bluuebunny/crossref_metadata_2025 huggingface dataset:
Trial in progress: Durvalumab and olaparib for the treatment of prostate cancer in men predicted to have a high neoantigen load.
Authors: Sokolova Alexandra , Gulati Roman , Cheng Heather H. , Beer Tomasz M. , Graff Julie N , Amador Melanie , Toulouse Andrea , Taylor Kamilah , Bailey Shawna , Smith Steven , Tabatabaei Shaadi , Sinit Ryan , Slottke Rachel , Vuky Jacqueline , Yezefski Todd , Grivas Petros , Yu Evan Y. , Schweizer Michael Thomas
Published: February 2022

TPS202

Background: Approximately 30% of patients (pts) treated with definitive surgical and/or radiation therapy for localized prostate adenocarcinoma develop biochemical recurrence (BCR). The optimal time to initiate androgen deprivation therapy (ADT) for such patients is controversial and depends on patient and provider preference, absolute PSA value, and PSA doubling time (PSADT), which has been associated with time to metastasis. Because the time from BCR to metastasis can be long in many cases, strategies allowing pts to avoid ADT while extending metastasis-free survival are desirable. Prior studies have shown that a high tumor neoantigen load correlates with response to anti-PD(L)1. We hypothesized that PARP inhibitor-induced genomic instability may sensitize tumors to anti-PD(L)1 through: i) increasing mutational burden and subsequent tumor neoantigen formation, and/or ii) through activation of other immunogenic pathways (e.g. the STING pathway). This trial investigates an ADT-sparing approach for men predicted to have high neoantigen load and who have BCR prostate cancer. Methods: This is a phase 2 clinical trial testing durvalumab (1500 mg IV every 4 weeks) and olaparib (300 mg PO twice a day) (one cycle = 4 weeks) in men with BCR (PSADT≤10 months) whose tumors are predicted to have high neoantigen load based on: biallelic CDK12 mutations (Cohort A), mismatch repair deficiency (MMRd)/high microsatellite instability (MSI-H) (Cohort B), or loss of function mutations in homologous recombination repair (HRR) genes (Cohort C). Cohorts A and B will receive 3 cycles of durvalumab followed by 3 cycles of the combination of durvalumab and olaparib. Given the proven efficacy of olaparib in prostate cancer patient whose tumors posses an HRR gene mutation, Cohort C will receive 6 full cycles of the combination. Ten patients will be enrolled in each cohort (total n = 30) at two collaborating sites. This study was designed to provide preliminary efficacy data across eligible cohorts, with a primary objective of estimating the proportion of pts with an undetectable PSA at 12 months within each cohort. Secondary objectives include safety, proportion of patients with ≥50% decline in PSA from baseline and quality of life measures. Correlative studies will assess blood and tissue molecular biomarkers for association with outcomes. The study is open with two patients enrolled at the time of abstract submission. Clinical trial information: NCT04336943.
KEYNOTE-365 cohorts G and H: Phase 1b/2 study of pembrolizumab + vibostolimab combination therapy in patients with adenocarcinoma metastatic castration-resistant prostate cancer (mCRPC) or treatment-emergent neuroendocrine mCRPC (t-NE).
Authors: Shore Neal D. , De Bono Johann S. , Kramer Gero , Joshua Anthony M. , Li Xin Tong , Poehlein Christian Heinrich , Schloss Charles , Yu Evan Y.
Published: February 2022

TPS204

Background: Treatment options are limited for patients with mCRPC that progresses after treatment with next-generation hormonal agents (NHAs)—such as enzalutamide and abiraterone acetate—or docetaxel. Approximately 20% of patients with adenocarcinoma mCRPC that progresses on androgen deprivation therapy develop t-NE mCRPC, which is associated with shortened overall survival (OS). The PD-1 inhibitor pembrolizumab showed antitumor activity as monotherapy in docetaxel-pretreated patients with adenocarcinoma mCRPC in the phase 2 KEYNOTE-199 trial. The T-cell immunoreceptor with Ig and ITIM domains (TIGIT) inhibitor vibostolimab showed antitumor activity when combined with pembrolizumab in pretreated patients with several tumor types in a phase 1 dose-escalation study. Combining PD-1 and TIGIT inhibition might have enhanced benefit in mCRPC, potentially both adenocarcinoma and t-NE. Methods: KEYNOTE-365 (NCT02861573) is a nonrandomized, open-label, multicohort, phase 1b/2 trial designed to evaluate the efficacy and safety of several pembrolizumab combination therapies in patients with mCRPC. Patients enrolled in cohort G will have confirmed adenocarcinoma of the prostate without small cell histology, per the investigator. Cohort H will enroll patients with t-NE (≥1% neuroendocrine cells in a recent biopsy specimen confirmed by central histology review). Each cohort will include patients who previously received docetaxel treatment for mCRPC. Prior treatment with ≤2 NHAs (for hormone-sensitive metastatic prostate cancer [mHSPC] or mCRPC) and 1 other chemotherapy for mCRPC is permitted. Enrollment in cohort H requires prostate cancer progression within 6 months of starting an NHA (for mHSPC or mCRPC) and within < 6 cycles of docetaxel for mCRPC. Each cohort will enroll 40-100 patients with Eastern Cooperative Oncology Group performance status score 0 or 1. Both cohorts will receive MK-7684A, a coformulation of pembrolizumab 200 mg and vibostolimab 200 mg, IV every 3 weeks. Treatment will continue until disease progression, withdrawal of consent, or other discontinuation event. Primary end points are safety and tolerability, prostate-specific antigen (PSA) response rate, and objective response rate (ORR) per RECIST v1.1 by blinded independent central review (BICR). Secondary end points include time to PSA progression; ORR and radiographic progression-free survival per Prostate Cancer Working Group 3 (PCWG3)–modified RECIST v1.1 by BICR; duration of response and disease control rate per RECIST v1.1 and PCWG3-modified RECIST v1.1 by BICR; and OS. These cohorts of KEYNOTE-365 are enrolling in Australia, Germany, New Zealand, Spain, and the United States. Clinical trial information: NCT02861573.
PSMAfore: A phase 3 study to compare 177Lu-PSMA-617 treatment with a change in androgen receptor pathway inhibitor in taxane-naïve patients with metastatic castration-resistant prostate cancer.
Authors: Sartor A. Oliver , Morris Michael J. , Chi Kim N. , De Bono Johann S. , Shore Neal D. , Crosby Michael , Kreisl Teri Nguyen , Fizazi Karim
Published: February 2022

