTED AND RELAPSED CLUBFOOT IN ADULTS: THE FUNCTIONAL OUTCOME OF ACUTE SURGICAL CORRECTION
Authors: Nogdallah S. , Fatooh M. , Khairy A. , Mohamed H. , Abdulrahman A. , Mohamed H.
Published: June 2024

Background

Neglected clubfoot in this series is defined as untreated equino-cavo-adducto-varus in older children, or adults. Relapsed clubfoot is the residual deformity that remains after single or multiple surgical interventions. Severe neglected clubfoot rarely exists today in developed countries, except in some emigrants from low- and middle-income countries. Acute surgical management with corrective mid-foot osteotomy and elongation of the Achilles tendon has excellent functional outcome.

Objective

To assess the functional outcome of acute correction of neglected Talipes-quino-varus deformity in adults.

Methods

This is cross sectional, hospital–based study that took place in Khartoum, Sudan. Forty patients were included in this study. Midfoot osteotomy and elongation of the Achilles tendon were performed to all patients. Data was collected using a questionnaire and the functional outcome has been assessed using the American Orthopaedic Foot and Ankle Society Score (AOFAS). This score was measured before surgery and one years after surgery.

Results

The mean age was 19.9±4.7 years. Males were 25 (62.5%) and females were 15 (37.5%). The mean preoperative AOFAS score was 37.7±7.1 (poor). This score improved to 80.7±13.7 (good to excellent), two years after surgery. However, this indicates significant change in the functional outcome after the operation (P value < 0.05). Excellent post-operative functional outcome was found among patients aged 18 – 23 years 18 (50%) P. value: 0.021. The majority of patients 36(90%) were fully satisfied with the operation, 2(5%) partially satisfied and 2(5%) were unsatisfied.

Conclusion

Acute correction of neglected and relapsed TEV with elongation of the Achilles tendon and single midfoot osteotomy has excellent functional outcome as assessed by AOFAS Score. The satisfaction with this procedure is impressive. The younger age population showed better outcomes with this procedure.
GÊNERO, TRABALHO E “ARETÊ” EM HESÍODO: AS CONCEPÇÕES DO SISTEMA JURÍDICO ARCAICO NA GRÉCIA DO SÉCULO VIII a.C.
Authors: Thayele Vitória Azevêdo Santana  , Brian Gordon Lutalo Kibuuka
Published: June 2024

Trabalhos e Dias é um poema que exalta a importância do trabalho no campo. Em relação ao contexto da pólis, sua temática principal está direcionada à justiça, mostrando que existe um discurso sobre o trabalho não apenas no campo, mas também na pólis. No texto, Hesíodo articula temas como corrupção, trabalho e justiça, especialmente nas representações femininas de Pandora e as Érides.
Relationship between mechanical behavior and process factors in friction stir welding aluminum alloys
Authors: DELLAL Nabila , MERZOUG Mohammed , MIMMI Abdelatif , BENAMARA Nabil
Published: June 2024

The friction stir welding (FSW) procedure is the main topic of this research study among the various welding techniques. The study focuses on the interaction between the mechanical properties of 3003 aluminum alloy and the process parameters (rotation speed, welding speed, and dwell time) in the form of rolled plates of 2 mm thickness, end-to-end and welded at 90° and 45°. The welds were made by varying the speed of rotation (1000, 2000 rpm) and setting the tool feed at 500 mm/min. This experimental approach is also based on varying the tilt of the welding tool from 0° to 2°. It has been shown that the studied parameters play an important role in the characterization and optimization of the above mentioned weld joints. Therefore, and based on the results obtained, the use of the 90° joint remains the best in terms of strength.
Fast and high-fidelity EUV curvilinear mask optimization by distance-versus-angle signature
Authors: Huang Weichen , Li Yanqiu , Yang He , Yuan Miao , Zhang Zhiwei , Li Zhaoxuan , Li Zhen
Published: June 2024

Curvilinear mask has received much attention in recent years due to its ability to obtain better image quality in advanced nodes. A common method for optimizing curvilinear mask in optical proximity correction (OPC) flow is moving control points on the edge directly (MCED-based OPC), but it requires storing mass data. This paper uses distance-versus-angle signature (DVAS), a one-dimensional function, to represent a two-dimensional boundary of mask. To the best of our knowledge, DVAS and its second derivative are applied for the first time to reduce the design data storage space and guide the direction of optimization in EUV lithography systems. Compared with storing the change distances of the control point in both horizontal and vertical directions, directly storing the amplitude change of the DVAS can effectively reduce the storage space consumption. Simulation results demonstrate that unlike the MCED-based OPC method, the DVAS-based OPC method using second derivative achieves a lower pattern error and requires less time while reducing the storage space.
Anisotropic regularization for sparsely sampled and noise-robust Fourier ptychography
Authors: Lee Kyung Chul , Chae Hyesuk , Xu Shiqi , Lee Kyungwon , Horstmeyer Roarke , Lee Seung Ah , Hong Byung-Woo
Published: June 2024

Fourier ptychography (FP) is a powerful computational imaging technique that provides super-resolution and quantitative phase imaging capabilities by scanning samples in Fourier space with angle-varying illuminations. However, the image reconstruction in FP is inherently ill-posed, particularly when the measurements are noisy and have insufficient data redundancy in the Fourier space. To improve FP reconstruction in high-throughput imaging scenarios, we propose a regularized FP reconstruction algorithm utilizing anisotropic total variation (TV) and Tikhonov regularizations for the object and pupil functions, respectively. To solve this regularized FP problem, we formulate a reconstruction algorithm using the alternating direction method of multipliers and show that our approach successfully recovers high-quality images with sparsely sampled and/or noisy measurements. The results are quantitatively and qualitatively compared against various FP reconstruction algorithms to analyze the effect of regularization under harsh imaging conditions. In particular, we demonstrate the effectiveness of our method on the real experimental FP microscopy images, where the TV regularizer effectively suppresses the measurement noise while maintaining the edge information in the biological specimen and helps retrieve the correct amplitude and phase images even under insufficient sampling.
Stably suppressing laser relative intensity noise on a 3 × 3 coupler interferometric system
Authors: Liu Xiaopeng , Wu Xuqiang , Luo Jiatong , Zhou Wen , Zhang Jihao , Xia Qiliang , Wang Tengfei , Shi Jinhui , Lin Zhiwei , Liu Yangzhou , Yu Benli
Published: June 2024

A 3 × 3 coupler multiphase demodulation scheme is proposed to eliminate the impact of working point drifting and the laser relative intensity noise (RIN) on a 3 × 3 coupler interferometric system. An ellipse-fitting algorithm (EFA) is applied to fit the two interference signals of the 3 × 3 coupler in order, then the ATAN algorithm is applied to obtain three noise-containing signals with specific trigonometric relationships. By averaging the three signals, the demodulated phase noise induced from RIN can be effectively eliminated. The experimental results show that compared with the asymmetric demodulation scheme without intensity noise control, the noise floor of the proposed scheme decreases from 4.5 to 1 µrad/√Hz at 1 kHz and 2.7 to 0.8 µrad/√Hz at 3 kHz. At high frequencies, the average noise floor level is reduced from 10 to 0.9 µrad/√Hz, a reduction of about 21 dB. Furthermore, the variation range of the average noise floor is reduced from 5.4 to 0.17 µrad /√Hz within 100 s.