TPS211

Background: [177Lu]Lu-PSMA-617 (177Lu-PSMA-617) is a high-affinity prostate-specific membrane antigen (PSMA)-targeted radioligand therapy that delivers β-particle radiation to PSMA-expressing cells and their surrounding microenvironment. In the phase 3 VISION trial, 177Lu-PSMA-617 significantly prolonged radiographic progression-free survival (rPFS) and overall survival (OS) in patients with metastatic castration-resistant prostate cancer (mCRPC) previously treated with ≥1 androgen receptor pathway inhibitor (ARPI) and 12 taxanes. PSMAfore is investigating the effect on rPFS in taxane-naïve patients with mCRPC treated with either 177Lu-PSMA-617 or a change in ARPI. Methods: PSMAfore (NCT04689828) is a multicenter, open-label, randomized phase 3 trial in adults with progressive mCRPC and confirmed PSMA expression by [68Ga]Ga-PSMA-11 PET/CT. Eligible patients are taxane-naïve in the metastatic setting and have: received one prior ARPI and are candidates for a change in ARPI; an Eastern Cooperative Oncology Group performance status of 0 or 1; a castrate level of serum/plasma testosterone ( < 50 ng/dL or < 1.7 nmol/L); and recovered to grade ≤2 from toxicities related to prior therapies. Approximately 450 patients will be randomized 1:1 to receive 177Lu-PSMA-617 (7.4 GBq i.v. every 6 weeks for 6 cycles) or a change in ARPI to either abiraterone or enzalutamide. Best supportive care is allowed in both arms. Stratification factors are prior ARPI use in castration-resistant vs hormone-sensitive prostate cancer settings and pain symptomatology (score 03 vs 410 on the worst pain intensity item of the Brief Pain InventoryShort Form). The primary endpoint is rPFS according to PCWG3-modified RECIST v1.1 criteria. Participants with blinded independent centrally confirmed radiographic progression in the ARPI arm can crossover to the 177Lu-PSMA-617 arm. The planned sample size provides 95% power to detect a hazard ratio of 0.56 for rPFS after 156 events with an overall one-sided significance level of 0.025. The key secondary endpoint is OS; other secondary endpoints include safety and tolerability of 177Lu-PSMA-617 and health-related quality of life. Previously presented at the 2021 European Society for Medical Oncology Congress, FPN 942, Morris M et al. Reused with permission. Clinical trial information: NCT04689828.
Phase 3 VERACITY clinical study of sabizabulin in men with metastatic castrate resistant prostate cancer who have progressed on an androgen receptor targeting agent.
Authors: Dreicer Robert , Chu Franklin , Cahn David J , Getzenberg Robert H. , Rodriguez Domingo , Barnette K. Gary , Steiner Mitchell S. , Saltzstein Daniel R. , Tutrone Ronald F. , Shore Neal D.
Published: February 2022

TPS217

Background: Sabizabulin is a first-in-class, oral agent that inhibits microtubule polymerization disrupting the cytoskeleton and arresting cellular proliferation. In prostate cancer, targeted inhibition of microtubule polymerization further blocks the transport of the androgen receptor into the nucleus. A phase 1b/2 clinical study was conducted to establish the MTD and evaluate the preliminary efficacy in men with metastatic castrate resistant prostate cancer (mCRPC) who progressed on at least one androgen receptor targeting agent (ARTA). The most common AEs reported were mild to moderate diarrhea, fatigue, nausea, and vomiting with no clinically relevant neurotoxicity or neutropenia. In the phase 1b/2, in all evaluable patients that would qualify for the VERACITY study (n=26), the ORR was 23.1%. Median radiographic progression free survival was >12 months (range 6-28+ months) in the phase 1b portion including responses >two years. The revised formulation for use in the Phase 3 study, with improved bioavailability, is 32mg PO qd. Methods: VERACITY is an ongoing phase 3 multicenter, randomized, active-control study designed to evaluate sabizabulin in the treatment of mCRPC who have progressed on at least one ARTA. Patients on the study will be chemotherapy naive. Subjects (n=245) are being randomized in a 2:1 ratio to receive sabizabulin (32 mg/d oral) or active control (alternative ARTA) and will remain on study until radiographic progression-free survival (rPFS). Randomization will be stratified by: measurable disease vs. bone-only disease and by prior exposure to ARTA (progressed on one vs more than one prior ARTA). The primary efficacy endpoint of the study is median rPFS. Secondary endpoints include: objective response rate (ORR), duration of objective response, overall survival and time to intravenous (IV) chemotherapy. The phase 3, VERACITY registration clinical trial is current ongoing in approximately 45 clinical sites with enrollment anticipated to be completed in 2022 and with unblinded results presented in 2023. Based upon the phase 1b/2 clinical trial, sabizabulin daily chronic oral dosing has a favorable safety profile, is feasible to administer chronically, and has significant and durable antitumor activity. Metastatic prostate cancer that has become refractory to newer generation ARTAs and prior to IV chemotherapy, remains an urgent unmet medical need for patients with advanced disease. Sabizabulin is an exciting first-in-class agent that will add to the armamentarium for the treatment of metastatic castration and ARTA resistant prostate cancer. Clinical trial information: NCT04844749.
KEYNOTE-365 cohort I: Phase 1b/2 study of pembrolizumab combined with platinum-containing chemotherapy and chemotherapy alone for treatment-emergent neuroendocrine prostate carcinoma (t-NE).
Authors: De Bono Johann S. , Joshua Anthony M. , Shore Neal D. , Kramer Gero , Li Xin Tong , Poehlein Christian Heinrich , Schloss Charles , Yu Evan Y.
Published: February 2022

TPS218

Background: In previously treated adenocarcinoma metastatic castration-resistant prostate cancer (mCRPC), approximately 20% of patients develop t-NE PC, which is aggressive with short overall survival (OS). t-NE PC treatment includes platinum-containing chemotherapy because of t-NE’s histologic, biologic, and clinical similarity to small cell/NE lung cancer. In the open-label, multicohort, phase 1b/2 KEYNOTE-365 study (NCT02861573), pembrolizumab, when combined with several agents for treatment of adenocarcinoma mCRPC, showed clinical activity and acceptable safety. To identify new treatment options for t-NE mCRPC, cohort I will help to evaluate platinum-containing chemotherapy alone or combined with pembrolizumab for patients with t-NE. Methods: Cohort I of the KEYNOTE-365 study will enroll patients with t-NE (≥1% neuroendocrine cells in a recent biopsy specimen confirmed by central histology review) and prior docetaxel treatment for mCRPC. Prior treatment with ≤2 next-generation hormonal agents (NHAs) for metastatic hormone-sensitive prostate cancer (mHSPC) or mCRPC and 1 other chemotherapy for mCRPC is permitted. Additionally, enrollment in cohort I requires previous prostate cancer progression within 6 months of starting an NHA (mHSPC or mCRPC) and within < 6 cycles of docetaxel for mCRPC. Each arm will enroll 40-100 patients with Eastern Cooperative Oncology Group performance status (ECOG PS) score of 0 or 1. Eligible patients will be randomly assigned 1:1 to receive pembrolizumab 200 mg IV on day 1 of each cycle every 3 weeks + carboplatin AUC of 5 IV on day 1 + etoposide 100 mg/m2 IV on days 1, 2, and 3 of each 21-day cycle for 4 cycles (arm 1) or the same chemotherapy regimen without pembrolizumab (arm 2). Pembrolizumab treatment will continue for up to 2 years until disease progression, unacceptable toxicity, or withdrawal of consent. Patients will be stratified by ECOG PS score (0 vs 1). Primary end points are safety and tolerability, prostate-specific antigen (PSA) response rate, and objective response rate (ORR) per RECIST v1.1 by blinded independent central review (BICR). Secondary end points include time to PSA progression; duration of response (DOR) and disease control rate (DCR) per RECIST v1.1 by BICR; ORR, DOR, DCR, and radiographic progression-free survival per Prostate Cancer Working Group 3–modified RECIST v1.1 by BICR; and OS. End points will be summarized for each arm without formal hypothesis testing. This cohort of KEYNOTE-365 is enrolling in Australia, Germany, New Zealand, Spain, and the United States. Clinical trial information: NCT02861573.
Randomized phase 2 trial of maintenance oral etoposide or observation following high-dose chemotherapy for relapsed metastatic germ cell tumor.
Authors: Ashkar Ryan , Adra Nabil , Abonour Rafat , Abu Zaid Mohammad Issam , Snow Christin I , Hanna Nasser H. , Einhorn Lawrence H.
Published: February 2022

TPS429

Background: High-dose chemotherapy (HDCT) and peripheral-blood stem-cell transplant (PBSCT) is effective salvage therapy in patients with relapsed germ-cell tumors (GCT). Utilizing HDCT and PBSCT in the 2nd line setting, cures can be achieved in about 60% of patients with relapsed non-seminoma. Maintenance daily oral etoposide after salvage therapy has been shown effective in inducing remissions (J Clin Oncol 1995;13:1167-9). We evaluate the efficacy and safety of maintenance daily oral etoposide after HDCT+PBSCT in patients with relapsed non-seminoma. Methods: This randomized phase II open label trial is evaluating maintenance oral etoposide after HDCT+PBSCT. Eligible patients are adults with metastatic non-seminomatous GCT who have progressive disease after first-line cisplatin-based combination chemotherapy. All patients will complete initial salvage with HDCT+PBSCT with the carboplatin/etoposide Indiana protocol x2 tandem cycles. All patients should have normal or declining tumor markers (AFP and/or hCG) at time of randomization and absence of progressive disease on imaging. Adverse events from prior therapy, including hematologic toxicity, should be recovered to grade≤2 at time of randomization. Randomization should occur within ≤16 weeks from time of the 2nd cycle of HDCT. Patients with primary mediastinal non-seminoma are eligible. Patients with relapsed pure seminoma are excluded. Patients are randomized in 1:1 ratio to receive maintenance etoposide vs. standard of care surveillance post HDCT. Randomization will be stratified by platinum refractory status defined as progression within 4 weeks of first-line chemotherapy (yes vs no). Patients randomized to treatment arm will receive oral etoposide 50mg/m2 daily for 21 consecutive days of 28 day cycles. A total of 3 cycles will be delivered. Weekly labs including CBC w differential will be checked to detect hematological toxicity. The primary objective is to compare the 12-month progression-free survival (PFS) for maintenance etoposide vs observation in patients with relapsed non-seminoma post HDCT. Secondary objectives include to assess the toxicity and tolerability of maintenance etoposide, and 12-month overall survival. Exploratory analysis of the biomarker micro-RNA371 at time of randomization and correlation with disease progression/relapse will be performed. As of September 20, 2021, 5 of the total sample (N = 64) have been enrolled and randomized. Clinical trial information: NCT04804007.
A phase 2, multiarm study of anti-CD47 antibody, magrolimab, in combination with docetaxel in patients with locally advanced or metastatic solid tumors.
Authors: Subbiah Vivek , Vaishampayan Ulka N. , Puri Sonam , Lin Lanjia , Chao Mark , Ramsingh Giri , Kummar Shivaani , Strauss James F. , Patel Sandip P.
Published: February 2022

TPS584

Background: Patients with solid tumors who progress on standard chemotherapy and/or immune checkpoint inhibitors have limited efficacy with existing standard-of-care chemotherapy options (objective response rates [ORRs] ̃10%). These patients have a significant unmet medical need. Novel agents that can safely enhance treatment efficacy are urgently needed. Magrolimab is a first-in-class monoclonal antibody that blocks the macrophage inhibitory immune checkpoint CD47, a “do not eat me” signal overexpressed on tumor cells. Preclinical studies provide compelling evidence that magrolimab triggers phagocytosis and eliminates cancer cells from human solid tumors and hematologic malignancies. Magrolimab has demonstrated clinical activity in both hematologic and solid tumor malignancies. Chemotherapeutic agents, including taxanes, enhance prophagocytic signals on tumor cells, leading to synergistic antitumor activity when combined with magrolimab. This study (NCT04827576) is evaluating the safety, tolerability, and efficacy of magrolimab with docetaxel in relapsed/refractory (R/R) metastatic urothelial cancer (mUC), non-small-cell lung cancer (mNSCLC), and small-cell lung cancer (mSCLC). Methods: This Phase 2, open-label, multi-arm study (NCT04827576) consists of a safety run-in cohort and a Phase 2 cohort. Eligible patients are ≥18 years old with chemotherapy- and/or immunotherapy-refractory mUC, mNSCLC, or mSCLC. Magrolimab is administered intravenously (IV) with an initial 1-mg/kg priming dose to mitigate on-target anemia, followed by a 30-mg/kg dose during cycle 1 (cycles are 21 days) in the safety run-in to identify any dose-limiting toxicities (DLTs) and determine a recommended Phase 2 dose (RP2D). De-escalation may occur for DLTs per protocol. In Phase 2, following the priming dose on day 1, the highest acceptable dose of magrolimab will be administered on days 8 and 15 of cycle 1; days 1, 8, and 15 of cycle 2; and day 1 for cycles 3 and beyond. Docetaxel 75 mg/m2 is administered IV on day 1 of each cycle for all study participants. Patients may continue treatment until unacceptable toxicity, progressive disease by RECIST 1.1, or patient/investigator choice to discontinue. The primary endpoints are incidence of adverse events (safety and Phase 2 cohorts) and ORR (Phase 2). Secondary endpoints (Phase 2) are progression-free survival, duration of response, and overall survival. Exploratory endpoints are to evaluate the pharmacodynamic, mechanism of action, and/or therapeutic response of biomarkers in blood and tumor biopsy samples and to explore biomarkers that may predict response to therapy. Enrollment began in August 2021. Planned enrollment is approximately 116 patients, and as of October 1, 2021 recruitment is ongoing. Clinical trial information: NCT04827576.
Mapping Systematic Reviews of Breast Cancer Survivorship Interventions: A Network Analysis
Authors: Kemp Emma B. , Geerse Olaf P. , Knowles Reegan , Woodman Richard , Mohammadi Leila , Nekhlyudov Larissa , Koczwara Bogda
Published: February 2022

PURPOSE

Despite a large volume of research, breast cancer survivors continue to experience high levels of unmet need. To better understand the breadth of evidence, we mapped systematic review-level evidence across cancer survivorship domains and outcomes and conducted network analyses of breast cancer survivorship care interventions.

METHODS

Umbrella review methodology was used to identify published systematic reviews reporting on survivorship care interventions for breast cancer survivors. Included reviews were mapped against domains and health care outcomes as specified by the Cancer Survivorship Quality Framework, and network analyses were conducted to determine the extent of clustering of reviews, and connectivity across domains and outcomes.

RESULTS

Of 323 included reviews, most focused on management of physical (71.5%) or psychologic (65.3%) effects, health-related quality of life (55.1%), and physical activity (45.2%). Few focused on financial/employment effects, chronic conditions, health care delivery domains, or health service use or cost outcomes. Network analysis indicated 38.6% of reviews were connected to a single domain, 35.0% to two domains, and 16.5% to three domains, indicating a relatively siloed nature of research, with greater community clustering between health care delivery domains but limited connection between these and the other domains. Reviews published between 2011 and 2021 were more likely to examine financial toxicity and chronic conditions, but these domains remained under-represented compared with physical and psychologic effects.

CONCLUSION

Despite vast volume of breast cancer survivorship intervention research, systematic review-level research is unevenly distributed, siloed, and with significant gaps in key domains and outcomes. Assessment of evidence gaps in primary research and strategic planning of future research, in consultation with survivors, is needed.
Monitoring of Dynamic Changes and Clonal Evolution in Circulating Tumor DNA From Patients With IDH-Mutated Cholangiocarcinoma Treated With Isocitrate Dehydrogenase Inhibitors
Authors: Lapin Morten , Huang Helen J. , Chagani Sharmeen , Javle Milind , Shroff Rachna T. , Pant Shubham , Gouda Mohamed A. , Raina Anjali , Madwani Kiran , Holley Veronica R. , Call S. Greg , Dustin Derek J. , Lanman Richard B. , Meric-Bernstam Funda , Raymond Victoria M. , Kwong Lawrence N. , Janku Filip
Published: February 2022

PURPOSE

IDH mutations occur in about 30% of patients with cholangiocarcinoma. Analysis of mutations in circulating tumor DNA (ctDNA) can be performed by droplet digital polymerase chain reaction (ddPCR). The analysis of ctDNA is a feasible approach to detect IDH mutations.

METHODS

We isolated ctDNA from the blood of patients with IDH-mutated advanced cholangiocarcinoma collected at baseline, on therapy, and at progression to isocitrate dehydrogenase (IDH) inhibitors.

RESULTS

Of 31 patients with IDH1R132 (n = 26) or IDH2R172 mutations (n = 5) in the tumor, IDH mutations were detected in 84% of ctDNA samples analyzed by ddPCR and in 83% of ctDNA samples analyzed by next-generation sequencing (NGS). Patients with a low variant allele frequency of ctDNA detected by NGS at baseline had a longer median time to treatment failure compared to patients with high variant allele frequency of ctDNA (3.6 v 1.5 months; P = .008). Patients with a decrease in IDH-mutated ctDNA on therapy by ddPCR compared with no change/increase had a trend to a longer median survival ( P = .07). Most frequent emergent alterations in ctDNA by NGS at progression were ARID1A (n = 3) and TP53 mutations (n = 3).

CONCLUSION

Detection of IDH mutations in ctDNA in patients with advanced cholangiocarcinoma is feasible, and dynamic changes in ctDNA can correspond with the clinical course and clonal evolution.
Motor-Sparing Nerve Blocks Can Improve the Results of Digit Tendon Surgery: A Case Report
Authors: Van Herreweghe Imré , Caekebeke Pieter , Balocco Angela Lucia , Van Boxstael Sam , Hadzic Admir
Published: February 2022

A 56-year-old woman presented with flexion dysfunction of the fifth digit 6 weeks after surgical repair of a flexor digitorum profundus laceration. She was scheduled for surgical adhesiolysis and restoration of the functionality of the finger. Intraoperative monitoring of the range of motion by active flexion was deemed important to prevent incomplete release of the tendon and residual dysfunction. Distal median and ulnar nerve blocks were used for anesthesia with the patient’s ability to flex the finger. This case suggests that motor-sparing peripheral nerve blocks can improve functional outcome in certain hand surgeries.
Development of Nonaqueous Electrolytes for High-Voltage K-Ion Batteries
Authors: Hosaka Tomooki , Komaba Shinichi
Published: February 2022

K-ion batteries (KIBs) are a widely attractive alternative to Li-ion batteries. While avoiding scarce/toxic elements in their construction, the low standard electrode potential of K+/K allows a low cut-off potential of the negative electrode and high operation voltages that are competitive with those observed in LIBs. Because of the wide operating potential range, developing improved non-aqueous electrolytes with higher oxidation stability and the ability to passivate low-potential negative electrodes is one of the major challenges of high-voltage KIB production. This account primarily covers our recent studies on non-aqueous electrolytes design based on potassium salt and solvent properties. We also discuss remaining/emerging challenges and provide our perspective on non-aqueous electrolytes for high-voltage KIBs.
Satisficing Models Under Uncertainty
Authors: Jaillet Patrick , Jena Sanjay Dominik , Ng Tsan Sheng , Sim Melvyn
Published: February 2022

Satisficing, as an approach to decision making under uncertainty, aims at achieving solutions that satisfy the problem’s constraints as well as possible. Mathematical optimization problems that are related to this form of decision making include the P-model. In this paper, we propose a general framework of satisficing decision criteria and show a representation termed the S-model, of which the P-model and robust optimization models are special cases. We then focus on the linear optimization case and obtain a tractable probabilistic S-model, termed the T-model, whose objective is a lower bound of the P-model. We show that when probability densities of the uncertainties are log-concave, the T-model can admit a tractable concave objective function. In the case of discrete probability distributions, the T-model is a linear mixed integer optimization problem of moderate dimensions. Our computational experiments on a stochastic maximum coverage problem suggest that the T-model solutions can be highly competitive compared with standard sample average approximation models.
Bypassing Performance Optimizers of Real Time Bidding Systems in Display Ad Valuation
Authors: Christopher Ranjit M. , Park Sungho , Han Sang Pil , Kim Min-Kyu
Published: February 2022

A vast majority of digital display advertisers rely on large digital ad platforms to run their ad campaigns. Although ad platforms managing real-time bidding systems offer state-of-the-art services to enhance the performance of ad campaigns, their inner workings are largely opaque to customers. As a result, advertisers who seek to value their campaigns in collaboration with third-party platforms must necessarily contend with the problem of estimation bias attributable to these algorithms in addition to the high cost of implementation. We propose an alternative approach to valuation for advertisers who choose to bypass automated performance optimizers of ad platforms. We show that external frequency caps that set upper limits on the number of ad impressions outside the purview of bidding algorithms can serve this purpose effectively. Eliminating performance optimizers allows the advertiser to value ads without relying on the support services of the DSP, with the added benefit of a broader customer reach and a markedly lower cost.
A Hashtag Is Worth a Thousand Words: An Empirical Investigation of Social Media Strategies in Trademarking Hashtags
Authors: Kumar Naveen , Qiu Liangfei , Kumar Subodha
Published: February 2022

Firms of all sizes are “joining the conversation” on social media platforms and increasingly trademarking hashtags related to their products and brands. This added effort to protect intellectual property and its impact on social media engagement have not been investigated in the literature. In this study, we find that trademarking hashtags plays a pivotal role in increasing social media audience engagement and information dissemination. More importantly, this positive effect is stronger for firms with fewer Twitter followers. Digging deeper into the underlying mechanisms, we find that trademarking hashtags makes composing tweets with certain linguistic styles more critical: It can amplify the positive effects of trademarking hashtags on social media audience engagement. Our findings highlight important managerial implications of trademarking hashtags. First of all, we examine whether trademarking a hashtag helps or hurts a firm in terms of its social media audience engagement. Further, we show, to maximize the effectiveness of trademarking hashtags, how firms should develop the right social media engagement strategies by taking specific communication and linguistic styles into account. Our results provide useful insights to firms in understanding the key benefits of signaling through trademarking hashtags on social media engagement.
Projection and Rescaling Algorithm for Finding Maximum Support Solutions to Polyhedral Conic Systems
Authors: Peña Javier , Soheili Negar
Published: February 2022

We propose a simple projection and rescaling algorithm that finds maximum support solutions to the pair of feasibility problems: [Formula: see text] where L is a linear subspace in [Formula: see text] and [Formula: see text] is its orthogonal complement. The algorithm complements a basic procedure that involves only projections onto L and [Formula: see text] with a periodic rescaling step. The number of rescaling steps and, thus, overall computational work performed by the algorithm are bounded above in terms of a condition measure of the above pair of problems. Our algorithm is a natural but significant extension of a previous projection and rescaling algorithm that finds a solution to the full support problem: [Formula: see text] when this problem is feasible. As a byproduct of our new developments, we obtain a sharper analysis of the projection and rescaling algorithm in the latter special case.
Pricing, Quality, and Stocking Decisions in a Manufacturer-Centric Dual Channel
Authors: Guo Xiaomeng , Kouvelis Panos , Turcic Danko
Published: February 2022

Problem description. We consider a dual channel in which a focal manufacturer (he) sells his output through his online store and an independent brick-and-mortar retailer (she). In this manufacturer-centric dual channel, we study product line, stocking, and pricing decisions in the presence of stochastic demand and inventory constraints. The pricing decisions include choosing whether to give price match guarantees (PMGs), standard in the U.S. retail practice. Methodology/Results. We analyze a game-theoretic model in which a focal manufacturer designs a product line, sets wholesale prices, and decides what products to sell in the dual channel. An independent brick-and-mortar retailer responds to the product line design and the wholesale prices by making stocking decisions in her store. Then, both stores observe demand and independently set retail prices subject to any PMGs that the stores gave to consumers. The brick-and-mortar store (online store) fulfills demand in a make-to-stock (make-to-order) fashion. We find that whenever one of the stores holds a competitive advantage, the manufacturer sells the same product line in both stores. If the brick-and-mortar store holds an advantage, it matches the online store’s retail price to obtain favorable wholesale pricing from the manufacturer. We find no equilibria where the online store price matches the brick-and-mortar store or the stores’ prices match each other. Finally, when neither store has a clear advantage, the manufacturer mitigates price competition by designing a different product for each store. Managerial implications. Our model helps identify optimal stocking and pricing strategies that depend on e-fulfillment cost and demand uncertainty and offers a novel reason for offering PMGs in a supply chain.
Real-Time Forecasting of Metro Origin-Destination Matrices with High-Order Weighted Dynamic Mode Decomposition
Authors: Cheng Zhanhong , Trépanier Martin , Sun Lijun
Published: February 2022

Forecasting short-term ridership of different origin-destination pairs (i.e., OD matrix) is crucial to the real-time operation of a metro system. However, this problem is notoriously difficult due to the large-scale, high-dimensional, noisy, and highly skewed nature of OD matrices. In this paper, we address the short-term OD matrix forecasting problem by estimating a low-rank high-order vector autoregression (VAR) model. We reconstruct this problem as a data-driven reduced-order regression model and estimate it using dynamic mode decomposition (DMD). The VAR coefficients estimated by DMD are the best-fit (in terms of Frobenius norm) linear operator for the rank-reduced full-size data. To address the practical issue that metro OD matrices cannot be observed in real time, we use the boarding demand to replace the unavailable OD matrices. Moreover, we consider the time-evolving feature of metro systems and improve the forecast by exponentially reducing the weights for historical data. A tailored online update algorithm is then developed for the high-order weighted DMD model (HW-DMD) to update the model coefficients at a daily level, without storing historical data or retraining. Experiments on data from two large-scale metro systems show that the proposed HW-DMD is robust to noisy and sparse data, and significantly outperforms baseline models in forecasting both OD matrices and boarding flow. The online update algorithm also shows consistent accuracy over a long time, allowing us to maintain an HW-DMD model at much low costs.
Cone beam computed tomography (CBCT) in paediatric dentistry
Authors: Campbell Faith , Timms Laura , Deery Chris , Drage Nicholas
Published: February 2022

Cone beam computed tomography (CBCT) is becoming increasingly available since its introduction in the late 1990s. The technique provides low-dose high-resolution images of the teeth and jaws. This article discusses the clinical applications of CBCT in children. CBCT is most commonly used in children for localization of teeth and the assessment of root resorption. CBCT can offer an advantage over conventional imaging in selected cases. The decision to image using CBCT should be judged for each individual, and should impact on management and outcome.

CPD/Clinical Relevance: CBCT affords low-dose, high-resolution imaging that can be used in appropriately selected paediatric cases.
Multilayer protection-at-lightpath for reliable slicing with isolation in optical metro-aggregation networks
Authors: Marotta A. , Cassioli D. , Tornatore M. , Hirota Y. , Awaji Y. , Mukherjee B.
Published: February 2022

The high reliability required by many future-generation network services can be enforced by proper resource assignments by means of logical partitions, i.e., network slices, applied in optical metro-aggregation networks. Different strategies can be applied to deploy the virtual network functions (VNFs) composing the slices over physical nodes, while providing different levels of resource isolation (among slices) and protection against failures, based on several available techniques. Considering that, in optical metro-aggregation networks, protection can be ensured at different layers, and the slice protection with traffic grooming calls for evolved multilayer protection approaches. In this paper, we investigate the problem of reliable slicing with protection at the lightpath layer for different levels of slice isolation and different VNF deployment strategies. We model the problem through an integer linear program (ILP), and we devise a heuristic for joint optimization of VNF placement and ligthpath selection. The heuristic maps nodes and links over the physical network in a coordinated manner and provides an effective placement of radio access network functions and the routing and wavelength assignment for the optical layer. The effectiveness of the proposed heuristic is validated by comparison with the optimal solution provided by the ILP. Our illustrative numerical results compare the impact of different levels of isolation, showing that higher levels of network and VNF isolation are characterized by higher costs in terms of optical and computation resources.
Advances in SDN control and telemetry for beyond 100G disaggregated optical networks [Invited]
Authors: Casellas Ramon , Martínez Ricardo , Vilalta Ricard , Muñoz Raul , González-Muñiz Alfredo , de Dios Oscar González , Fernández-Palacios Juan-Pedro
Published: February 2022

This tutorial considers the evolution of software-defined networking (SDN) control for optical transport networks (OTNs) in disaggregated scenarios, focusing on its requirements and challenges when applied to “beyond 100G” networks, a term that jointly refers to the use of coherent technology, data rates beyond 100G, and the evolution of OTN standards to support rates such as 200G, 400G, or 800G. The tutorial covers use-case-driven SDN development, new challenges, and requirements, such as the need to account for physical impairments, multiband/space-division multiplexing control, improved fault/alarm management, and optical telemetry and streaming. Finally, the tutorial provides an overview of new trends such as network sharing.
Near-term forecasting of companion animal tick paralysis incidence: An iterative ensemble model
Authors: Clark Nicholas J. , Proboste Tatiana , Weerasinghe Guyan , Soares Magalhães Ricardo J.
Published: February 2022

Tick paralysis resulting from bites from Ixodes holocyclus and I. cornuatus is one of the leading causes of emergency veterinary admissions for companion animals in Australia, often resulting in death if left untreated. Availability of timely information on periods of increased risk can help modulate behaviors that reduce exposures to ticks and improve awareness of owners for the need of lifesaving preventative ectoparasite treatment. Improved awareness of clinicians and pet owners about temporal changes in tick paralysis risk can be assisted by ecological forecasting frameworks that integrate environmental information into statistical time series models. Using an 11-year time series of tick paralysis cases from veterinary clinics in one of Australia’s hotspots for the paralysis tick Ixodes holocyclus, we asked whether an ensemble model could accurately forecast clinical caseloads over near-term horizons. We fit a series of statistical time series (ARIMA, GARCH) and generative models (Prophet, Generalised Additive Model) using environmental variables as predictors, and then combined forecasts into a weighted ensemble to minimise prediction interval error. Our results indicate that variables related to temperature anomalies, levels of vegetation moisture and the Southern Oscillation Index can be useful for predicting tick paralysis admissions. Our model forecasted tick paralysis cases with exceptional accuracy while preserving epidemiological interpretability, outperforming a field-leading benchmark Exponential Smoothing model by reducing both point and prediction interval errors. Using online particle filtering to assimilate new observations and adjust forecast distributions when new data became available, our model adapted to changing temporal conditions and provided further reduced forecast errors. We expect our model pipeline to act as a platform for developing early warning systems that can notify clinicians and pet owners about heightened risks of environmentally driven veterinary conditions.
MxB inhibits long interspersed element type 1 retrotransposition
Authors: Huang Yu , Xu Fengwen , Mei Shan , Liu Xiaoman , Zhao Fei , Wei Liang , Fan Zhangling , Hu Yamei , Wang Liming , Ai Bin , Cen Shan , Liang Chen , Guo Fei
Published: February 2022

Long interspersed element type 1 (LINE-1, also L1 for short) is the only autonomously transposable element in the human genome. Its insertion into a new genomic site may disrupt the function of genes, potentially causing genetic diseases. Cells have thus evolved a battery of mechanisms to tightly control LINE-1 activity. Here, we report that a cellular antiviral protein, myxovirus resistance protein B (MxB), restricts the mobilization of LINE-1. This function of MxB requires the nuclear localization signal located at its N-terminus, its GTPase activity and its ability to form oligomers. We further found that MxB associates with LINE-1 protein ORF1p and promotes sequestration of ORF1p to G3BP1-containing cytoplasmic granules. Since knockdown of stress granule marker proteins G3BP1 or TIA1 abolishes MxB inhibition of LINE-1, we conclude that MxB engages stress granule components to effectively sequester LINE-1 proteins within the cytoplasmic granules, thus hindering LINE-1 from accessing the nucleus to complete retrotransposition. Thus, MxB protein provides one mechanism for cells to control the mobility of retroelements.
Tick borne relapsing fever - a systematic review and analysis of the literature
Authors: Jakab Ákos , Kahlig Pascal , Kuenzli Esther , Neumayr Andreas
Published: February 2022

Tick borne relapsing fever (TBRF) is a zoonosis caused by various Borrelia species transmitted to humans by both soft-bodied and (more recently recognized) hard-bodied ticks. In recent years, molecular diagnostic techniques have allowed to extend our knowledge on the global epidemiological picture of this neglected disease. Nevertheless, due to the patchy occurrence of the disease and the lack of large clinical studies, the knowledge on several clinical aspects of the disease remains limited. In order to shed light on some of these aspects, we have systematically reviewed the literature on TBRF and summarized the existing data on epidemiology and clinical aspects of the disease. Publications were identified by using a predefined search strategy on electronic databases and a subsequent review of the reference lists of the obtained publications. All publications reporting patients with a confirmed diagnosis of TBRF published in English, French, Italian, German, and Hungarian were included. Maps showing the epidemiogeographic mosaic of the different TBRF Borrelia species were compiled and data on clinical aspects of TBRF were analysed.

The epidemiogeographic mosaic of TBRF is complex and still continues to evolve. Ticks harbouring TBRF Borrelia have been reported worldwide, with the exception of Antarctica and Australia. Although only molecular diagnostic methods allow for species identification, microscopy remains the diagnostic gold standard in most clinical settings. The most suggestive symptom in TBRF is the eponymous relapsing fever (present in 100% of the cases). Thrombocytopenia is the most suggestive laboratory finding in TBRF. Neurological complications are frequent in TBRF. Treatment is with beta-lactams, tetracyclines or macrolids. The risk of Jarisch-Herxheimer reaction (JHR) appears to be lower in TBRF (19.3%) compared to louse-borne relapsing fever (LBRF) (55.8%). The overall case fatality rate of TBRF (6.5%) and LBRF (4–10.2%) appears to not differ. Unlike LBRF, where perinatal fatalities are primarily attributable to abortion, TBRF-related perinatal fatalities appear to primarily affect newborns.
An alternative estimation of the death toll of the Covid-19 pandemic in India
Authors: Guilmoto Christophe Z.
Published: February 2022

The absence of reliable registration of Covid-19 deaths in India has prevented proper assessment and monitoring of the coronavirus pandemic. In addition, India’s relatively young age structure tends to conceal the severity of Covid-19 mortality, which is concentrated in older age groups. In this paper, we present four different demographic samples of Indian populations for which we have information on both their demographic structures and death outcomes. We show that we can model the age distribution of Covid-19 mortality in India and use this modeling to estimate Covid-19 mortality in the country. Our findings point to a death toll of approximately 3.2–3.7 million persons by early November 2021. Once India’s age structure is factored in, these figures correspond to one of the most severe cases of Covid-19 mortality in the world. India has recorded after February 2021 the second outbreak of coronavirus that has affected the entire country. The accuracy of official statistics of Covid-19 mortality has been questioned, and the real number of Covid-19 deaths is thought to be several times higher than reported. In this paper, we assembled four independent population samples to model and estimate the level of Covid-19 mortality in India. We first used a population sample with the age and sex of Covid-19 victims to develop a Gompertz model of Covid-19 mortality in India. We applied and adjusted this mortality model on two other national population samples after factoring in the demographic characteristics of these samples. We finally derive from these samples the most reasonable estimate of Covid-19 mortality level in India and confirm this result using a fourth population sample. Our findings point to a death toll of about 3.2–3.7 million persons by late May 2021. This is by far the largest number of Covid-19 deaths in the world. Once standardized for age and sex structure, India’s Covid-19 mortality rate is above Brazil and the USA. Our analysis shows that existing population samples allow an alternative estimation of deaths due to Covid-19 in India. The results imply that only one out of 7–8 deaths appear to have been recorded as a Covid-19 death in India. The estimates also point to a very high Covid-19 mortality rate, which is even higher after age and sex standardization. The magnitude of the pandemic in India requires immediate attention. In the absence of effective remedies, this calls for a strong response based on a combination of non-pharmaceutical interventions and the scale-up of vaccination to make them accessible to all, with an improved surveillance system to monitor the progression of the pandemic and its spread across India’s regions and social groups.